Studies on the substrate specificity of human intestinal UDP-glucuronosyltransferases 1A8 and 1A10

Although the liver has been considered the most important organ involved in glucuronidation, recent studies have focused on the role of the gastrointe stinal tract in the glucuronidation of xenobiotics and endobiotics. Two UDP -glucuronosyltransferase (UGT) isoforms of human intestinal mucosa, which a re absent in liver, have been identified by reverse transcriptase-polymeras e chain reaction. mRNAs of UGT1A8 and UGT1A10 were detected in both the sma ll intestine and the colon. The corresponding cDNAs for UGT1A8 and UGT1A10 were cloned from ileal RNA and inserted into the mammalian expression vecto r pcDNA3. Transfection of the cDNAs into human embryonic kidney 293 cells w as carried out and stable expression was achieved. Membrane preparations fr om human embryonic kidney 293 cells expressing either UGT1A8 or UGT1A10 wer e isolated and the expression of each isoform was analyzed by Western blot. The catalytic activity of stably expressed UGT1A8 toward catechol estrogen s, coumarins, flavonoids, anthraquinones, and phenolic compounds was much h igher than that of UGT1A10. UGT1A8, but not UGT1A10, catalyzed the glucuron idation of opioids, bile acids, fatty acids, retinoids, and clinically usef ul drugs, such as ciprofibrate, furosemide, and diflunisal. These studies s uggest that human intestinal UGTs may play an important role in the detoxif ication of xenobiotic compounds and, in some cases, limit the bioavailabili ty of therapeutic agents.