Biotransformations of Drugs and Chemicals
67
Fig. 14
Addition of glutathione
to the epoxide of styrene oxide
and the activated aromatic ring
of a herbicide. GSH stands for
glutathione.
O
G-SH
OH
S-G
+
S-G
OH
N
N
N
ET
2
N
N
CN
Cl
N
N
N
ET
2
N
N
CN
S-G
G-SH
OH
HN
O
P450
O
N
O
G-SH
O
N
O
S-G
H
OH
HN
O
S-G
Acetaminophen
Fig. 15
Acetaminophen is oxidized by cytochrome P450 to a chemically
reactive iminoquinone structure that is trapped by glutathione to give a
glutathione conjugate. In the absence of glutathione, the iminoquinone
alkylates multiple liver proteins.
and glycine are frst removed From the
conjugate by the ordered, sequential action
oF a
γ
-glutamyl transpeptidase and a pep-
tidase (±ig. 13). High concentrations oF
these enzymes are Found in the kidney.
The cysteine conjugate obtained by re-
moval oF the two protective amino acids is
then
N
-acetylated by the action oF an acetyl
CoA–dependent
N
-acetyltransFerase (See
Sect. 4.3).
N
-Acetylation converts the zwit-
terionic
amino
acid
derivative
into
a
simple carboxylic acid and thus prevents
reabsorption oF the conjugate From the
kidney by amino acid transporters. The
N
-acetyl cysteine conjugates, known as
mercapturic acids, are generally excreted
in the urine.
The cysteine conjugates prior to
N
-
acetylation, or regeneration by hydrolysis
oF the
N
-acetyl group oF the mercapturic
acid
derivatives,
are
subject
to
an
alternative
metabolic
pathway
initiated
by a
β
-lyase. This pyridoxal phosphate-
dependent
enzyme
catalyzes
removal
oF
the
proton
adjacent
to
the
amino
group with concomitant elimination oF
the thioether or thioester group. The
products oF the reaction are the sulFhydryl
derivatives oF the original xenobiotic and
pyruvic
acid
(CH
3
COCO
2
H)
(±ig. 16).
The
Free
sulFhydryl
group
is
then
methylated by an
S
-adenosyl-
L
-methione-
dependent
S
-methyl
transFerase
(See
Sect. 4.4).
The
thiomethyl
product
is
relatively nonpolar and can be oxidized
by a cytochrome P450 or flavin-containing
monooxygenase
to
the
corresponding
sulFoxide.
The high concentrations oF glutathione
present in most tissues provide a reserve
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