64
Biotransformations of Drugs and Chemicals
sulfate derivatives may be formed but react
rapidly with glutathione or other protein
sulfhydryls to give disulFde products. Sul-
fation accelerates xenobiotic excretion but,
in a few instances, converts prodrugs to
their active form. The best example of this
is conversion of the vasodilatory prodrug
minoxidil to its physiologically active sul-
fate metabolite (±ig. 10).
4.3
N
-Acyl Transferases
N
-Acyl transferases are involved in three
pathways of xenobiotic metabolism: (1)
conjugation of the carboxyl group of xeno-
biotics to the
α
-amino group of various
amino acids to give amino acid conjugates,
(2) acetylation
of
the
amino
functions
of xenobiotics, and (3) acetylation of the
cysteine conjugates produced by the glu-
tathione transferase pathway (Sect. 4.5). In
each of these acetylation reactions, the
carboxyl group is Frst activated by en-
zymatic conversion to the corresponding
CoA ester. This reaction is catalyzed by
ATP-dependent acid:CoA ligases that are
also involved in the formation of medium-
length fatty acid CoA esters. ±or the
formation of amino acid conjugates, the
carboxyl group of the xenobiotic is acti-
vated, whereas acetyl CoA provides the ac-
tivated carboxyl function for
N
-acetylation
of the amino functions in xenobiotics or
the
α
-amino groups of cysteine conjugates
(Sect. 4.5). Transfer of the activated acyl
moiety from the acyl CoA to the amino
group of the acceptor is catalyzed by
N
-acyl
transferases.
The most common amino acids in-
volved in the formation of amino acid
conjugates in mammals are glycine, glu-
tamine, and taurine, although conjugates
with arginine, asparagine, histidine, ly-
sine, and serine are also formed in a
species-dependent manner. The
N
-acyl
transferases and the enzymes that synthe-
size the acyl CoA esters belong to enzyme
families located primarily in the matrix of
liver and kidney mitochondria. The range
of xenobiotics susceptible to amino acid
conjugation is restricted to compounds
with a carboxylic acid function. The reac-
tion is catalyzed by acyl-CoA:amino acid
N
-acyltransferases. The increase in po-
larity achieved by this transformation is
modest because the reaction replaces one
carboxylic acid function with another and
therefore does not greatly alter the ioniza-
tion state of the xenobiotic. The conversion
of benzoic acid to hippuric acid by conju-
gation with glycine is a case in point.
PhCO
2
H
−−−→
PhCOSCoA
−−−→
PhCONHCH
2
CO
2
H
The acetyl CoA–dependent acetylation
of xenobiotic amino groups is catalyzed
by cytosolic
N
-acetyl transferases. In man,
one form of the enzyme predominates in
the liver and gut and another in extrahep-
atic tissues. Arylamines and hydrazines
are the most commonly
N
-acetylated func-
tions, although the reaction also occurs
with sulfonamides, aliphatic amines, and
related functions. Typical examples of this
process are the
N
-acetylation of isoni-
azid and sulfamethazine (±ig. 11). Because
acetylation decreases rather than increases
the polarity of the xenobiotic, it can occur
at any stage in the metabolic process.
The ability to
N
-acetylate xenobiotics is
polymorphically distributed in the human
population and has therapeutic and toxi-
cological consequences. ±or a given dose
of a drug, slow acetylators accumulate
higher concentrations of the parent drug
than fast acetylators. This can have clini-
cal and pathological consequences if the
therapeutic index of the drug is fairly
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