Biotransformations of Drugs and Chemicals
61
important pathways of drug and xenobiotic
metabolism. The reaction is catalyzed by
a family of membrane-bound enzymes
known as UDP-glucuronosyltransferases
(or glucuronyl transferases). The number
of
enzymes
in
this
family
is
not
known,
but
evidence
exists
for
at
least
a
dozen
rat
enzymes
and
a
corresponding
number
of
human
enzymes.
UDP-glucuronosyltransferases
transfer
the
glucuronic
acid
moiety
from the endogenous donor uridine-5
0
-
diphospho-
α
-D-glucuronic acid (UDPGA)
to
an
acceptor
function
on
the
drug
or
xenobiotic
(Fig. 7).
Glucuronidation
greatly increases the polarity and water
solubility
of
most
xenobiotics
due
to
the
high
ratio
of
oxygen
to
carbon
atoms in glucuronic acid and the fact
that its carboxyl group (p
K
a
=
3
.
5) is
highly
ionized
at
physiological
pH.
This
increase
in
ionic
character
and
polarity greatly accelerates excretion of
the xenobiotic. Glucuronidation usually
occurs
only
once
and
it
is
the
last
step in a metabolic sequence because
the
glucuronide
metabolite
is
usually
too
polar
to
interact
ef±ciently
with
the membrane-bound enzymes of drug
metabolism and is readily excreted. A
few lipophilic compounds are known,
however, that are glucuronidated twice.
Bilirubin produced endogenously by the
catabolism
of
heme
is
one
of
these
compounds.
Glucuronidation involves displacement
of the UDP phosphate group by a nu-
cleophile in the xenobiotic. The stere-
ochemistry of the glucuronic acid car-
bon involved in the reaction is inverted,
in accord with a backside displacement
mechanism (Fig. 7). The glucuronic acid
moiety
can
be
transferred
by
UDP-
glucuronosyltransferases to most nucle-
ophilic groups if they can be deprotonated
at
physiological
pH
to
accommodate
O
HO
HO
OH
CO
2
H
O
H
P
O
O
O
P
O
O
O
HO
OH
N
HN
O
O
HO-R
UDPGA
O
HO
HO
OH
CO
2
H
H
OR
P
O
O
O
P
O
O
O
HO
OH
N
HN
O
O
+
O
O
O
Fig. 7
Glucuronidation by glucuronosyl transferases involves
transfer of the glucuronic acid moiety from
uridine-5
0
-diphospho-
α
-D-glucuronic acid (UDPGA) to the
substrate, illustrated here by an alcohol (ROH).
previous page 735 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 737 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off