Neste artigo:
- Amazônia: Potencial Genético na Mira das Indústrias Farmacêuticas
- Denúncia partiu de conselheiros da BioAmazônia
- Farmacogenética
- Benefícios da Farmacogenética
- Desvendando Polimorfismos de Nucleotídeos
- Testes de Farmacogenética
- O Futuro da Farmacogenética
"A farmacogenética institui-se no mundo moderno como uma promissora área do desenvolvimento
da indústria farmacêutica, podendo trazer numerosas vantagens para a produção de
medicamentos com menores reações colaterais e interações medicamentosas prejudiciais. Ao
mesmo tempo, os estudos desta nova ciência suscitam as mais variadas cobiças e a Amazônia,
tesouro de material genético, já está no alvo de organizações internacionais. Confira aqui estas
disputas e também o potencial desta revolução biotecnológica que está se avizinhando neste
terceiro milênio".
Amazônia: Potencial Genético na Mira das Indústrias Farmacêuticas
O mapeamento genético, em nome do desenvolvimento da ciência, estimula a ambição da
indústria farmacêutica, que vê nos novos descobrimentos da genética, possibilidades de ampliar
seus ganhos e cifras.
O método de decodificação e seqüenciamento dos genes, desenvolvido pelo Projeto Genoma
Humano, dá início a uma autêntica revolução biotecnológica para o século 21. Com o novo
conceito, o Brasil expõe-se como o maior detentor de riquezas naturais do mundo, já que possui a
mais rica reserva de fauna e flora distribuídas pela Mata Atlântica e principalmente pela Floresta
Amazônica.
A corrida pelo ouro já começou, e o contrato entre a BioAmazônia (Associação Brasileira para Uso
Sustentável da Biodiversidade da Amazônia) e o laboratório suíço Novartis Pharma AG, assinado
no último dia 29 de abril, mostra, conforme denúncia de alguns membros do Conselho de
Administração e do Conselho Técnico-Científico da BioAmazônia, que o patrimônio genético tanto
pode significar uma importante alternativa de desenvolvimento econômico e científico para o Brasil,
como pode resultar em mais uma oportunidade de negócio rentável entregue por valores
subavaliados a grupos estrangeiros.
Pelo acordo, o Brasil enviaria material genético vivo (germoplasma) em larga escala em troca de
R$ 6,4 milhões, a serem repassados pela Norvatis durante o período de três anos.
Denúncia Partiu de Conselheiros da BioAmazônia
O acordo foi denunciado por alguns membros do Conselho de Administração e do Conselho
Técnico-Científico da BioAmazônia, alguns dias antes de ser assinado. Segundo esses
conselheiros, há mais de um ano o presidente da BioAmazônia vinha negociando com a Novartis.
Após o escândalo na comunidade científica, o Ministério do Meio Ambiente brecou a parceria entre
a Associação e a indústria suíça. Segundo o ministro José Sarney Filho, o Contrato de Gestão
firmado pelo Poder Público com a BioAmazônia para implementar o Programa Brasileiro de
Ecologia Molecular para Uso Sustentável da Biodiversidade da Amazônia (Probem/Amazônia), não
autoriza a entidade a realizar acordos, convênios ou contratos de bioprospecção com bio
indústrias.
O Ministério do Meio Ambiente afirma que o Contrato de Gestão limita a interferência da
BioAmazônia com as bioindústrias no sentido de articulação de oportunidades de formação de
parcerias e participação em negociações juntamente com os segmentos públicos e privados
envolvidos na implantação de um vasto projeto de desenvolvimento do potencial bioindustrial da
Floresta.
Os termos impostos pela Norvatis foram desaprovados pela comunidade científica, parlamentares
e pesquisadores, que ficaram sabendo do conteúdo do contrato após a divulgação de um
documento encaminhado pelo professor da Universidade do Amazonas, Spartaco Astolfi Filho,
representante dos associados no Conselho de Administração e coordenador do Conselho TécnicoCientífico da BioAmazônia.
O cientista acredita ser perigosa a permissão ao amplo acesso à biodiversidade da região, sem
que exista uma legislação específica em vigor. Ele criticou as cláusulas e condições impostas pela
Norvatis, em que torna a BioAmazônia apenas uma assistente de transferência física de material
genético brasileiro para o aproveitamento comercial exclusivo de seus parceiros. Outra crítica feita
por Astolfi Filho ao contrato deve-se ao fato de que não há transferência de tecnologia, nem
investimento de recursos suficientes para desenvolver no Brasil uma base laboratorial, como está
previsto no Probem.
Um novo acordo entre a BioAmazônia e a suíça Norvatis está para ser anunciado ainda este ano.
Farmacogenética
A reação do indivíduo na resposta às drogas é um problema clínico substancial. Tal variação se dá
desde uma falha na resposta a um remédio até reações adversas à medicamentos e interações
droga-droga, quando várias delas são administradas concomitantemente. As conseqüências
clínicas variam desde um desconforto do paciente até uma fatalidade ocasional. Um estudo
realizado na Inglaterra sugeriu que aproximadamente uma a cada 15 internações hospitalares é
devida a reações adversas à droga, e uma pesquisa americana recente estimou que 106.000
pacientes morrem e 2,2 milhões são prejudicados a cada ano por reações adversas a
medicamentos prescritos.
Com as recentes descobertas, fica evidente que grande parte da individualidade na resposta à
droga é hereditária: esta variabilidade é determinada geneticamente e define a área de pesquisa
conhecida como farmacogenética.
Com o seqüenciamento do código genético humano, a pesquisa em farmacogenética ganha
enorme impulso. Graças ao surgimento de novas tecnologias que permitem o rápido rastreamento
para polimorfismos específicos, assim como o conhecimento, recentemente conquistado, das
seqüências genéticas de genes alvo, tais como aqueles que codificam para enzimas, canais de íon
e outros tipos de receptores na resposta à medicamentos.
De acordo com artigo publicado pelos cientistas Roland Wolf, Gillian Smith e Robert Smith, todos
de centros de pesquisa localizados na Inglaterra, o trabalho em farmacogenética está se
desenvolvendo atualmente em duas direções principais: primeiramente, identificando genes
específicos e produtos gênicos associados a várias doenças que podem atuar como alvos para
novos medicamentos e, em segundo lugar, identificando genes e alelos variantes de genes que
alteram nossa resposta aos medicamentos atuais.
Benefícios da Farmacogenética
Os estudiosos prevêem que com o desenvolvimento das pesquisas no campo do polimorfismo dos
genes, será possível eliminar as reações adversas no tratamento de pacientes, reduzindo o quadro
de intoxicações e de ineficiência das drogas. Será possível a recomendação da prescrição médica
relacionando a dose ao genótipo, o que evidenciará a possibilidade de interações medicamentosas
quando múltiplos medicamentos forem prescritos concomitantemente.
