Court Lab Blurb for Sackler web site

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Members:
Suwagmani Hazarika, M.Sc., Research Assistant
2000 - BSc (honors), Zoology, Banaras Hindu University, Banaras, India.
2002 - MSc, Biotechnology, India Institute of Technology, Roorke, India.
Carrie Mosher, Ph.D., Postdoctoral Fellow
1998 - BSc, Biological and Environment Sciences, University of Notre Dame,
Notre Dame, IN.
2002 - MSc, Pharmaceutical Chemistry, Idaho State University, Pocatello, ID.
2008 - PhD, Medicinal Chemistry, University of Washington, Seattle, WA.
Awewura Kwara, MB.ChB., MPH&TM, NIH-K23 Award Trainee
1992 - MB.ChB., Medical School, University of Ghana, Accra, Ghana.
1999 - Residency, Cook County Hospital, Chicago, IL.
2001 - MPH&TM, School of Public Health and Tropical Medicine, Tulane
University, New Orleans, LA.
2004 - Assistant Professor of Medicine, Brown University, Providence, RI.
Laboratory of Comparative and Molecular Pharmacogenomics
The long-term goal of the research being conducted in our laboratory is
personalized therapeutics - the safe and effective treatment of an individual’s
disease using the right dose of the right medicine tailored specifically for that
patient. Unfortunately, many drugs used today are characterized by high
interindividual variability in therapeutic response and adverse effects
necessitating a trial and error approach using escalating doses and different
classes of drugs to achieve a successful outcome. Our research involves
identifying significant causes of this variability, particularly those resulting from
differences in the genetic makeup of an individual (i.e. pharmacogenomics). The
ultimate outcome of this work will be the development of rational drug treatment
algorithms based on a patient’s genotype, predictive biomarkers, demographics,
disease state, as well as other coadministered drugs.
Drug glucuronidation enzymology and pharmacogenomics
The UDP-glucuronosyltransferases (UGTs) are an unappreciated and
understudied superfamily of drug metabolizing enzymes that metabolize and
inactivate drugs by conjugation with glucuronic acid (i.e. glucuronidation). UGTs
are second only to the cytochromes P450 (CYPs) in terms of the number of
clinically important drugs that are substrates for these enzymes. Primary
pharmaceutical substrates for the UGTs that have been extensively studied in
our lab include acetaminophen (Tylenol), azidothymidine (AZT), morphine,
mycophenolic acid, oxazepam, and lorazepam. Published and ongoing studies
involve establishing the responsible UGT isoforms for each of these (and other)
drugs, as well as identifying genetic variants that predict increased or decreased
rates of drug glucuronidation in a patient.
Fig. 1. Variability in glucuronidation of probes specific for UGT1A1, 1A4, 1A6,
1A9, 2B7 and 2B15 measured in the same bank of human liver microsomes.
Also shown are activities for midazolam 1’-hydroxylation and chlorzoxazone 6hydroxylation, as probes for CYP3A and CYP2E1. Data for each activity are
given relative to the mean activity for all livers. Also shown are the coefficients of
variation (CV%) for each activity.
Acetaminophen-induced acute liver failure
Acetaminophen is one of the most commonly used drugs in the world, but is also
the leading cause of acute liver failure in the United States and Europe. While
many cases result from intentional overdose (i.e. suicide attempts), as many
cases are the result of therapeutic use of this drug for chronic pain relief. We are
currently conducting studies using cell and tissue-based model systems, human
volunteers, and DNA collected from patients that developed acetaminopheninduced acute liver failure, to identify genotypes predictive of altered
acetaminophen metabolism and increased risk for developing liver injury. Such
genotypes would be used to identify individuals that should avoid or perhaps
minimize the use of acetaminophen.
Fig. 2. Etiology of acute liver failure in the United States as determined by the
Acute Liver Failure Study Group multicenter trial (courtesy Will Lee, UTSW,
2009). Almost half of the cases are the result of acetaminophen ingestion, and of
those approximately half were taking acetaminophen for therapeutic purposes.
HIV drug pharmacogenomics and TB drug interactions
Antiretroviral drug combination therapies have had a substantial impact on
reducing the morbidity and mortality associated with HIV infection. However,
certain highly effective antiretroviral drugs, such as efavirenz, demonstrate high
interindividual variability in blood levels resulting in either adverse neurological
effects (high levels) or potential virologic failure (low levels). Research in our
laboratory and others have established that polymorphisms in the gene encoding
CYP2B6 are largely responsible for high variability in efavirenz metabolism. In
collaboration with researchers at Brown University, University of North Carolina,
and the University of Ghana, we are identifying genetic variants in CYP2B6 and
other genes that are predictive of slow as well as fast metabolism of efavirenz
using DNA samples from a cohort of HIV-infected Ghanaians. We are also
exploring the molecular basis for variable drug-drug interactions between
efavirenz and the drugs used to treat tuberculosis (TB), a common comorbid
infection in HIV-infected patients. The ultimate goal is to develop rational
therapeutic protocols based on patient genotype and coadministered drugs.
Fig. 3. Scatter plot showing the relationship between log10 pharmacogeneticpredicted efavirenz mid-dose plasma concentrations (y-axis) and log10 observed
concentration (x-axis) in 94 HIV-infected patients. Log10 efavirenz mid-dose
plasma concentrations predictions for each subject were made based on their
genotype carrier status (CYP2B6 c.516TT, CYP2A6*9 or *17 and/or UGT2B7*1a
as indicated by arrows) using the pharmacogenetic algorithm derived by multiple
linear regression analysis (model and associated goodness of fit statistics are
shown at the top of graph).
Veterinary pharmacogenomics
Substantial differences in drug metabolism capacity also exist between different
breeds of dog and between different species of animal. These phenomena are
important to investigate for comparative purposes (especially humans versus
laboratory animals) as well as for improving the health and welfare of our
companion animals. Several projects are investigating why Greyhound dogs
metabolize certain anesthetic agents more slowly compared with other dog
breeds, and why cats have a poor capacity to metabolize certain drugs by
glucuronidation.
Fig. 4. Phylogram showing the established evolutionary relationships between
species in the suborder Feloidea in relation to the appearance of disruptive
mutations within the UGT1A6 gene. All Felidae share 5 mutations that likely
originated between 11 and 35 million years ago resulting in UGT1A6
pseudogenization. MY - estimated times of divergence in millions of years ago.
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