INDUCTION OF CYTOCHROME-P450 1A2 BY MUSK ANALOGS AND OTHER INDUCING AGENTS IN RAT-LIVER

We characterized the inducing effects of two musk analogues, musk xyle ne and musk ambrette, on phase I and phase II drug-metabolizing enzyme s in rat liver and compared their effects with 3-methylcholanthrene, i sosafrole and 2(3)-tert-butylhydroxyanisole (BHA) at 0.1 mmol/kg dose level. Musk xylene and isosafrole increased more efficiently the metab olic activation of 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (G lu-P-1) to mutagen than that of benzo(a)pyrene. Musk ambrette increase d both the activation of Glu-P-1 and benzo(a)pyrene to the same extent . Western blot analyses revealed that musk xylene, musk ambrette, isos afrole and BHA induced more strongly cytochrome P450 1A2 (CYP1A2) in m icrosomes than CYP1A1. 3-Methylcholanthrene induced CYP1A1 in preferen ce to CYP1A2. On the other hand, all drugs except for 3-methylcholanth rene did not show remarkable increases in phase II enzyme activities, such as DT-diaphorase, glutathione S-transferase and UDP-glucuronyltra nsferase, at 0.1 mmol/kg dose level. These results show that musk xyle ne, musk ambrette, isosafrole and BHA at the dose level used in this s tudy possess the potency to induce CYP1A2 without remarkable induction of CYP1A1 and phase II enzyme activities as observed for 3-methylchol anthrene, although they have been considered to induce both phase I an d phase II drug-metabolizing enzymes at higher doses.