Glucuronidation represents the major route of sugar conjugation, although conjugation with xylulose and ribose are also possible. Quantitatively, glucuronide formation is the most important form of conjugation both for drugs and endogenous compounds and can occur with very different substrates. The synthesis of ether, ester, carboxyl, carbamoyl, carbonyl, and sulphuryl and nitrogenyl glucuronides generally leads to an increase in their polarity, and consequently their aqueous solubility and thus suitability for excretion. Mechanistically, glucuronidation is an SN2 reaction in which an acceptor nucleophilic group on the substrate attacks an electrophilic C-1 atom of the pyranose acid ring of UDPGA (uridine 5 -diphosphateglucuronic acid) which results in the formation of a glucuronide, a È•-Dglucopyranosiduronic acid conjugate. Thus, many electrophilic groups such as hydroxyl, carboxyl, sulphhydryl (thiol), or phenol can serve as acceptors. N-glucuronides may be formed by certain nitrogen containing groups such those in tertiary or aromatic amines.

Esterification of the hemiacetyl hydroxyl group of glucuronic acid to organic acids forms acyl or ester glucuronides. The acyl glucuronides, unlike glucuronides formed with alcohols and phenols, have a great susceptibility to nucleophilic substitution and intramolecular rearrangement. It has even been proposed that the formed acyl glucuronides, acting as electrophiles and reacting with thiol and hydroxyl groups of cell macromolecules, might be responsible for toxicity of some compounds. Renewed interest in this process from pharmaceutical companies has focused on development of drugs that avoid glucuronidation as a biotransformation pathway, thereby improving bioavailability. Glucuronidation is conjugation with D-glucuronic acid and is indeed the most widespread of the conjugation reactions, probably due to the relative abundance of the cofactor for the reaction, UDP-glucuronic acid.

The transfer of glucuronic acid from UDP- glucuronic acid (UDPGA) to an aglycone is catalysed by a family of enzymes generally designated as UDPglucuronosyltransferases (UGTs). These ubiquitous microsomal enzymes are present principally in the liver, but also occur in a variety of extrahepatic tissues. Their location in the endoplasmic reticulum has important physiological effects in the neutralization of reactive intermediates generated by the CYTP450 enzyme system and in controlling the levels of reactive metabolites present in these tissues. There are 50 known microsomal membrane-bound is enzymes in humans, found in liver, lung, skin, intestine, brain and olfactory epithelium; however, the major site of glucuronidation is the liver. Thus the liver, being the central organ for a variety of anabolic and catabolic functions, plays a significant role in drug metabolism, toxicity and especially in detoxication processes. Structural and functional aspects of human UDPglucuronosyltransferases have been reviewed with details of the mechanisms of glucuronidation of both drugs and endogenous compounds. Characterization of the active site in terms of amino acids and peptide domains that bind substrates and effectors in such reactions is also discussed. Genetic differences in the expression of UDPglucuronosyltransferases in humans result in interindividual variations. This topic has also been reviewed recently. Characterization of genetic multiplicity and regulatory patterns of UGTs is being aided by new developments in the field of genetics.

Best Regards,
Nancy Ella
Associate Managing Editor
Drug Designing: Open Access