Benefícios econômicos também vão resultar da evolução da farmacogenética. O teste de
identificação de genes reduzirá substancialmente a necessidade de hospitalização e seus custos
associados, devido às reações adversas aos medicamentos. A indústria farmacêutica também
poderá desenvolver novas drogas para pacientes com genótipos específicos - a chamada
"estratificação medicamentosa".
Desvendando Polimorfismos de Nucleotídeos
Com o avanço de novas pesquisas e o aumento do conhecimento na área genética, principalmente
através do projeto Genoma Humano, possibilita-se a busca pela identificação de polimorfismos de
nucleotídeos únicos - diferenças entre pessoas de um único par de bases em seu DNA. Estes
polimorfismos podem ser usados para identificar genes específicos associados a várias doenças
tais como o câncer, o diabete e a artrite. Há esperança que muitas das proteínas codificadas por
esses genes tornem-se produtos para novos medicamentos. Por estes genes terem sido
identificados por análise de polimorfismo, as drogas direcionadas para tais alvos podem ter
diferentes efeitos em pacientes diversos e algumas drogas serão mais eficazes em pacientes com
variantes gênicas específicas. Isso leva ao conceito de estratificação da droga ou ao tratamento
medicamentoso individualizado, no qual a escolha da droga é influenciada pelo "status" genético
do doente.
O maior desafio dos próximos anos será determinar a função de cada gene polimórfico ou do
produto gênico e suas formas diversas. É obrigatório determinar se um produto gênico tem
importância farmacológica ou toxicológica e se as variantes alélicos individuais têm importância
terapêutica. De acordo com os pesquisadores ingleses, estes são os maiores obstáculos e se
passarão muitos anos até que este aspecto da farmacogenética seja praticável no
desenvolvimento das drogas, o que trará grande rentabilidade financeira para as indústrias
farmacêuticas.
Testes de Farmacogenética
Até pouco tempo a única forma de identificar um paciente com um fator de risco genético para uma
reação colateral a um medicamento era através de "testes de fenotipagem", com a administração
de um marcador específico da droga ou de uma substância de teste. Esses procedimentos eram
cansativos e envolviam a administração invasiva da substância de teste, a coleta de amostras e
subseqüente análise bioquímica. Os testes modernos baseados no DNA que requerem apenas
uma pequena amostra de tecido - sangue de uma ponta de dedo, células provenientes de um
lavado oral ou células de folículo piloso - possibilitam a rápida e inequívoca determinação do "perfil
farmacogenético" ou genótipo de um paciente.
A aplicabilidade clínica do teste farmacogenético depende da importância relativa de cada
polimorfismo na determinação do resultado terapêutico. Os médicos precisam saber se a droga
que eles estão prescrevendo está sujeita à variabilidade farmacogenética e como usar esse
conhecimento. Além disso, é preciso haver disponível um serviço de teste confiável, baseado no
DNA. Para alguns polimorfismos farmacogenéticos, acredita-se que atualmente há conhecimento
suficiente sobre as implicações das variações geneticamente determinadas para proporcionar
bases populacionais para testes farmacogenéticos.
Os detalhes de mais de 20 drogas que são conhecidas como substratos de CYP2D6 estão
disponíveis tanto no ABPI Compendium of Data Sheets, na Grã-Bretanha, quanto no Physicians
Desk Reference, nos Estados Unidos. Isso pode permitir a escolha e doses de medicamentos
específicos, particularmente aqueles para tratamento de doenças psiquiátricas, para uso mais
apropriado. No momento, as reações colaterais às drogas ocorrem numa proporção substancial de
pacientes: um estudo americano recente mostrou que, em pacientes com prescrição de
medicamentos psiquiátricos que são substratos de CYP2D6, as reações adversas ao medicamento
foram observadas em todos os pacientes com mutações hereditárias que inativam o gene do
CYP2D6.
O Futuro da Farmacogenética
O teste farmacogenético pode proporcionar o primeiro exemplo de um mecanismo em que o
exame baseado em DNA pode ser aplicado a populações, mas ainda temos um longo caminho a
percorrer até obtermos um "chip" farmacogenético de DNA que os clínicos gerais possam usar
para identificar todas as drogas às quais um paciente em particular é sensível. No entanto, há
evidências crescentes de que a farmacogenética será extremamente importante no serviço de
saúde. Um dia poderá ser considerado não ético não realizar tais testes rotineiramente para evitar
a exposição dos indivíduos a doses de medicamentos que podem lhes ser prejudiciais. A
capacidade de identificar indivíduos sensíveis, tanto antes da administração de uma droga como
após uma reação adversa, também pode ter importância econômica, já que iria evitar o empirismo
associado a unir o medicamento mais adequado à dose ideal para cada paciente. Também poderá
reduzir substancialmente a necessidade de hospitalização, e seus custos associados, devido a
reações adversas aos medicamentos.
Nosso conhecimento cada vez maior dos mecanismos de ação das drogas, a identificação de
novos alvos de medicamentos e o entendimento dos fatores genéticos que determinam nossa
resposta às drogas podem nos permitir projetar drogas que sejam especificamente direcionadas a
determinadas populações ou que evitem a variabilidade genética em sua resposta terapêutica. A
extensão do polimorfismo genético na população humana indica que a variabilidade
farmacogenética será provavelmente um problema para a maior parte dos novos medicamentos.
O desenvolvimento da farmacogenética propicia pelo menos um mecanismo para reduzir o
empirismo atual e progredir no sentido de um tratamento medicamentoso mais "individualizado".
Levando em conta o impulso que a farmacogenética está tomando, principalmente após o Projeto
Genoma Humano, é essencial que o tema seja ensinado como parte do currículo nas faculdades
de medicina de todo Brasil.
Farmacogenômica: oportunidades e desafios
Todos nós diariamente cuidamos de pacientes que respondem de maneira variada ao
mesmo tratamento. Ao receber dose equivalente de uma mesma medicação, alguns
pacientes não têm a menor resposta, outros apresentam efeitos colaterais graves, e outros
respondem muito bem com remissão completa do quadro clínico. Em alguns casos, o
clínico tem como prever a resposta terapêutica baseado na história pessoal ou familiar dos
pacientes e na relação entre eficácia, efeitos colaterais e interações medicamentosas. Porém,
em número enorme de casos não há como prever a resposta clínica a uma determinada
droga.
