56
Biotransformations of Drugs and Chemicals
hydrocarbon chains are most commonly
hydroxylated at the next-to-the-last (
ω
1)
position, although the CYP4 family of cy-
tochrome P450 enzymes has speciFcally
evolved to promote the thermodynamically
more difFcult terminal (
ω
)hyd
roxy
la
t
ion
of fatty acids. Oxidation by cytochrome
P450 is particularly critical for hydrocar-
bons and other nonpolar structures that
do not have a functional group that can
be used for further metabolism. This is
clearly illustrated, as already mentioned, by
the fact that polyhalogenated hydrocarbons
(e.g. hexachlorinated biphenyls) that are
resistant to cytochrome P450–catalyzed
oxidation are very poorly excreted and ac-
cumulate in adipose tissue.
The diversity of the products formed
by the cytochrome P450 system is greatly
enhanced by the decomposition or rear-
rangement of unstable oxidation products
to stable metabolites. The best example
of this is hydroxylation adjacent to a
heteroatom, which is normally followed
by elimination of the heteroatom and
conversion of the hydroxyl group to a
carbonyl function. Alkyl ethers are thus
O
-dealkylated (±ig. 1), alkyl amines
N
-
dealkylated, alkyl thioethers
S
-dealkylated,
and alkyl halides dehalogenated.
The second general cytochrome P450 re-
action is transfer of the activated oxygen
to the
π
-bondo
fano
leFn
,ana
roma
t
i
c
ring, or another unsaturated substruc-
ture to give the epoxide or a product
formally obtained by rearrangement of
such an epoxide. In general, electron-rich
π
-bonds are more readily oxidized than
electron-deFcient
π
-bonds. The epoxides
formed
in
this
reaction
are
relatively
reactive and potentially toxic, but their
toxicity is attenuated by the presence of
epoxide hydrolases (see Sect. 3.6) and glu-
tathione transferases (see Sect. 4.5) that
convert the epoxides to less-reactive vicinal
diols and glutathione adducts, respectively.
The oxidation of aromatic rings yields par-
ticularly unstable epoxides that are subject
to the so-called
NIH rearrangement
to give
phenolic products (±ig. 2). Indeed, it is un-
clear in some instances whether the epox-
ideisanac
tua
lin
termed
ia
teoraspec
ies
closer to a transition state in the conversion
of the aromatic ring to a phenol.
The
third
general
cytochrome
P450
reaction is addition of the activated oxygen
to the electron pair of a heteroatom. A
trisubstituted nitrogen is thus converted to
an N-oxide and a disubstituted sulfur to a
sulfoxide (±ig. 3). Whereas hydroxylation
and epoxidation reactions are primarily
catalyzed
by
cytochrome
P450,
the
oxidation of heteroatoms is also catalyzed
by
flavin-containing
monooxygenases.
OCH
3
D
OCH
3
O
H
D
OCH
3
OH
OCH
3
H
(H) D
O
D
Fig. 2
The cytochrome
P450–catalyzed epoxidation of
aromatic rings is commonly
followed by the ‘‘NIH Shift’’, a
nonenzymically catalyzed
rearrangement that converts the
epoxide to the
corresponding phenol.
previous page 730 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 732 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off