Biotransformations of Drugs and Chemicals
63
4.2
Sulfotransferases
Sulfotransferases
are
soluble
enzymes
that transfer the sulfate group from 3-
phosphoadenosine-5
0
-phosphosulfate to a
nucleophile on the drug or xenobiotic
(Fig. 9). The p
K
a
value (
∼−
7) of the
sulfate
function
is
such
that
the
re-
sulting sulfate conjugates are completely
ionized, and therefore more readily elim-
inated, under all physiological conditions.
Sulfation of drugs and xenobiotics is
almost as common as glucuronidation.
The physiological sulfate pool appears
to be limited, however, so that the pro-
portional importance of sulfation often
decreases as the dose of the drug or xeno-
biotic increases.
The range of functionalities that un-
dergo sulfation is similar to, but more
Fig. 9
Sulfation catalyzed by
sulfotransferases involves transfer of the
sulfate group of
3-phosphoadenosine-5
0
-phosphosulfate
(PAPS) to the substrate, represented in
the Fgure by an alcohol (ROH).
OS
O
O
O
P
O
O
O
O
H
2
O
3
PO
OH
N
N
N
N
NH
2
PAPS
R-OSO
3
+
OP
O
O
O
O
H
2
O
3
PO
OH
N
N
N
N
NH
2
HO-R
limited than, the range that undergoes
glucuronidation. Hydroxyl groups, partic-
ularly phenolic groups such as that in
terbutalin (Fig. 10), and amino functions
are the most commonly sulfated. The sulfa-
tion of carboxylic acids, trialkylamines, and
sulfhydryl groups, unlike glucuronidation,
is not observed. In the case of sulfhydryl
groups, limited evidence suggests that
HO
NH-tBu
OH
OH
Terbutalin
O
NH-tBu
OH
OH
S
O
O
O
N
N
N
+
NH
2
NH
2
O
Minoxidil
N
N
N
+
NH
2
NH
2
O
S
O
O
O
Fig. 10
Sulfation of the phenol function of terbutalin increases its
polarity and excretability. Sulfation of the N-oxide group of minoxidil
is unusual and produces a metabolite that is responsible for the
vasodilatory properties of the drug (actually a prodrug).
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