A farmacogenômica é uma nova área da medicina, que tem uma interface com a
farmacologia clássica e a nova ciência da genômica. A farmacogenômica tem dois campos
de interesse altamente relacionados. Primeiramente, há o estudo de como marcadores
genômicos podem ser usados para identificar tipos de resposta ao tratamento
farmacológico. Essa é a grande promessa do tratamento individualizado. O objetivo final
dessa linha de trabalho é usar marcadores genômicos para prever a resposta às drogas. Para
que isso ocorra, é necessário que vários estudos clínicos sejam desenvolvidos analisando de
maneira estatisticamente rigorosa a relação entre fenótipo e genótipo. Ou seja, ao se tratar o
paciente em estudos bem conduzidos, a resposta clínica favorável ou desfavorável é
descrita de maneira estruturada e relacionada ao genótipo do paciente para a identificação
de genótipos que respondam de maneira específica ao tratamento. Isto facilitará muito a
escolha de drogas para determinado paciente e certamente revolucionará a prática da
medicina.
Outro aspecto importante da farmacogenômica é a possibilidade de usar a evolução
genômica para a identificação de novos genes que são regulados por drogas. Muitos dos
tratamentos usados hoje foram descobertos por experiência clínica, e não se sabe seu
mecanismo de ação. Por exemplo, os antidepressivos agem nas monoaminas em questão de
horas, enquanto seu efeito clínico é tardio, demorando várias semanas para se manifestar.
Vários grupos de pesquisa, inclusive o nosso, estão testando a hipótese de que o tratamento
crônico com antidepressivos afeta a regulação de genes ainda não identificados. Qual a
importância disso? Em termos clínicos e econômicos, os avanços terapêuticos são
manifestados pelo desenvolvimento de novas classes de drogas. Ou seja: a primeira droga
de uma classe (por exemplo, o primeiro bloqueador seletivo de captação de serotonina, no
caso, a fluoxetina) representa um avanço clínico e econômico maior do que outras drogas
que simplesmente têm o mesmo mecanismo de ação. O uso de técnicas genômicas
identificará genes que servirão como alvos terapêuticos para o desenvolvimento de novas
classes de drogas que terão novos mecanismos de ação e, possivelmente, menos efeitos
colaterais e maior tolerabilidade.
Em futuro não muito remoto, todo clínico terá de ter conhecimentos de farmacogenômica
para poder prescrever as drogas ideais para seus pacientes. Isto causará um grande impacto
na prática e no ensino da medicina. No entanto, a necessidade de fazer testes genéticos para
determinação da conduta terapêutica abrirá uma série imensa de problemas éticos, legais,
sociais e econômicos.
Inicialmente, em termos éticos, precisam-se estabelecer mecanismos adequados para a
coleta e o armazenamento do DNA do paciente, além de garantir segurança e sigilo em
relação ao genótipo obtido. Quem terá acesso a esses dados? O paciente, o médico, o
hospital, o governo, as companhias farmacêuticas, as companhias privadas de seguro
médico? O custo do seguro-saúde será mais alto para aqueles indivíduos classificados como
não respondedores a drogas usadas para o tratamento de doenças comuns como o diabetes e
a hipertensão? Além disso, há a parte legal. Se uma droga é recomendada para pessoas com
um genótipo específico, o que ocorre se o médico precisar usar essa droga em pessoas que
não têm o genótipo certo, mas não respondem a outras intervenções? Quem pagará por tal
tratamento? As companhias de seguro podem usar motivos farmacogenômicos para
bloquear o reembolso de certos tratamentos, dizendo que não são recomendados pela
análise de genótipo. Além disso, há agora um processo legal nos Estados Unidos iniciado
por um paciente que sofreu efeito colateral causado por um medicamento. Trabalhos
publicados em revistas científicas mostram que uma certa percentagem de pessoas com um
polimorfismo específico não se deram bem com aquela droga. O paciente teve seu genótipo
testado, confirmou possuir o tal poliformismo e agora processa a companhia farmacêutica
que não registrou na bula uma contra-indicação farmacogenômica. Como se pode ver, a
farmacogenômica e a individualização de tratamento farmacológico não serão só um
avanço científico e clínico – haverá certamente uma imensa revolução na prática da
medicina e também em suas conseqüências econômicas, sociais e legais.
Outra área complicadíssima é a do envolvimento das minorias étnicas nesse tipo de
trabalho. Alelos que influenciam resposta a medicamentos, como os genes da superfamília
do citocroma P450, que são responsáveis pelo metabolismo de grande parte dos
psicotrópicos, têm poliformismos com distribuição variada em diferentes populações. Para
se estudar isto, é necessário investigar vários grupos étnicos. A inclusão de pessoas, em
estudos clínicos, não só por causa de seu diagnóstico mas também devido à cor de sua pele
ou à sua origem geográfica abre uma série enorme de questões éticas que só agora estão
sendo abordadas.
Em conclusão, a farmacogenômica tem o potencial de individualizar o tratamento
farmacológico e de descobrir novos alvos terapêuticos para o desenvolvimento de novas
classes de drogas. Tais avanços repercutirão imensamente na prática e no ensino da
medicina e também afetarão de maneira profunda os aspectos éticos, econômicos e legais
da profissão. A psiquiatria estará entre as primeiras especialidades afetadas pela
farmacogenômica, de modo que é importante que os psiquiatras se mantenham a par dos
avanços dessa nova área da medicina do século XXI.
What are pharmacogenetics and pharmacogenomics?
Pharmacogenetic studies investigate the affects of genetic factors on the inconsistency of
drug response by assessing the extent of the contribution of variant forms of human genes
to the observed variability in drug disposition, drug action or drug toxicity. The primary
goal of pharmacogenetics is to identify the right dose of the right drug for a given
individual. Typically, genotyping or phenotyping strategies focus on a single gene (e.g.
CYP2D6 pharmacogenetics). Pharmacogenomic investigations use constantly emerging
and evolving genomic technologies to encompass comprehensive, genome-wide strategies
targeted at identifying all factors that influence the response of a patient to small molecules
that have been administered with therapeutic intent. Although many different definitions for
‘pharmacogenomics’ have been presented in the literature, from a drug development
perspective, pharmacogenomics is best described as identifying (developing) the right drug
for a given disease in the context of complex genomic factors.
Application of pharmacogenetic and pharmacogenomic approaches to the treatment of
pediatric diseases requires an appreciation of the dynamic changes in gene expression that
accompany maturation from embryo through fetal development, the neonatal period,
infancy, childhood and adolescence. It can be readily appreciated that individual gene
expression does not occur in isolation during development but is instead an integral
component of larger, complex networks of genes that interact during, for example,
organogenesis, the establishment of receptor systems and neural networks, drug
biotransformation activities and the acquisition of immune functions. In other words, the
patterns of gene expression and the nature of the gene interactions that contribute to the
pathogenesis of pediatric diseases (thereby serving as potential targets for pharmacologic
intervention) might only be discernable or relevant at specific, crucial points in the
developmental continuum. Thus, defining ‘pharmacogenomics’ as the study of how
interacting systems of genes determine drug response [[1]] is particularly appealing in a
pediatric and developmental context because this definition captures the essence of the
developmental processes that characterize maturation from the time of birth through to
adulthood while retaining a focus on the individual.
