Glucuronidation is a major detoxification pathway in vertebrates. The react
ion is catalyzed by a family of UDP-glucuronosyltransferases (UGTs) and inv
olves conjugation of many endobiotic and xenobiotic substances with glucuro
nic acid, forming inactive water-soluble glucuronides. UGT prevents the acc
umulation of potentially toxic compounds and/or their subsequent bioactivat
ion to more toxic intermediates, although biologically active glucuronides
are also known. Impairment of UGTs may have important toxicological consequ
ences. Substances found to inhibit or down-regulate UGT activity include en
dogenous compounds, a wide range of clinically used drugs, environmental co
ntaminants, and natural toxic substances present in the diet. The developme
nt of selective, active-site-directed UGT inhibitors greatly enables the st
udy of various UGT isoenzymes, A promising approach offers the design of tr
ansition-state analogs of the glucuronidation reaction. (C) 2001 Elsevier S
cience Inc. All rights reserved.