66
Biotransformations of Drugs and Chemicals
increased by methylation. Methylation and
N
-acetylation are therefore the two general
pathways that decrease substrate polarity.
4.5
Glutathione Transferases
Glutathione is a tripeptide in which the
carboxyl and amino groups of cysteine
are linked respectively to a glycine and
the
γ
-carboxyl group of glutamic acid
(Fig. 13). Incorporation of cysteine into
this tripeptide protects it from utilization
in protein synthesis and makes possi-
ble the accumulation of high (5–10 mM)
concentrations of the cysteine sulfhydryl
in
tissues.
These
high
concentrations
are desirable because glutathione serves
as the major line of defense against
electrophilic, chemically reactive species,
including xenobiotics, xenobiotic metabo-
lites,
and
reactive
oxygen
derivatives.
Highly reactive electrophilic metabolites
can be trapped by direct, uncatalyzed
reaction with the glutathione sulfhydryl
group, but the addition of glutathione to
moderately or weakly electrophilic com-
pounds is catalyzed by a family of en-
zymes known as glutathione transferases.
The glutathione transferases have broad,
overlapping substrate speci±cities and are
primarily, but not exclusively, located in
the cytosol.
Glutathione reacts chemically or with
the catalytic assistance of a glutathione
transferase with essentially all electrophilic
functionalities, including alkyl and acyl
halides (Fig. 13), epoxides (Fig. 14), elec-
trophilically activated aromatic ring sys-
tems (Fig. 14), and
α, β
-unsaturated car-
bonyl compounds (Fig. 15). The products
of the reactions are the thioethers or
thioesters in which the cysteine sulfhydryl
has added to the electrophilic center,
usually with concomitant displacement
of a leaving group from the same cen-
ter. The glutathione transferases promote
these reactions, in part, by simply bind-
ing the lipophilic, electrophilic substrates
in close proximity to the enzyme-bound
glutathione.
Glutathione conjugates are usually more
polarand/orhighlyionizedthantheparent
xenobiotic due to the hydrophilic nature
o
ft
h
et
r
i
p
e
p
t
i
d
ea
n
dt
h
ep
r
e
s
e
n
c
eo
f
ionizable amino and carboxyl functions
in it. Glutathione conjugates are actively
transported out of cells, but the con-
jugates undergo further transformation
before they are excreted. Glutamic acid
HN
NH
CO
2
H
HS
O
O
CO
2
H
NH
2
CH
3
Br
HN
NH
CO
2
H
CH
3
S
O
O
CO
2
H
NH
2
Glutathione
NH
2
NH
CH
3
S
O
CO
2
H
NH
2
OH
CH
3
S
O
NHCOCH
3
CO
2
H
CH
3
S
Fig. 13
The sequence of steps involved in conjugation of the tripeptide glutathione
with an electrophilic substrate, here methyl bromide, and subsequent processing of
the glutathione conjugate to the
N
-acetylcysteine conjugate that is actually excreted.
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