Application of developmental pharmacogenomics to drug
discovery
Undoubtedly, there are several areas in which developmental pharmacogenetic and
pharmacogenomic strategies can be applied to improve the use of currently marketed drugs
or to optimize the development of new therapeutic entities intended for use in adult and
pediatric populations. In this context, it is important to distinguish between the
pharmacogenetics and pharmacogenomics of development and of interindividual variation.
The scenario presented in Figure 1 (for a hypothetical gene) illustrates how the
pharmacogenetic polymorphism of a gene could result in the presence of distinct
phenotypes in adults (i.e. extensive and poor metabolizers) that characterize the
interindividual variability of that gene product in the population. However, this degree of
interindividual variation might not be apparent in neonates or infants because of the
developmental delay in the acquisition of that particular activity. Therefore, the
pharmacogenetics of development seeks to characterize the genetic basis of the change in
phenotype that occurs in a given individual throughout maturation, with the potential for
the occurrence of distinct developmental profiles in the population. The pharmacogenomics
of development takes into consideration that the level of expression of networks of genes,
rather than individual genes, varies as children mature and thus contributes to
interindividual variability in drug response. The remainder of this review will address four
broad applications of pharmacogenetics and pharmacogenomics that are relevant to the safe
and effective use of medications in clinical pediatrics.
Pharmacogenetics in Patient Care
Pharmacogenetics will give clinicians the tools to predetermine response to
pharmacotherapy by looking for specific polymorphisms in Cytochrome P450 and other
enzymes involved in drug metabolism. Pharmacogenetics also will have an important role
in determining or predicting patient response to environmental toxins. There have been
many programs dealing with pharmacogenetics in drug discovery. AACC presents a
program on how pharmacogenetics will change patient care.
Speakers:
Introduction
Roland Valdes, PhD, Moderator
Director Clinical Chemistry and Pharmacogenetics
Department of Pathology & Laboratory Medicine
University of Louisville
Louisville, KY
What is Pharmacogenetics?
David Cooper, MD, PhD
Founder and Editor-in-Chief, Molecular Diagnostics
Populations and Polymorphisms
Wendell Weber, MD, PhD
Department of Pharmacology
University of Michigan, Ann Arbor, MI
Pharmacogenetic Technologies
Michael Shi, MD, PhD
Parke-Davis Pharmaceutical Research
Ann Arbor, MI
How Payors View Pharmacogenetics
Barry Berger, MD, PhD
Department of Pathology
Harvard Vanguard Medical Associates
Cambridge, MA
Pharmacogenetics in Neurology/Psychiatry
Judes Poirer, PhD
Director, McGill Aging Research Center
Montreal, PQ, Canada
Pharmacogenetics in Hematology/Oncology
Mark Ratain, MD
Professor of Medicine and Chair, Committee
on Pharmacology
University of Chicago Medical Center, Chicago, IL
Pharmacogenetics in Cardiology
David Flockhart, MD
Department of Clinical Pharmacology
Georgetown UniversityWashington, DC
Pharmacogenetics in Environmental Medicine
Jun-Yan Hong, MD
Laboratory of Cancer Research
College of Pharmacy
Rutgers University
Piscataway, NJ
Introduction
Roland Valdes, Ph.D.
University of Louisville School of Medicine
Over the last five years there’s been a tremendous amount of activity in pharmacogenetics,
a discipline that has developed for a number of years in a basic science environment but
now looks poised to enter the clinical arena. Numerous articles in publications like Nature
Biotechnology and the American Medical Association’s Health and Science have noted that
"Soon, physicians will be able to leave behind trial and error prescribing. Instead, they’ll
choose drugs depending on a patient’s genetic make-up."
Underdosing, overdosing, and misdosing cost the US more than one hundred billion dollars
a year, and can be considered a leading cause of death in this country. Pharmacogenetics
can help address why some individuals respond to drugs and others do not. It can also help
physicians understand why some individuals require higher or lower dosing for optimum
response to a drug. It could potentially tell physicians who will respond to a drug and who
will have toxic side effects.
Systemic drug concentration is the end result of drugs ingestion absorption, metabolism,
clearance and excretion. Much of pharmacogenetics has focused on the mechanisms that
control the systemic drug concentration. But the drugs also act on receptors that can
themselves have polymorphisms. The receptor side of this is very important, and we’re just
beginning to scratch the surface of the application of this field to receptors.
The following presentations explore pharmacogenetics as it applies to neurology, oncology,
cardiology, and even to environmental medicine. As you read them, ask yourself what the
role of the clinical laboratory should be in applying pharmacogenetics to medical care. One
role might be to develop genetic profiling strategies to maximize the sensitivity and
specificity of tests in predicting phenotypes. Another role might be to reduce the cost of the
test and the technical difficulty of the test. A third possible role, perhaps the most
important, is to increase the availability of this testing which is now being done in very few
laboratories, and mostly in pharmaceutical companies.
When should the testing be done—before the patient goes on medication or after there’s
therapeutic failure? How should dosing be adjusted? Should alternative therapy be
considered at any point based on a patients genetic make-up? These are the kinds of
questions we absolutely need to answer before we can begin to apply this field and make it
a routine part of laboratory medicine.
What is Pharmacogenetics?
David L. Cooper, M.D., Ph.D.
Founder and Editor-in-Chief, Molecular Diagnostics
Why is it that a drug can help one patient and not another? Geneticists have set their sights
on answering that question and their discoveries will revolutionize clinical laboratory
medicine.
Pharmacogenetics is the study of the hereditary basis for differences in populations’
response to a drug. The same dose of a drug will result in elevated plasma concentrations
for some patients and low concentrations for others. Some patients will respond well to the
drugs, while others will not. A drug might be toxic to some patients but not to others. For
years physicians have noted these differences but had no way to predict them.
Pharmacogenetics promises to change that forever.
Now that the new DNA technologies allow extensive mapping and analysis of the genetic
code, researchers can identify candidate genes that might influence the effectiveness of a
drug. They do this by looking for polymorphisms, changes in the DNA sequence of genes
between individual people or chromosomes that correlate with a certain clinical outcome.
Most people think of genetic mutations as being harmful, but most polymorphisms simply
contribute to individual diversity, including a variable affinity for drugs. The ability to
detect polymorphisms is the cornerstone of pharmacogenetics.
