Iba transcript 3


















Important that you can recognize functional groups and have an idea what metabolic
pathway a particular drug is undergoing
Oxidation at a Carbon  oxidize a carbon that is alpha to heteroatom (N, S, )  you end
up with 2 products  you form an intermediate that is very unstable and will decompose
to form an aldehyde
All the other oxidations, you form one product but When you oxidize a Carbon  alpha
to an O  you hydroxylate the carbon  intermediate is unstable  continuously
nonenzymatically decomposes to an alcohol and aldehyde
To a nitrogen  intermediate is unstable  decomposes to amine and an aldehyde
Can also oxidize a sulfur  you oxidize a carbon the oxygen will substitute for a sulfuer
so you end up with a carbonyl , remove sulfur  known as oxidative desulfuration
sulfur atoms are exceedingly lipid soluble, and oxygen is less lipid soluble than sulfur
containing cmpds
Can also oxidize at the nitrogen itself  hydroxylamine  oxidize the nitrogen as a
tertiary function  end up with a product that’s very polar  N-oxide (not a
hydroxylamine)  2ndary Nitrogen  has a hydroxylamine
Tertiary  N-oxide, written with an arrow
Sulfur oxidation  form a sulfoxide
Can also happen on phosphorous atom
All of these are cytp450 dependent
This particular reaction the formation of N-oxide is very actively metabolized by the
other mixed function oxidase flavin monooxygenase FMO  most people think that
its not very active in catalyzing oxidation of carbon atoms, but it will oxidize S,N,and P
Major difference between cytp450 and flavin monooxygenase  both are mixed function
oxidases in ER
the major difference between the two is that p450 is inhibited by CO whereas FMO is
not FMO is most active in oxidizing heteroatoms, whereas P450 is active at oxidizing
Carbon atoms as well as heteroatoms
the next reactions
Alcohol oxidation by alcohol dehydrogenaseADH product is always an aldehyde
very toxic, very reactive  so they need to be eliminated  oxidized to less toxic by
ALDH  oxidize aldehydes to acids
these are not p450 reactions
oxidative enzymes  they will not always introduce oxygens into drug molecules 
sometimes just simply removing hydrogens and electrons from drug substrates  what
oxidation is  don’t necessarily have to introd. O atoms - depends on the enzyme and
the substrate  good example is ADH  one oxygen in the substrate, theres also one
oxygen in the product, no additional oxygen , just removal of Hydrogen atom
oxidative deamination  primary amine to aldehyde and ammonia not so much a drug
metabolizing enzyme  MAOs terminate the actions of neurotransmitters  enzyme
whos fxn is mostly associated with physiological mechanisms  capable of oxidizing
foreign chemicals, drugs and other toxicants




Reduction actions  phase 1
Reduce nitro drugs to primary amines  sequence eof reactions are involved
Quinones  para quinone, ortho quinone so that the 2 keto groups are next to each other
 these are very toxic compounds, will form from drugs so the enzyme NQO1 and
reduces them to hydroquinones which are less toxic  will go back and forth
 Carbonyl groups in aliphatic molecules  reduced to alcohols  carbonyl reductase
 NQO1 the same will also reduce carbonyls
 Azo double bond N=N
 Aliphatic hydrocarbons  can undergo reductive dehalogenation  and the intermediate
is always a free radical and that is a toxic reaction, when you remove halogen from
Carbon  p450 reduces so you don’t have the few instances that p450 will catalyze
reduction reaction, so that the halogenation reaction Is catalyzed by p450 and p450 will
also reduce nitro groups
 Cyp450 is largely an oxidation enzyme
 Hydrolytic reaction 
o Ester alcohol and acid
o Amides  amines and acids
o Epoxides  formed by p450s are very toxic and reactive and the enzyme that
detoxifies epoxides  epoxide hydrolase  forms cmpd with 2 hydroxy grps 
detoxification reaction
P450 can catalyze the reduction of nitro groups and the dehalogenation reactions are exclusively
by p450
Unlike the enzymes that catalyze the metabolism of endogenous cmpds, these do not have rigid
specificity
Phase 2 reactions March 2
 a lot of drugs do not require phase 1 before it goes into phase II  these phase 2
reactions  these are only 3 of the several phase 2 reactions he’ll talk about
 sequence in previous slide, phase 2 reactions is to enhance the polarity of cmpds  some
phase 2 reactions that actually the decrease of their products
 the whole ideais to increase polarity to enhance excretion, but there are some
exceptions can be less polar than parent cmpd.  the products of phase II can be more
toxic or more pharmacologically active than their precursors


Recap. About phase 1 reactions. Oxidations do not always involve an O atom to a drug.
all dehydrogenases, will remove hydrogens and the product is an oxygenation product
without an additional O, of all the oxidative enzymes there are only 2 that are categorized
as MFOs 2 enzymes are cytp450 and FMO
The enzyme MAO  not a mixed function oxidase and not a microsomal enzyme!
Pie chart
 Grp of enzymes that exist in multiple forms  case of acetylation at the Nitrogen is an
important phase 2 reaction  2 forms that catalyze acetylation at the nitrogen
 GST multiple forms


Sulfur transferase 
Glucuronidation accounts for at least 45% of all phase 2 metabolism of all drugs
Phase II
As by name, it refers to the
 Condensation of 2 products  1 is an endogenous compound with an endogenous
compound  cofactor is an endogenous compound in most cases, the essence of the
conjugation reaction is to enhance the solubility of the product with exceptions
 Cofactor for p450 reactions is NADPH
 Cofactor for FMO I  NADPH
 For ADH and ALDH  NAD,+
 Activated glucose molecule  glucoronidation



The important thing is to recognize which functional groups undergo which phase II
reactions
Among the grps that undergo
Gsh conjugation is very important in terms of protecting the body against reactive, toxic
intermediates  includes epoxides, substitute for nitro (displacement rxns), add
glutathione across a double bond, replace halogen with glutathione