68
Biotransformations of Drugs and Chemicals
NH
2
OH
RS
O
RSH
+
O
OH
O
RC
H
3
S
O
RC
H
3
S
Fig. 16
The cysteine
β
-lyase pathway
for the metabolism of cysteine
conjugates derived by normal
proteolytic processing of glutathione
conjugates. The thiol derivative released
from the cysteine conjugate by the
action of cysteine
β
-lyase can be
methylated by an
S
-methyltransferase
andsubsequent
lyoxid
izedtothe
sulfoxide by a monooxygenase.
for the detoxiFcation of reactive, elec-
trophilic compounds. This reserve is nev-
ertheless limited and exposure to large
amounts of electrophilic species can result
in its temporary depletion. Depletion of
the glutathione reservoir in the face of
continued exposure to electrophilic prod-
ucts can result in life-threatening cell and
organ damage. The relationship between
glutathione depletion and cell damage has
been most extensively studied with ac-
etaminophen, a small fraction of which
is oxidized by cytochrome P450 to a
highly reactive iminoquinone derivative
that is normally detoxiFed by glutathione
(±ig. 15). The protection provided by glu-
tathione is such that normal doses of
this over-the-counter analgesic agent are
nontoxic.
Ingestion
of
large
doses
of
acetaminophen, however, results in the
formation of sufFciently large amounts of
the reactive metabolite that the glutathione
reservoir is depleted. The iminoquinone
metabolite is then free to react with cellu-
lar constituents, causing hepatic necrosis
and, if the damage is sufFciently exten-
sive, death. The same toxic consequences
are observed but at a lower dose of
acetaminophen if the glutathione concen-
tration is Frst depleted by administration
of a second agent or if the proportion of the
reactive metabolite is increased by induc-
tion of the appropriate cytochrome P450
enzyme.
5
Xenobiotic Metabolism and Toxicity
The
low
reaction
control
implicit
in
the broad speciFcity of drug-metabolizing
enzymes and
the
unpredictable
diver-
sity of xenobiotic structures make drug
metabolism a major contributor to the
toxicity
and
carcinogenicity
of
xeno-
biotics.
±or
example,
the
cytochrome
P450–catalyzed oxidation of aflatoxin and
polycyclic aromatic hydrocarbons to epox-
ides (±ig. 6) that bind covalently to DNA
is directly responsible for the carcino-
genic
properties
of
these
substances.
The analogous covalent binding of re-
active metabolites to proteins is respon-
sible for the toxic properties of many
xenobiotics. Thus, the oxidation of allyl
alcohol by alcohol dehydrogenases pro-
duces acrylaldehyde (CH
2
=
CHCH
2
OH
CH
2
=
CH
CH
=
O), a reactive electrophi-
lic agent that alkylates proteins and causes
tissue damage. As noted in Sect. 4.4,
a
major
role
of
the
glutathione
sys-
tem
is
to
prevent
tissue
damage
by
trapping metabolically produced reactive
species. The relationship between the glu-
tathione system and toxicity has been
most clearly deFned in the case of ac-
etaminophen. Thus, the metabolism of
lipophilic compounds is essential for their
elimination but not infrequently produces
species of higher toxicity than the parent
structure.
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