Chemistry Reference
In-Depth Information
Box 12.7
Glucuronides in drug metabolism
One of the principal ways by which foreign compounds are removed from the body is to conjugate them to
glucuronic acid
. This conjugation process not only binds the unwanted compound, but also converts it into a
highly polar material that is water soluble and can be excreted in aqueous solution, typically via the kidneys. The
polarity is provided both by the hydroxyl groups and by the ionizable carboxylic acid group. Typical chemicals
that may become conjugated with glucuronic acid include alcohols, phenols, carboxylic acids, amines, and thiols.
Drugs must also be considered as foreign compounds, and an essential part of drug treatment is to understand
how they are removed from the body after their work is completed. Glucuronide formation is the most important
of so-called phase II metabolism reactions. Aspirin, paracetamol, morphine, and chloramphenicol are examples
of drugs excreted as glucuronides.
Glucuronides
are formed in mammals by reaction with uridine diphosphoglucuronic acid (UDPglucuronic acid;
UDP-GA) in processes catalysed by uridine diphosphoglucuronyltransferase enzymes. This reaction is entirely
analogous to the enzymic glycosylation process we looked at above (see Box 12.4). The reaction with UDP-GA
can be envisaged as a simple S
N
2 nucleophilic displacement reaction, with an appropriate nucleophile, e.g. an
alcohol or amine, and a phosphate derivative as the leaving group. UDP glucuronyltransferase enzymes have very
broad substrate specificity, and can catalyse reactions with a wide variety of foreign molecules and drugs.
S
N
2 reaction
ROH
OH
HO
2
C
O
O
O
O
HO
HO
HO
HO
H
H
HN
HN
NAD
+
O
O
O
O
HO
HO
P
P
O
P
O
P
O
N
O
N
O
O
CH
2
O
O
CH
2
enzymic oxidation of
primary alcohol group
O
O
OH
OH
OH
OH
HO
OH
HO
OH
UDPglucose
UDPglucuronic acid
UDP-GA
CO
2
H
O
HO
HO
OR
UDP
HO
H
O
-β-
D
-glucuronide
UDP-GA is formed from UDPglucose (see Box 12.4) by enzymic oxidation of the primary alcohol group.
We have already noted in Section 12.6 that UDPglucose is also the biochemical precursor of glucose-containing
polysaccharides, e.g. starch and glycogen (see Section 12.7).
The opium alkaloid
morphine
is one of the most valuable analgesics for relief of severe pain. It is known to be
metabolized in the body to
O
-glucuronides, by reaction at the phenolic and alcoholic hydroxyls. The glucuronides
formed are water soluble and readily excreted. An interesting feature is that the two monoglucuronides have
significantly different pharmacological activities. Although morphine 3-
O
-glucuronide is antagonistic to the
analgesic effects of morphine, morphine 6-
O
-glucuronide is actually a more effective and longer lasting analgesic
than morphine itself, and with fewer side-effects.
