Biotransformations of Drugs and Chemicals
57
N
N
CN
CH
3
HN
N
N
H
S
H
N
N
CN
CH
3
HN
N
N
H
S
H
O
+
Cimetidine
N
N
CH
3
N
N
+
CH
3
O
Nicotine
Fig. 3
Cytochrome P450 and the flavin-containing monooxygenase
(FMO) catalyze the oxidation of nitrogen and sulfur, as illustrated by the
sulfoxidation of cimetidine and the N-oxidation of nicotine.
The
flavin-containing
monooxygenases,
or FMOs, are generally limited to the
NADPH- and oxygen-dependent oxidation
of
nitrogen
and
sulfur
atoms
and
therefore have a more restricted metabolic
scope than cytochrome P450 enzymes.
Nevertheless they can play an important
role in the metabolism of individual drugs.
Both the cytochrome P450 and flavin-
containing monooxygenases preferentially
oxidize electron-rich heteroatoms.
Cytochrome P450 enzymes can catalyze
oxidative reactions other than the three
general reactions described above, includ-
ing reactions such as the dehydrogenation
of alkyl groups, deformylation of aldehy-
des, and cleavage of carbon–carbon bonds.
Although relatively rare, these reactions
have been more frequently observed in
the past few years. Under conditions of
low oxygen tension, cytochrome P450 en-
zymes also catalyze reductive reactions,
including the reduction of nitro and azo
groups to amines and the dehalogenation
of haloalkanes.
3.2
Monoamine Oxidase
Monoamine
oxidase
is
an
oxygen-
dependent mitochondrial flavoprotein that
oxidizes
endogenous
neurotransmitter
amines and related xenobiotics to the
corresponding imines. The imines are
subsequently hydrolyzed in the aqueous
medium to the carbonyl derivatives and
either ammonia or an amine, as shown
below for 2-phenylethylamine.
PhCH
2
CH
2
NH
2
−−−→
PhCH
2
CH
=
NH
−−−→
PhCH
2
CHO
+
NH
3
Primary amines are particularly good sub-
strates for the enzyme, but secondary
amines in which one of the substituents is
a methyl or another small alkyl group are
readily oxidized. The oxidation of trisubsti-
tuted amines often results in inactivation
of the enzyme, a phenomenon exploited
in the development of clinically useful in-
hibitors of the monoamine oxidases.
3.3
Alcohol and Aldehyde Dehydrogenases
Alcohol dehydrogenases are members of
a family of cytosolic enzymes that catalyze
the NAD-dependent oxidation of alcohols
to aldehydes or ketones as well as the
reverse reaction, the NADH-dependent re-
duction of carbonyl compounds to alcohols
(Fig. 4). At least 16 different alcohol dehy-
drogenase isoforms have been identi±ed
in human liver. Less well characterized
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