To look for significant polymorphisms, researchers can pick candidate genes in a number of
different ways. In general, they choose a candidate gene from known genes, from new
genes, or through whole genome marker strategies. High-throughput technologies like
DNA chips will allow simultaneous analysis of thousands of genes for thousands of people,
providing information that could then be correlated with clinical outcomes data. An
interesting polymorphism could then be examined by pharmaceutical companies in
prospective and/or retrospective clinical trials of a drug.
While pharmacogenetics has to do with individuals’ response to certain drugs,
pharmacogenomics is a broader term used to describe the commercial application of
genomic technology in drug development and therapy. Pharmacogenomics is not about the
discovery of new genes and new gene functions although that is a part of it. In the short
term, it is probably the study of known polymorphisms and known metabolic enzyme
families of known drug targets. In the medium term, it is the role of polymorphisms and
candidate genes and drug therapy and toxicity. In the long term, it will be the discovery of
new drug response genes and development of novel molecules to target these genes. After
genes are linked with disease pathogenesis, pharmacogenomics will validate targets as
appropriate sites of therapeutic intervention. Then scientists will identify or design
therapeutic agents that interact with these targets in a way that achieves positive clinical
outcome and minimal toxicity.
In the future, specific disease diagnoses may be based on molecular mechanisms involved
rather than clinical presentation. Common diseases like hypertension, diabetes, and cancers
will be subdivided based on differences in molecular mechanisms. This subdivision of
common diseases is going to be important. Such an approach requires improved molecular
diagnostic capabilities and substantial interpretation of more biological data and less
reliance on clinical presentation. Molecular diagnostics will revolutionize the practice of
medicine.
Doctors will use genetic tests to predict clinical progression, likeliness of therapeutic
response, and environmental influences. This will be coupled with drug development that
will be rationally based on our understanding of molecular pathogenesis. The role of genes
in determining disease susceptibility, progression, complications, and its response to
treatment will be equally important.
The managed care community will embrace appropriate use pharmacogenomics. In a
managed care environment, pharmacogenomics can identify the patients for whom a drug
would be safe and effective. A diagnostic product that enables the drug to be selectively
prescribed to these patients would provide cost savings to the health care providers. It has
the potential to increase drug efficacy, reduce follow-up and doctor visits, eliminate costly
ineffective drug alternatives, eliminate prescription by trial-and-error and eliminate possible
drug toxicity at "normal" doses in non-metabolizers.
Populations and Polymorphisms
Wendell W. Weber, M.D., Ph.D.
Professor Emeritus Pharmacology,
University of Michigan
Population frequencies of many pharmacogenetics traits have been shown to depend on
ethnic specificity. Most allelic variance could only be inferred before we began to use
molecular genetics to investigate them, but now they can very often be explained in
molecular terms. Knowledge of ethnic specificities of pharmacogenetic traits is essential for
new drug development and clinical care.
Generally speaking, humans are classified into three major groups: the Negroid,
Mongoloid, and Caucasoid. Traditional categories used to distinguish between different
races are geography, anthropology (similarity in appearance among individuals), language,
and an ill-defined category called ethnicity. The human race is believed to have originated
in Africa. Then great waves of migration occurred throughout the world over the course of
100,000 to 150,000 years—a minuscule amount of time compared to the entire evolution of
the human race and its biology.
The first pharmacogenetic trait to be identified was phenylthiourea "taste blindness." It was
the first demonstration that a chemical sensitivity was heritable and that chemical
sensitivity could serve as a means of distinguishing between individuals. African Blacks
had an incidence of around six percent, but American Blacks had anything from two to
twenty-three percent. American Whites had around thirty percent, while Chinese had
around six percent and Eastern Eskimos had around forty percent. Another early example
of a pharmacogenetic trait was drug-induced hemolysis due to G-6-PD (glucose-6phosphate dehydrogenase) deficiency. This occurs in ten to fifteen percent of African and
Mediterranean peoples. Alcohol sensitivity is another trait that's been recognized for a long
time. Genetic ALDH (aldehyde dehydrogenase) and ADH (alcohol dehydrogenase) variants
are very common in Asians, particularly among the Japanese.
The first studies of populations and polymorphism frequency were carried out mainly by
chance or just because the investigators were curious about how one race might compare
with another. But the amount of information that was accumulated quickly suggested that
these types of studies should be a standard part of any comprehensive examination of a
pharmacogenetic trait. And so now population studies of human genotype frequencies of
numerous genes of pharmacogenetic interest are automatically carried out. What would we
like to know about these drug-related ethnic specificities? One of the first questions is how
frequent these differences are. Also, do they offer a starting point for further investigation
of the trait? A third question that can be addressed is whether the differences might be
important for additional development and testing of new drugs. And of course the question
arises as to whether the differences are clinically significant.
The N-acetyl tranferase (NAT) polymorphism that was discovered in the 1950s
demonstrated remarkable variability in allele frequency among different ethnic. And it’s
fascinating that when you look at the worldwide distribution, as the latitude increases the
slow acetylator allele frequency decreases. A high proportion of slow acetylators is present
in populations around the equator, and higher and higher proportions of rapid acetylators as
one moves north.
Large differences between racial groups also occur for GST (glutathione-S-transferase), an
enzyme involved in detoxification of environmental toxins. The GST null allele has been
shown to affect individuals’ susceptibility to various forms of cancer. Among Blacks the
allele frequency is about 0.31; among Caucasians the frequency ranges from .39 to 0.54.
Another trait that has received a lot of attention is CYP2D6 (the abbreviation "CYP"
indicates a variant of the enzyme Cytochrome P450), an enzyme that metabolizes at least
30 or 40 commonly used drugs. The variation in this particular gene goes both ways, with
some individuals being poor metabolizers and others being very rapid metabolizers. About
5 to 10 percent Blacks and Caucasians are poor metabolizers, while very few Asians are
poor metabolizers. The Ethiopian and Saudi Arabian populations demonstrate a high
frequency of ultra-rapid metabolizers. Another pharmacogenetic trait that has been
investigated is the CYP2C19 genetic variant. Two mutations that truncate the gene and
produce a gene product with virtually no activity are present in 10 to 20% of the Japanese
population. Caucasians, on the other hand, have a somewhat lower frequency of 2C19
deficiency at about 3 to 5%.
These studies show that you want to be very careful about extrapolating across races with
respect to substrates for the variant enzymes. Another point is that predicting unusual
responses across races is unsafe. Are these specificities important in new drug development
and testing? We might anticipate the answer is going to be "yes".
Technologies
Michael Shi, M.D., Ph.D.
