4-Hydroxyretinoic acid, a novel substrate for human liver microsomal UDP-glucuronosyltransferase(s) and recombinant UGT2B7

It is suggested that formation of more polar metabolites of all-trans-retin oic acid (atRA) via oxidative pathways limits its biological activity. In t his report, we investigated the biotransformation of oxidized products of a tRA via glucuronidation. For this purpose, we synthesized 4-hydroxy-RA (4-O H-RA) in radioactive and nonradioactive form, 4-hydroxy-retinyl acetate (4- OH-RAc), and 5,6-epoxy-RA, all of which are major products of atRA oxidatio n. Glucuronidation of these retinoids by human liver microsomes and human r ecombinant UDP-glucuronosyltransferases (UGTs) was characterized and compar ed with the glucuronidation of atRA. The human liver microsomes glucuronida ted 4-OH-RA and 4-OH-RAc with 6- and 3-fold higher activity than atRA, resp ectively. Analysis of the glucuronidation products showed that the hydroxyl -linked glucuronides of 4-OH-RA and 4-OH-RAc were the major products, as op posed to the formation of the carboxyl-linked glucuronide with atRA, 4-oxo- RA, and 5,6-epoxy-RA. We have also determined that human recombinant UGT2B7 can glucuronidate atRA, 4-OH-RA, and 4-OH-RAc with activities similar to t hose found in human liver microsomes. We therefore postulate that this huma n isoenzyme, which is expressed in human liver, kidney, and intestine, play s a key role in the biological fate of atRA. We also propose that atRA indu ces its own oxidative metabolism via a cytochrome P450 (CYP26) and is furth er biotransformed into glucuronides via UGT-mediated pathways.