The Human UGT1A3 Enzyme Conjugates Norursodeoxycholic Acid into a C23-ester Glucuronide in the Liver
2010
Norursodeoxycholic acid (norUDCA) exhibits efficient anti-cholestatic properties in an animal model of sclerosing cholangitis. norUDCA is eliminated as a C23-ester
glucuronide(norUDCA-23G) in humans. The present study aimed at identifying the human UDP-
glucuronosyltransferase(UGT) enzyme(s) involved in hepatic norUDCA
glucuronidationand at evaluating the consequences of single nucleotide polymorphisms in the coding region of UGT genes on norUDCA-23G formation. The effects of norUDCA on the formation of the cholestatic
lithocholic acid-
glucuronidederivative and of
rifampicinon hepatic norUDCA
glucuronidationwere also explored. In vitro
glucuronidationassays were performed with microsomes from human tissues (liver and intestine) and HEK293 cells expressing human UGT enzymes and variant allozymes. UGT1A3 was identified as the major hepatic UGT enzyme catalyzing the formation of norUDCA-23G. Correlation studies using samples from a human liver bank (n = 16) indicated that the level of UGT1A3 protein is a strong determinant of in vitro norUDCA
glucuronidation. Analyses of the norUDCA-conjugating activity by 11 UGT1A3 variant allozymes identified three phenotypes with high, low, and intermediate capacity. norUDCA is also identified as a competitive inhibitor for the hepatic formation of the pro-cholestatic
lithocholic acid-
glucuronidederivative, whereas norUDCA
glucuronidationis weakly stimulated by
rifampicin. This study identifies human UGT1A3 as the major enzyme for the hepatic norUDCA
glucuronidationand supports that some coding polymorphisms affecting the conjugating activity of UGT1A3 in vitro may alter the pharmacokinetic properties of norUDCA in
cholestasistreatment.
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