Biotransformations of Drugs and Chemicals
55
cytochrome P450–inducing
agents
are
phenobarbital, the polycyclic aromatic hy-
drocarbons, clofbrate, and agents such as
dexamethasone, although compounds as
simple as ethanol are known to elevate
the concentrations oF specifc cytochrome
P450 enzymes. In a general sense, the cy-
tochrome P450 enzymes that are induced
are those that bind, and usually metab-
olize, the inducing drug or xenobiotic.
The induction response thus permits the
organism to increase its ability to clear
oFFending xenobiotics.
Cytochrome P450 monooxygenases cat-
alyze the insertion oF one atom oF molec-
ular oxygen into their substrates with
concomitant reduction oF the other oxy-
gen atom to a molecule oF water. The
electrons required For this reductive ac-
tivation oF molecular oxygen are pro-
vided by reduced pyridine nucleotides. A
flavoprotein known as cytochrome P450
reductase mediates the transFer oF elec-
trons From NADPH to the cytochrome
P450 enzymes oF interest in mammalian
drug metabolism. The mitochondrial cy-
tochrome P450 enzymes are primarily
involved in the metabolism oF endogenous
sterols and, like most bacterial cytochrome
P450 enzymes, obtain their electrons From
NADH via a two-protein system consist-
ing oF a flavoprotein reductase and an iron
Fig. 1
Examples of cytochrome
P450–catalyzed hydroxylation reactions.
Hydroxylation of the methyl group in
tolbutamide (a) and the amide nitrogen
in phenacetin (b) yields, respectively,
the corresponding alcohol and
N
-hydroxyamide metabolites.
Alternative hydroxylation of the ethyl
ether function in phenacetin produces a
hemiacetal that decomposes to the
phenol and acetaldehyde, a classic
example of a cytochrome
P450–catalyzed
O
-dealkylation.
SO
2
NHCONHC
4
H
9
CH
3
SO
2
NHCONHC
4
H
9
CH
2
OH
(a)
HN
O
N
O
(b)
O
HO
O
HN
O
HN
OH
O
O
OH
+
CH
3
CHO
sulFur protein. In contrast to the diver-
sity oF cytochrome P450 enzymes, there
is relatively little diversity in the reduc-
tase components.
One oF the three general oxidative re-
actions supported by cytochrome P450
is insertion oF the catalytically activated
oxygen atom into a C–H or N–H bond
to give the corresponding hydroxylated
p
roduc
t(±
ig
.1
)
.Inp
r
inc
ip
le
,theoxygen
can be inserted into the bond between a
hydrogen and any other heavy atom. In the
absence oF enzyme-imposed steric or sub-
strate orientation Factors, the reactivity oF a
C–H bond is inversely correlated with the
strength oF the bond, so that tertiary alco-
hols are more easily Formed than primary
alcohols. One consequence oF this is that
