Biotransformations of Drugs and Chemicals
65
N
CONHNH
2
N
CONHNHCOCH
3
Isoniazid
SO
2
NH
H
2
N
N
N
CH
3
CH
3
SO
2
NH
CH
3
CONH
N
N
CH
3
CH
3
Sulfamethazine
Fig. 11
N
-Acetylation of a hydrazine (isoniazid) and an aryl amine (sulfamethazine),
two typical reactions catalyzed by
N
-acetyl transferases.
narrow.
For
example, slow
acetylators
are more susceptible to the peripheral
neuropathy associated with isoniazid or
the lupus erythematosus side effect of
hydralazine. The variability of the
N
-
acetylation phenotype in humans is due,
at least in part, to point mutations in the
N
-acetyltransferase genes.
4.4
Methyl Transferases
N
-,
O
-, and
S
-methylations of xenobiotics
are catalyzed by
S
-adenosyl-
L
-methionine-
dependent
methyltransferases,
includ-
ing
enzymes
such
as
catechol
O
-
methyltransferase and indolethylamine
N
-
methyltransferase, whose primary sub-
strates are endogenous neurotransmitters
and their metabolites (Fig. 12). The sub-
strate speciĀ±cities of these enzymes are
broad enough that they often also methy-
late drugs that have the required func-
tionality and structurally resemble the
endogenous substrates.
Methylation of
the meta-hydroxyl group in a catechol
substrate such as dopamine (Fig. 12) is
usually favored over methylation of the
para-hydroxyl, although both products are
formed. One consequence of the fact that
the primary function of the
N
-and
O
-
methyltransferases is the metabolism of
endogenous substrates is that methylation
of hydroxyl and amine groups primarily
occurs with xenobiotics that structurally
resemble endogenous neurotransmitters.
A second consequence is that the polarity
of the substrate is decreased rather than
HO
NH
2
HO
Dopamine
HO
NH
2
CH
3
O
N
NH
2
H
Indolethylamine
N
NHCH
3
H
Fig. 12
Methylation of the catechol group of dopamine and
the primary amine group of indolethylamine.
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