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Vol. 27, Issue 10, 1165-1170, October 1999
Department of Pharmacology, The University of Iowa, Iowa City, Iowa
(Z.C., T.R.T.); and Department of Biochemistry and Molecular Biology,
University of Arkansas for Medical Sciences, Little Rock, Arkansas
(A.R.-P.)
Although the liver has been considered the most important organ
involved in glucuronidation, recent studies have focused on the role of
the gastrointestinal tract in the glucuronidation of xenobiotics and
endobiotics. Two UDP-glucuronosyltransferase (UGT) isoforms of human
intestinal mucosa, which are absent in liver, have been identified by
reverse transcriptase-polymerase chain reaction. mRNAs of UGT1A8 and
UGT1A10 were detected in both the small intestine and the colon. The
corresponding cDNAs for UGT1A8 and UGT1A10 were cloned from ileal RNA
and inserted into the mammalian expression vector pcDNA3. Transfection
of the cDNAs into human embryonic kidney 293 cells was carried out and
stable expression was achieved. Membrane preparations from human
embryonic kidney 293 cells expressing either UGT1A8 or UGT1A10 were
isolated and the expression of each isoform was analyzed by Western
blot. The catalytic activity of stably expressed UGT1A8 toward catechol estrogens, coumarins, flavonoids, anthraquinones, and phenolic compounds was much higher than that of UGT1A10. UGT1A8, but not UGT1A10, catalyzed the glucuronidation of opioids, bile acids, fatty
acids, retinoids, and clinically useful drugs, such as ciprofibrate, furosemide, and diflunisal. These studies suggest that human intestinal UGTs may play an important role in the detoxification of xenobiotic compounds and, in some cases, limit the bioavailability of therapeutic agents.
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