62
Biotransformations of Drugs and Chemicals
the
glucuronic acid
moiety. Hydroxyl,
carboxyl,
amino,
and
sulfhydryl
func-
t
i
o
n
ss
u
c
ha
st
h
o
s
ef
o
u
n
di
np
h
e
-
nols,
alcohols,
enols,
carboxylic
acids,
hydroxylamines,
primary
amines,
and
mercaptans
are
thus
commonly
glu-
curonidated. Acetaminophen, cloFbrate,
and 1-naphthylamine are examples of
drugs and xenobiotics that are extensively
glucuronidated (±ig. 8).
Trisubstituted amines, nitrogen hetero-
cycles, and a few other nitrogen-containing
functionalities are unique in that they can
be glucuronidated in the absence of de-
protonation to give quaternary, charged
products. An example of such a trans-
formation is the glucuronidation of ke-
totifen (±ig. 8). Carbon glucuronidation
is
possible
with
compounds
such
as
phenylbutazone that have highly acidic
carbon atoms.
Glucuronyl transferase activity depends
on a variety of factors, including age,
diet,
genetic
factors,
hormonal status,
and
cigarette
smoking.
The
increase
in glucuronidation observed during the
neonatal period is very important be-
cause bilirubin, the catabolite of heme,
is not readily excreted unless it is Frst
glucuronidated. The low levels of glu-
curonosyltransferase activity at birth can
result in bilirubin accumulation, jaundice,
and nervous system damage unless mea-
sures (usually phototherapy) are taken to
eliminate bilirubin by other mechanisms
until the appropriate glucuronosyltrans-
ferase increases to the appropriate func-
tional level.
O
HO
HO
OH
CO
2
H
O
NHCOCH
3
(a)
O
HO
HO
OH
CO
2
H
O
(b)
O
O
Cl
H
O
HO
HO
OH
CO
2
H
NH
(c)
O
HO
HO
OH
CO
2
H
N
+
(d)
H
S
O
H
H
Fig. 8
Examples of glucuronides in which the functionality that is
glucuronidated is (a) the phenol group of acetaminophen, (b) the carboxylic acid
of cloFbrate, (c) the amino group of 1-naphthylamine, and (d) the trisubstituted
amine group of ketotifen.
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