UDP-glucuronosyltransferases (UGTs) represent major Phase II enzymes involved in detoxification of endo- and xenobiotics, including many drugs. The intraluminal orientation of the active site of UGTs in endoplasmic reticulum membranes necessitates a number of transporters in these membranes, for example, for UDP-glucuronic acid and glucuronides, the latter being insufficiently characterized. In addition, accumulating evidence suggests that UGTs are functional as homo- and heterodimers in monoglucuronide formation. They may form tetramers in diglucuronide formation. UGT oligomers probably serve to stabilize UGT monomers and fine-tune UGT activity. Glucuronide disposition may also be influenced by endoplasmic reticulum-localized beta-glucuronidase, possibly involved in hydrolysis of hormone and drug glucuronides in target cells. The present commentary reviews recent advances and addresses open questions. Resolution of these questions may help to understand many problems of glucuronide synthesis and disposition in vivo, for example, under-prediction of the in vivo clearance of drugs mostly eliminated by glucuronidation by in vitro enzyme kinetic parameters of UGTs.
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