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0090-9556/04/3208-870-875$20.00
DMD 32:870-875, 2004

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SEQUENTIAL METABOLISM OF 2,3,7-TRICHLORODIBENZO-P-DIOXIN (2,3,7-triCDD) BY CYTOCHROME P450 AND UDP-GLUCURONOSYLTRANSFERASE IN HUMAN LIVER MICROSOMES

Noriyuki Kasai, Toshiyuki Sakaki, Raku Shinkyo, Shin-ichi Ikushiro, Takashi Iyanagi, Maya Kamao, Toshio Okano, Miho Ohta, and Kuniyo Inouye

Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kitashirakawa, Oiwake-cho, Sakyoku, Kyoto, Japan (N.K., T.S., R.S., K.I.); Biotechnology Research Center, Faculty of Engineering, Toyama Prefectural University, Kurokawa, Kosugi, Toyama, Japan (T.S.); Department of Life Science, Graduate School of Science, Himeji Institute of Technology, Harima Science Garden City, Hyogo, Japan (S.-i.I.); Department of Hygienic Sciences, Kobe Pharmaceutical University, Kobe, Japan (M.K., T.O.); and Laboratory of Nutrition, Koshien College, Kawarabashi-cho, Nishinomiya, Japan (M.O.)

Metabolism of polychlorinated dibenzo-p-dioxins by cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) was examined using a recombinant enzyme system and human liver microsomes. We analyzed the glucuronidation of 2,3,7-trichlorodibenzo-p-dioxin (2,3,7-triCDD) by rat CYP1A1 expressed in yeast microsomes and human UGT expressed in baculovirus-infected insect cells. Multiple UGT isozymes showed glucuronidation activity toward 8-hydroxy-2,3,7-triCDD (8-OH-2,3,7-triCDD), which was produced by CYP1A1. Of these UGTs, UGT1A1, 1A9, and 2B7, which are constitutively expressed in human livers, showed remarkable activity toward 8-OH-2,3,7-triCDD. The apparent kinetic parameters of glucuronidation, Km and kcat, were estimated to be 0.8 µM and 1.8 min-1, respectively, for UGT1A1, 0.8 µM and 1.8 min-1, respectively, for UGT1A9, and 3.9 µM and 7.0 min-1, respectively, for UGT2B7. In human liver microsomes with NADPH and UDP-glucuronic acid, 2,3,7-triCDD was first converted to 8-OH-2,3,7-triCDD, then further converted to its glucuronide. We compared the ability of 10 human liver microsomes to metabolize 2,3,7-triCDD and observed a significant difference in the glucuronidation of 2,3,7-triCDD that originated from the difference of the P450-dependent hydroxylation of 2,3,7-triCDD.

Address correspondence to: Dr. Toshiyuki Sakaki, Biotechnology Research Center, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Kosugi, Toyama 939-0398, Japan. E-mail: tsakaki{at}pu-toyama.ac.jp




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N. Kasai, T. Sakaki, R. Shinkyo, S.-i. Ikushiro, T. Iyanagi, M. Ohta, and K. Inouye
METABOLISM OF 26,26,26,27,27,27-F6-1{alpha},23S,25-TRIHYDROXYVITAMIN D3 BY HUMAN UDP-GLUCURONOSYLTRANSFERASE 1A3*
Drug Metab. Dispos., January 1, 2005; 33(1): 102 - 107.
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