Senior Research Associate
Parke-Davis Pharmaceutical Research
The technologies available to assess a person’s polymorphism and likely response to
specific drugs can be divided into two approaches--.phenotyping and genotyping. A
phenotype is an observable biochemical parameter, usually a biochemical reaction. A
genotype is the genetic constitution of an organism, for example, the human genome. There
are advantages and disadvantages in both approaches.
Phenotyping can be subdivided into functional and metabolic phenotyping. Functional
phenotyping usually involves an invasive procedure, such as getting liver tissue to perform
a Cytochrome P-450 enzyme activity assay. This is not usually practical because it's hard to
get people to donate tissue for analysis. A more commonly used method for phenotyping is
metabolic phenotyping. A drug is given to a patient who is then monitored as the drug
metabolizes. For example, after patient is given a dose of caffeine and the urine and breath
can be tested for metabolites. An analysis of the metabolites indicates the enzymatic
pathways that patient would use to metabolize drugs analogous to caffeine. Phenotyping is
straightforward but has the disadvantage that it usually involves an invasive procedure.
Furthermore, if the drug is given to a poor metabolizer, the subject might actually
experience unpleasant (or worse!) side effects.
Many people would like to use the genotype as a predictive factor. One way to determine a
person’s genotype is to use the polymerase chain reaction (PCR), a very simple technique
that can amplify the nucleic acid to a measurable concentration in a short period of time.
This is usually coupled with restriction fragment length polymorphism (RFLP). To increase
the throughput, you can multiplex several PCR reactions together in the same tube. But
RFLP and PCR have real limitations. A very skilled technician can test only 50 samples at
a time, and it usually takes a couple of days. If you have a small number of samples that
you want to genotype, this technique is the most appropriate. For a large number of
specimens, laboratories are increasingly looking at four options: oligonucleotide ligation
assay (OLA), TaqMan® allelic discrimination, microsequencing, and chip or microarrays:
TaqMan was developed by Perkin-Elmer. The TaqMan probe is a very short
oligonucelotide complementary to the target DNA of interest, labeled with dyes. During the
PCR reaction, a recorder dye is released and generates a unique fluorescence that can be
quantified. OLA is similar, in that it also involves labeled probes that give a fluorescent
signal. Both of these are high-throughput and can be automated.
A very promising technique is the DNA chip array. Hundreds of thousands of
oligonucleotides can be attached to a solid glass or silicone surface in an ordered array.
These single oligonucleotide probes serve as target-specific probes. By incorporating a
fluorescent nucleotide into the PCR product, and applying it to the array, you will see a
strong fluorescent signal if there is a match between the target DNA and one of the probes
on the array. One company already has a chip to genotype 2D6 and 2C19 (2D6 and 2C19
are variants of Cytochrome P450), which is currently available for research applications.
The chips incorporate about twenty polymorphisms of 2D6 and three polymorphisms of
2C19. In one reaction you can actually monitor all these polymorphisms. This technology
could become a very powerful tool for clinical diagnosis.
All of these high-throughput techniques using probes for genotyping are based on known
polymorphisms. There are also circumstances where you want to identify new
polymorphisms. One common procedure for this is Single-stranded Conformation
Polymorphism (SSCP). SSCP is based on the principle that single-stranded molecules with
single-base pair differences will have unique DNA structures. When these molecules are
put on a gel, they form unique secondary structures that can be quantified. This is a very
economic way to identify a novel polymorphism. Another way to do genotyping of known
or novel polymorphisms is microsequencing. Computer software exists that can recognize a
single base-pair difference. It can actually recognize a single nucleotide difference.
How Payers View Pharmacogenetics
Barry M. Berger, M.D., FCAP
Director, Pathology and Laboratory Medicine
Harvard Vanguard Medical Associates
Harvard Vanguard Medical Associates is a multi-site, multi-specialty medical group that
cares for approximately 300,000 patients in the greater Boston area. The group is
exclusively contracted to the Harvard Pilgrim Health Care Area, the largest managed health
care organization in that region. If routine use of pharmacogenetics is ever to become a
reality, someone will have to pay for it, and it will have to be proven cost-effective through
convincing outcomes studies. When it comes to making a decision about how to pay for a
medical service, the decision process depends on whether the service is likely to be low
volume/low cost, low volume/high cost, high volume/low cost, or high volume/high cost.
Pharmacogenetics is unlikely to be either. If pharmacogenetics can become sufficiently
automated and high-throughput, it may become a relatively low cost/high volume service,
something like the conventional Pap smear. This would be the ideal situation. But
pharmacogenetics may end up being high volume/high cost, and that raises concerns about
the economics of integrating it into health care practice.
Things get difficult when there is tension between who is saving money and who is
spending money. Once we have significant genetic phenotypes to look for, the testing only
has to be done once, until a new polymorphism is discovered. Who will bear the cost and
how can the costs be shared? Potentially pharmacogenetics could give us more effective
treatments—a shorter time to cure, fewer side effects, and enhanced compliance. Will
pharmacogenetics give managed care organizations a competitive advantage in reducing
costs or improving patient satisfaction? Organizations that are early adopters may have a
big benefit if they can manage the additional expense.
In terms of customer satisfaction, patients may or may not embrace pharmacogenetics. We
expected many people would want BRCA testing, but the demand has not been as large as
we expected. There is probably nothing as intensely private as your genotype and people
fear that this information will get misused. For example, will people be denied access to
drugs based on this information?
Taking a look at the most expensive drugs for managed care shows that pharmacogenetics
could potentially prove cost-effective, if it lives up to its promise. One major expense is
cholesterol-lowering drugs, and identifying rapid metabolizers (and non-metabolizers)
could enable patients to lower their cholesterol more quickly with less risk of side-effects.
It would be extremely helpful to identify patients that will not respond without waiting
three or four months before trying another drug.
But if the end result is to tailor-make drugs for individuals, can we really afford the cost?
Will patients really be that much better off? These are the open questions, and the only
thing that will answer them is careful outcomes studies.
Pharmacogenetics in Cardiology
David A. Flockhart, M.D., Ph.D.
Director of Pharmacogenetics Core Laboratory
Georgetown University
For the past six years I have worked in a pharmacogenetics core lab that has primarily been
providing P450 and NAT2 genotypes for the National Institutes of Health, the Food and
Drug Administration, academics, and the pharmaceutical industry. Pharmacogenetics will
provide us with numerous new drug targets, as well as allow us to better tailor the use of
drugs we already have. This will be of enormous significance in the field of cardiology.
