DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

phase 1 enzymes. Once subjected to oxidation, drugs
can be directly conjugated by the UGTs (in the lumen
of the endoplasmic reticulum) or by the cytosolic transferases
such as GST and SULT. The metabolites can
then be transported out of the cell through the plasma
membrane where they are deposited into the bloodstream.
Hepatocytes, which constitute >90% of the cells
in the liver, carry out most drug metabolism and can
produce conjugated substrates that can also be transported
though the bile canalicular membrane into the
bile, from which they are eliminated into the gut (see
Chapter 5).
PHASE 1 REACTIONS
The Cytochrome P-450
Superfamily: the CYPs
The CYPs are a superfamily of enzymes, all of which
contain a molecule of heme that is non-covalently
bound to the polypeptide chain (Figure 6–2). Many
other enzymes that use O 2
as a substrate for their reactions
also contain heme. Heme is the oxygen-binding
moiety found in hemoglobin, where it functions in the
binding and transport of molecular oxygen from the
lung to other tissues. Heme contains one atom of iron in
a hydrocarbon cage that functions to bind oxygen in the
CYP active site as part of the catalytic cycle of these
enzymes. CYPs use O 2
, plus H + derived from the
cofactor-reduced nicotinamide adenine dinucleotide
phosphate (NADPH), to carry out the oxidation
of substrates. The H + is supplied through the
enzyme NADPH-cytochrome P450 oxidoreductase.
Metabolism of a substrate by a CYP consumes one
molecule of molecular oxygen and produces an oxidized
substrate and a molecule of water as a by-product.
However, for most CYPs, depending on the nature of
the substrate, the reaction is “uncoupled,” consuming
more O 2
than substrate metabolized and producing
what is called activated oxygen or O 2-
. The O 2-
is usually
converted to water by the enzyme superoxide dismutase.
Elevated O 2-
, a reactive oxygen species (ROS),
can give rise to oxidative stress that is detrimental to
cellular physiology and associated with diseases including
hepatic cirrhosis.
Among the diverse reactions carried out by
mammalian CYPs are N-dealkylation, O-dealkylation,
aromatic hydroxylation, N-oxidation, S-oxidation,
deamination, and dehalogenation (Table 6–2). More
than 50 individual CYPs have been identified in
humans. As a family of enzymes, CYPs are involved in
the metabolism of dietary and xenobiotic chemicals, as
well as the synthesis of endogenous compounds (e.g.,
steroids; fatty acid-derived signaling molecules, such
as epoxyeicosatrienoic acids). CYPs also participate in
the production of bile acids from cholesterol.
In contrast to the drug-metabolizing CYPs, the CYPs that catalyze
steroid and bile acid synthesis have very specific substrate preferences.
For example, the CYP that produces estrogen from testosterone,
CYP19 or aromatase, can metabolize only testosterone or
androstenedione and does not metabolize xenobiotics. Specific
inhibitors for aromatase, such as anastrozole, have been developed for
use in the treatment of estrogen-dependent tumors (see Chapters 40
and 60-63). The synthesis of bile acids from cholesterol occurs in the
liver, where, subsequent to CYP-catalyzed oxidation, the bile acids
are conjugated with amino acids and transported through the bile duct
and gallbladder into the small intestine. Bile acids are emulsifiers that
facilitate the elimination of conjugated drugs from the liver and the
absorption of fatty acids and vitamins from the diet. In this capacity,
> 90% of bile acids are reabsorbed by the gut and transported back to
the hepatocytes. Similar to the steroid biosynthetic CYPs, CYPs
involved in bile acid production have strict substrate requirements and
do not participate in xenobiotic or drug metabolism.
The CYPs that carry out xenobiotic metabolism have the
capacity to metabolize diverse chemicals. This is due both to multiple
forms of CYPs and to the capacity of a single CYP to metabolize many
structurally distinct chemicals. There is also significant overlapping
substrate specificity amongst CYPs; a single compound can also be
metabolized, albeit at different rates, by different CYPs. Additionally,
CYPs can metabolize a single compound at different positions on the
molecule. In contrast to most enzymes in the body that carry out highly
specific reactions involved in the biosynthesis and degradation of
important cellular constituents in which there is a single substrate and
one or more products, or two simultaneous substrates, the CYPs are
promiscuous in their capacity to bind and metabolize multiple substrates
(Table 6–2). This property, which is due to large and fluid substrate
binding sites in the CYP, sacrifices metabolic turnover rates;
CYPs metabolize substrates at a fraction of the rate of more typical
enzymes involved in intermediary metabolism and mitochondrial electron
transfer. As a result, drugs have, in general, half-lives in the range
of 3-30 hours, while endogenous compounds have half-lives of the
order of seconds or minutes (e.g., dopamine and insulin). Even though
CYPs have slow catalytic rates, their activities are sufficient to metabolize
drugs that are administered at high concentrations in the body.
This unusual feature of extensive overlapping substrate specificities
by the CYPs is one of the underlying reasons for the predominance of
drug-drug interactions. When two co-administered drugs are both
metabolized by a single CYP, they compete for binding to the
enzyme’s active site. This can result in the inhibition of metabolism of
one or both of the drugs, leading to elevated plasma levels. If there is
a narrow therapeutic index for the drugs, the elevated serum levels
may elicit unwanted toxicities. Drug-drug interactions are among the
leading causes of adverse drug reactions (ADRs).
The Naming of CYPS. The CYPs are the most actively studied of the
xenobiotic metabolizing enzymes since they are responsible for
metabolizing the vast majority of therapeutic drugs. Genome
sequencing has revealed the existence of 102 putatively functional
127
CHAPTER 6
DRUG METABOLISM