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INVOLVEMENT OF HUMAN HEPATIC UGT1A1, UGT2B4, AND UGT2B7 IN THE GLUCURONIDATION OF CARVEDILOL

Project Team for Pharmacogenetics (A.O., Y.S., N.H., H.J., M.S., S.O., J.S.), Division of Environmental Chemistry (A.O., N.H., H.J., M.A.), Division of Pharmacology (S.O.), and Division of Biochemistry and Immunochemistry (Y.S., J.S.), National Institute of Health Sciences, Tokyo, Japan

Carvedilol ((±)-1-carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol) is metabolized primarily into glucuronide conjugates. In the present study, we identified the human UDP-glucuronosyltransferase (UGT) isoforms involved in the glucuronidation of carvedilol by thin-layer chromatography using microsomes from human liver or insect cells expressing recombinant UGT isoforms. We observed two forms of carvedilol glucuronides, namely G1 and G2, in hepatic microsomes. The glucuronidation of carvedilol was catalyzed by at least three recombinant UGT isoforms: UGT1A1, UGT2B4, and UGT2B7. UGT2B4 formed both G1 and G2, whereas UGT1A1 and UGT2B7 were responsible for the formation of glucuronide G2 and G1, respectively. The enzyme kinetics for carvedilol glucuronidation by UGT1A1, UGT2B4, and UGT2B7 in addition to human liver microsomes were examined by Lineweaver-Burk analysis. The values of K_m and V_max for human liver microsomes were 26.6 µM and 106 pmol/min/mg protein for G1, and 46.0 µM and 44.5 pmol/min/mg protein for G2, respectively. The K_m values for UGT1A1, UGT2B4, and UGT2B7 for G1 and G2 (22.1-55.1 µM) were comparable to those of the liver microsomes, whereas the V_max values were in the range of 3.33 to 7.88 pmol/min/mg protein. The K_m and V_max/K_m values for UGT2B4 and UGT2B7 for G1 were similar, whereas UGT2B4 had lower Km and higher V_max/K_m values for G2 compared with those of UGT1A1. These results suggest that G1 formation is catalyzed by UGT2B4 and UGT2B7, whereas G2 is formed by UGT2B4 and UGT1A1. These three hepatic UGT isoforms may have important roles in carvedilol metabolism.

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