60
Biotransformations of Drugs and Chemicals
10
7
8
9
P450
O
Epoxide
hydrase
P450
OH
O
HO
OH
HO
Fig. 6
The epoxidation of
benzo[a]pyrene by cytochrome P450 is
followed by enzymatic hydrolysis of the
epoxide and a second cytochrome
P450–catalyzed epoxidation reaction.
The resulting highly reactive diol
epoxide alkylates DNA and this reaction
is at least partially responsible for the
carcinogenic properties of this polycyclic
aromatic hydrocarbon.
endoplasmic reticulum and the cytosol.
The membrane-bound and soluble en-
zymes have somewhat different substrate
speciFcities, but both formally catalyze
backside addition of water to the epox-
idetogiveatrans-diolproduct
.Theactual
mechanism of the reaction, however, is
addition of a carboxylic acid group of the
enzyme to the epoxide followed by internal
hydrolysis of the resulting protein-bound
ester. In general, increasing the number
of substituents on the epoxide decreases
th
er
a
t
eo
fen
z
ym
a
t
i
ch
yd
r
o
l
y
s
i
sb
yth
e
membrane-bound enzyme but has less ef-
fect on hydrolysis of the epoxide by the
soluble enzyme. Although epoxide groups
are usually not found in drugs or xenobi-
otics because of their chemical reactivity,
the ability to detoxify epoxides is very im-
portant because epoxides are formed
in
situ
by the cytochrome P450–catalyzed
oxidation of oleFns and aromatic rings
(Sect. 3.1). Epoxides are also detoxiFed
by the glutathione transferase–mediated
addition of glutathione (Sect. 4.5). The re-
dundancy represented by the abilities of
both epoxide hydrolases and glutathione
transferases to detoxify epoxides reflects
the importance of doing so to the well-
being of the host.
Epoxide hydrolysis is normally a detox-
ifying reaction because it converts chem-
ically reactive epoxides into nonreactive
diols that can be glucuronidated or sul-
fated. Nevertheless, the potential delete-
rious interplay between cytochrome P450
enzymes and epoxide hydrolases is well
illustrated by the bioactivation of carcino-
genic polycyclic aromatic hydrocarbons. In
the case of benzo[a]pyrene, one of the
reaction sequences thought to play an
important role in carcinogenesis involves
oxidation of the 7,8-double bond of the
hydrocarbon by cytochrome P450, hydrol-
ysis of the epoxide to the
trans
-7,8-diol by
epoxide hydrolase, and epoxidation of the
9,10-double bond by cytochrome P450 to
give the 9,10-epoxy-7,8-diol (±ig. 6). This
highly reactive diol epoxide alkylates DNA,
causing a lesion that engenders a carcino-
genic response.
4
Phase II Enzymes
4.1
Glucuronyl Transferases
Glucuronidation
is
among
the
most
common
and
quantitatively
most
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