TY - JOUR T1 - Metabolism-dependent covalent binding of (S)-[5-3H]nicotine to liver and lung microsomal macromolecules. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 397 LP - 402 VL - 16 IS - 3 AU - M K Shigenaga AU - A J Trevor AU - N Castagnoli, Jr Y1 - 1988/05/01 UR - http://dmd.aspetjournals.org/content/16/3/397.abstract N2 - Incubation of (S)-[5-3H]nicotine with rabbit liver microsomes in the presence of dioxygen and NADPH results in the formation of metabolites that bind covalently to microsomal macromolecules (250-550 pmol/mg of protein/hr). The partition ratio [(S)-nicotine metabolized/(S)-nicotine equivalents covalently bound] ranged between 250:1 and 500:1. The addition of SKF 525-A, cytochrome c, or n-octylamine inhibited both (S)-nicotine metabolism and covalent binding whereas phenobarbital pretreatment increased the rates of metabolism and covalent binding. Sodium cyanide, which forms stable adducts with the cytochrome P-450-generated iminium ion metabolites of (S)-nicotine and a variety of other tertiary amines, inhibited covalent binding but also decreased the rate of (S)-nicotine metabolism. The metabolism-dependent covalent binding of (S)-nicotine and its conversion to the delta 1',5'-iminium species were observed also in microsomal incubations prepared from rabbit lung and human liver tissues. ER -