We have, for example, very few antiarrhythmic drugs that we actually prescribe on a
routine basis for disease like the Long QT syndrome. This is a rare syndrome in which
people have a slower repolarization of the myocardium after depolarization. It is due to
mutations in the heart’s ion channels, particularly the sodium and potassium channels, and
at least five genes have been implicated. Looking at genetics, patients usually have either
an LQT2 mutation that encodes a potassium channel or a LQT3 mutation that encodes a
sodium channel. How people with this syndrome will respond to drugs seems to depend on
what mutation they have.
The actual clinical application of genetic tests for these is likely to be valuable because the
disorder is so rare. In this case pharmacogenetics may identify targets for pharmaceutical
development. Right now patients are treated with numerous non-cardiac drugs that delay
cardiac repolarization. These include antibiotics, neuroleptics, antidepressants, and
antihistamines. My present area of research happens to be neuroleptics, and finding ways to
identify individuals who may be at cardiac risk for these drugs.
Another interesting cardiology application for pharmacogenetics involves antihypertensive
drugs. In 1995, a group at Vanderbilt University School of Medicine in Nashville compared
forearm blood-flow responses to isoproterenol in young black and white men with normal
blood pressure. What was seen very clearly was that the white men had an increase in the
forearm blood flow with increasing isoproterenol while the black men did not. This is a
great example of an effect for which we have not worked out genetics. We are testing
things like the beta 2-adrenergic receptors and angiotensin-converting enzyme to try to
determine which specific genetics tests we might use.
Looking at the 2D6 mutation in the CYP drug metabolizing enzymes, we see that this
mutation is responsible for the metabolism of a large number of cardiac drugs like betablockers. Beta-blockers are wisely used for the treatment of both hypertension and
congestive heart failure. Poor metabolizers can have two to three-fold higher plasma
concentrations and can have a higher rate of dizziness. Dizziness seems like something that
might be irrelevant during drug development, but it could make someone not take his or her
drug and would be useful for a doctor to be able to predict this response. You can see the
same effect in heart rate response to eye drops administered to the elderly to relieve
glaucoma.
One example of where a genetic test could clearly improve treatment is in the use of the
antiarrhythmic drug called propafenone or Rythmol™. When the same dose of the drug is
given to poor and hyper metabolizers, as judged by their 2D6 genotype, it is clear that
concentrations of the drug are higher in the poor metabolizers. But significantly, it is a
metabolite made from Rythmol by 2D6 that is responsible for the arrhythmia suppression
effect. Poor metabolizers have a higher plasma concentration of Rhythmol and less
metabolite, so a higher dose of the drug is required to for the patient to have the same
concentration of active metabolite. These patients will have a greater incidence of central
nervous system side effects. Consequently, another drug might be considered for these
patients. It is a good application of pharmacogenetics to prescribe a drug that I knew was
likely to be as effective and less toxic.
Another good example of the importance of pharmacogenetics is the 2C9 enzyme and
warfarin, also called Coumadin™. Essentially if warfarin is overdosed, you kill people.
About one percent of Caucasians and Africans are poor metabolizers. Patients that take
warfarin and that don’t have the particular active gene, 2C9, ought to be on a dose of about
five milligrams a week as rather than the normal dose of five milligrams a day. These are
patients that we would protect by having this particular genetic test available. We are
overdosing a small percentage of people but we do not know for sure because we do not
have an epidemiological study to demonstrate that.
In conclusion, rational prescribing for cardiovascular disease would be improved by the
availability of FDA approved pharmacogenetic tests. It is likely that such testing would
lower the cost and improve the effectiveness of the care of patients with cardiovascular
disease, but we have no data so far.
Pharmacogenetics in Neurology/Psychiatry
Judes Poirier, Ph.D.
Director, McGill Aging Research Center
McGill University
Probably the best example of how pharmacogenetics will change the future of medicine
comes from the treatment of Alzheimer’s disease. Alzheimer's disease is the fourth leading
cause of death in North America and costs the U.S. $93 billion per year in direct and
indirect costs. There are two major forms of Alzheimer's disease, familial and sporadic. The
sporadic form comprises 85% of all cases worldwide, and 50 to 60% of these cases have
been linked to the apolipoprotein gene.
Apolipoprotein E (ApoE) is involved in the transport of cholesterol and phospholipids. It is
implicated in synaptic remodeling and regeneration, amyloid metabolism, and appears to
modulate Alzheimer’s pathology. There is a clear association with the number of ApoE4
isoforms a person has and the risk of developing the disease, the age of onset, and the
accumulation of brain markers of Alzheimer’s disease. From one’s parents, it is possible to
inherit one copy, zero copies, or two copies. ApoE not only affects the risk but also the
exact age at which the disease starts. Two copies of E-4 are linked to an Alzheimer's
disease that starts roughly at 60 years of age. One copy of E-4 produces an Alzheimer's
disease that starts around the age of 75 years old. And for those patients with no copies of
E-4, the age of onset is normally around 85 years.
A natural question to ask is whether a person’s ApoE genotype would affect his or her
response to memory-enhancing drugs. First, using the placebo arm of two large drug trials,
we found that the ApoE genotype can determine disease progression over six months.
Individuals lacking ApoE4 tend to degrade about 2 to 3 times faster than individuals
carrying 1 or 2 copies of E4. This came as a shock to many observers in the pharmaceutical
industry, because they always assumed that when patients are recruited for a drug trial, they
are the same. What this study told us is that if a placebo is given to two groups of subjects-one group has exclusively E4s, the other group has non-E4s--a statistically significant
difference will be seen in the two groups simply because Alzheimer's is a disease with two
distinct rates of degradation.
When we looked at the genotype and drug response, it became clear that the non-ApoE4
subjects responded quite well to a drug called Tacrine™, while the ApoE4 subjects did not.
Pharmacogenetics seemed to indicate an effect on the response of Alzheimer’s disease to
other drugs as well, even if they worked through other mechanisms than Tacrine. While
Tacrine works by blocking the enzyme that degrades acetylcholine, another drug
Xanomeline™ simply replaces acetylcholine and would be expected to work for everyone.
Unexpectedly, we found that patients with two copies of ApoE3 responded quite well,
those with one copy of ApoE3 and one of ApoE4 did fairly well, and those with two copies
of ApoE4 actually did worse than those taking a placebo. As another example, researchers
looked at a drug called S-12024 that does not have anything to do with acetylcholine; it
works through another pathway in the brain and completely bypasses the cholinergenic
system. Yet in this case, people with two copies of ApoE4 clearly showed improvement,
while the non-ApoE4s showed continued deterioration over the course of the drug trial.
Now, if you go around the world and talk to everybody involved in anti-Alzheimer's drug
development, they will all tell you that they do ApoE genotype stratification, not at the end
of the drug trial but at the beginning. We have learned, so far, that those drugs designed to
stimulate the cholinergic system tend to work well in the non-E4 patient, whereas those
agents that are non-cholinergenic will work in the E4 subject. Pharmacogenetics is here
today—for Alzheimer’s disease, we can use genetic information to prescribe the right drug
to the right patient.
