TY - JOUR T1 - SEQUENTIAL METABOLISM OF 2,3,7-TRICHLORODIBENZO-<em>P</em>-DIOXIN (2,3,7-triCDD) BY CYTOCHROME P450 AND UDP-GLUCURONOSYLTRANSFERASE IN HUMAN LIVER MICROSOMES JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 870 LP - 875 DO - 10.1124/dmd.32.8.870 VL - 32 IS - 8 AU - Noriyuki Kasai AU - Toshiyuki Sakaki AU - Raku Shinkyo AU - Shin-ichi Ikushiro AU - Takashi Iyanagi AU - Maya Kamao AU - Toshio Okano AU - Miho Ohta AU - Kuniyo Inouye Y1 - 2004/08/01 UR - http://dmd.aspetjournals.org/content/32/8/870.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -