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Vol. 26, Issue 9, 860-867, September 1998
Department of Pharmacology, The University of
Iowa
Conjugation of many primary, secondary, and tertiary
amine-containing xenobiotics with glucuronic acid can result in the
formation of N-glucuronide metabolites. For carcinogenic
arylamines and their N-hydroxylated metabolites,
N-glucuronidation can result in the formation of either
inactive metabolites or labile conjugates, which can be transported to
their target tissue (urinary bladder) where they may be converted to
reactive metabolites. Drugs with primary amine (e.g.
dapsone) or secondary amine moieties (e.g. sulfadimethoxine
and clozapine) can also be metabolized to N-glucuronides. The metabolism of a number of tertiary amine-containing
pharmacological agents to quaternary ammonium-linked glucuronides
represents a unique and important metabolic pathway for these compounds
that is highly species-dependent. This review summarizes our present knowledge of the uridine diphosphate (UDP)-glucuronosyltransferase enzymes involved in catalyzing N-glucuronide formation. Of
the more than 30 UDP-glucuronosyltransferases that have been purified or cloned and expressed, many catalyze N-glucuronide
formation for primary and secondary amine substrates. In contrast, only human UDP-glucuronosyltransferases 1A3 and 1A4 have been shown to
catalyze quaternary ammonium-linked glucuronide formation for aliphatic tertiary amines. The structure of the UGT1 gene
complex is highly conserved across species, and it appears that a
mutation in the first exon encoding UDP-glucuronosyltransferase 1A4,
resulting in a pseudo-gene, may explain the inability of some species
to form quaternary ammonium-linked glucuronides.
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