Pharmacogenetics in Hematology/Oncology
Mark J. Ratain, M.D.
Professor of Medicine
Chairman, Committee on Clinical Pharmacology
University of Chicago Medical Center
Oncologists deal with double-edged swords every day. On the one hand, chemotherapy
agents can attack tumors and metastases, but on the other hand they attack healthy cells as
well. Oncologists would like to give the highest safe dose, but clinical experience shows
that the best dose varies greatly from individual to individual. The new field of
pharmacogenetics promises to give oncologists unparalleled ability to predict how a patient
will respond to a drug.
One early example of pharmacogenetics in oncology appeared back in 1988, when The
Journal of Clinical Investigation reported on the case of a 40-year old woman being treated
for breast cancer. She developed profound neurotoxicity and almost died from the standard
dose of chemotherapy agents like 5-fluorouracil (5FU). This woman was the first
recognized case of dihydropyrimidine dehydrogenase (DPD) deficiency. Luckily for
oncologists, DPD deficiency is still very rare. But in this case, an understanding of the
pharmacogenetics behind a drug response led to an entirely new approach to treatment. A
pharmaceutical company developed a drug that inhibits this enzyme, so physicians
wouldn’t have to worry about DPD deficiency when giving 5FU because everybody would
be artificially DPD deficient. And the enzyme inhibitor also enhances the bioavailability of
the drug so it can be given orally at low doses.
In contrast, an example of a pharmacogenetics failure in drug development comes from the
clinical trials of the drug amonafide. The initial clinical safety trials were interesting in that
they ended up with two very different conclusions about the appropriate safe dose. One
institution recommended a dose of 250 mg/m2, while clinical trials at another suggested
400 mg/m2. Later trials split the difference and used a dose of 300 mg/m2. The decision to
use an average drug dose of 300 mg/ m2 in clinical trials led to very few patients
responding. They either received too low a dose to get any benefit or they received a dose
that forced them to withdraw from the study. We now know that the major determinant of
toxicity was the extent of N-acetylation to an active metabolite. Patients given the same
dose would fall into one of two groups: one had relatively low concentrations of metabolite,
and the other had relatively high concentrations. More precise dosing became possible once
researchers realized they could use caffeine to phenotype polymorphisms of NAT2, one of
the first drug-metabolizing enzymes known to be polymorphic. (This was before there was
really accurate genotyping for NAT2.)
Another interesting drug whose toxicity was regarded as "unpredictable" in early clinical
trials is CPT-11. The most important side effect of its administration was severe, choleralike diarrhea that might last for weeks. CPT-11 is hydrolyzed by the enzyme carboxyl
esterase to 7-ethyl-10-hydroxycamptothecin (SN-38), which undergoes conjugation to form
the corresponding SN-38 glucuronide (SN-38G). We conceived that the toxicity of the
drug, and therefore the diarrhea, was due to the amount of SN-38 that was entering the
intestine. Obviously the amount of glucuronidation of the drug was going to be an
important determinant, because the more drug that is glucuronidated, the less drug that will
be transported.
Our next challenge was to try and figure out which enzyme was involved in the
glucuronidation. Enzymes that form a glucuronide fall into two families of UDP-glucuronyl
tranferases (where UDP is uridine diphosphoglucuronic acid or UDPGA) called UGT*1
and UGT*2. Patients with a disease called Crigler-Najjar syndrome lack UGT 1.1, the
enzyme responsible for bilirubin conjugation, and patients with a mutation in that enzyme
can have Gilbert’s Syndrome, also associated with increased elevated serum bilirubin
concentration. Further laboratory studies have clearly shown that this enzyme is also the
one that is responsible for the metabolism of CPT11. An important question that we're
trying to study now in the clinic is: "Is there a correlation between the UGT-1A1 promoter
genotype and CPT-11 toxicity?" Researchers are looking to see if people with Gilbert’s
syndrome are more susceptible to diarrhea when given the drug, for example. Obviously if
there is a relationship, it would become appropriate to genotype for this polymorphism
before giving this highly toxic drug to a patient.
Pharmacogenetics in Environmental Medicine
Jun-Yan Hong, Ph.D.
Assistant Professor, Rutgers University, College of Pharmacy
Human disease is the consequence of both genetic susceptibility and environmental
exposure. By identifying the genes and variants that affect the individual response to
environmental toxins, we can better predict health risk and develop environmental policies
that can protect the most vulnerable sub-group of the population. When people with the
most common genotype are exposed to a particular environmental agent, then the common
genotype may increase the risk. People with a polymorphism that makes them more
susceptible, however, will have a much higher risk. The environmental exposure could be
something like a chemical that is carcinogenic, or it could even be a virus like HIV. People
with one kind of p53 polymorphism, for example, will have a higher risk of cervical cancer
if they get exposed to human papilloma virus. One could imagine someday screening
people to see what environmental risk factors might be most damaging to them, and then
advising them to minimize their contact with these environmental factors as a means of
prevention.
We know most environmental carcinogens are metabolically activated or inactivated by
xenobiotic metabolizer enzymes like the variants of Cytochrome P450 (CYP 450 or CYP).
Inhibition of these enzymes in laboratory studies has shown an increase in cancer induction
in animal carcinogenesis models. Some human population studies have also shown that
CYP polymorphisms like CYP2D6 are linked to a higher incidence of various cancers.
CYP2E1, for example, is a major CYP enzyme induced by alcohol, isonazid, fasting, and
diabetes. It has several known polymorphisms that have been linked to cancers of the lung,
stomach, liver, and nasopharynx. But results of numerous trials have shown conflicting
results, probably because of insufficient sample and lack of statistical power, ethnic
differences in allele distribution, and different environmental etiology factors.
These metabolizing enzymes are also involved in the response to drugs, but unlike studying
pharmacogenetics for drug response, environmental pharmacogenetics becomes much more
complicated. Human carcinogenesis is usually a long-term, multiple step process involving
many different genes. And except for occupational exposed populations, the identity, the
number and exposure levels of environmental carcinogens are often unknown. Over 40
carcinogens are found in tobacco smoke alone. And researchers do not yet know how
dietary considerations can change the expression of CYP enzymes, because without that
knowledge the functional significance of a polymorphism may be missed.
Besides metabolizer mutations, people might be at higher risk of cancer or other diseases if
they have polymorphisms in their DNA repair genes. In my lab, for example, we have
recently identified some genetic polymorphisms for O6-alkylguanine-DNA alkyltransferase
(AGT) that would make it less able to repair DNA damage.