HYDROXYLATION AND DEALKYLATION OF METHYL-N-BUTYLNITROSAMINE AND ROLE OF CERTAIN CYTOCHROME-P-450 ISOZYMES IN THESE REACTIONS

We studied the metabolism of methyl-n-butylnitrosamine (MBN), a carcinogen for the rat esophagus and liver. The 2-, 3- and 4-hydroxy derivatives were identified as new metabolites of MBN. In studies on tissue slices freshly removed from MRC-Wistar rats, MBN metabolism resembled that of the previously studied methylamylnitrosamine in the esophagus catalyzed 2- and 3- hydroxylation; liver, omega-1 hydroxylation; and lung, omega-hydroxylation of both nitrosamines. Liver microsomes from Sprague-Dawley rats catalyzed 2-, 3- and 4-hydroxylation of MBN, as well as the previously studied activating reactions of demethylation and debutylation. Phenobarbital induced all five reactions of MBN by rat liver microsomes, especially debutylation; 3-methylholanthrene induced 3-hydroxylation and debutylation and isoniazid induced demethylation and debutylation. Monoclonal antibodies that inhibit specific cytochrome P-450 isozymes were used to identify the isozymes involved in each reaction. Antibody 4-7-1 appeared more specific than the previously used antibody 2-66-3 for inhibiting P-450 2B1 and/or 2B2. For the metabolism of both MBN and methylamylnitrosamine by rat liver microsomes, the antibody results indicated that P-450 2C11 mainly catalyzed demethylation and omega-1 hydroxylation, P-450 1A1 or 1A2 catalyzed 3-hydroxylation and debutylation or depentylation, P-450 2E1 produced demethylation and P-450 2B1 or 2B2 produced omega-1 hydroxylation, demethylation and debutylation or depentylation.