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The NADPH-dependent microsomal metabolism of [C]procarbazine, labeled on the terminal N-methyl group, resulted in the covalent binding of the drug to exogenously added DNA; this reaction was inhibited by metyrapone. Procarbazine metabolism was also shown to result in covalent binding of the methyl group of the drug to microsomal protein upon metabolism, but the extent of protein binding was at least an order of magnitude smaller than that seen with its primary oxidative metabolite. N-isopropyl-α-(2-methylazo)--toluamide. The characteristics of the reactions leading to the covalent binding of the N-methyl group of the azo derivative to microsomal protein and its metabolism to form the hydrocarbon, methane, possessed a number of similarities in the apparent kinetic parameters ( and ), induction, and inhibition patterns indicating a common pathway of metabolism to form a reactive intermediate and the involvement of cytochrome P-450. Reduced glutathione stimulated methane formation and inhibited covalent binding to protein. One azoxy derivative, N-isopropyl-α-(2-methyl-ONN-azoxy)--toluamide, was chemically unstable and its decomposition was shown to lead to covalent binding to microsomal protein. A diazene intermediate and a methyl radical are proposed to be intermediates in the formation of methane during the oxidative metabolism of the azo derivative of procarbazine and a common intermediate in the activation of procarbazine may result in both covalent binding to cellular macromolecules and methane production. In addition, chemical decomposition of the azoxy metabolites may also contribute to a small portion of the covalent binding, but not to methane formation. [ABSTRACT FROM PUBLISHER]

Utilizing the technique of alkaline elution analysis, the ability of N-nitrosomethyl(2-oxopropyl)amine (MOP), a potent pancreatic carcinogen, to damage pancreatic DNA in rats and hamsters was examined. Pancreatic DNA isolated from hamsters exposed for 1 h to MOP given i.p. at doses of 7–60 mg/kg showed dose-related DNA damage. A similar dose-response was observed in the pancreas of rats receiving 20 — 180 mg MOP/kg, suggesting that hamsters were 2–3 times more sensitive than rats. In contrast to the results obtained , functionally viable acinar cells from both rat and hamster pancreas, when exposed to levels of MOP comparable to those (20–180 μ/ml), failed to show dose-related DNA damage. Acinar cells from hamsters pretreated with 5, 6-benzoflavone, an inducer of cytochrome P-450 activity, showed greatly enhanced drug-metabolizing capability, but again no DNA damage was observed upon exposure to MOP. Minced hamster or rat pancreas also failed to show DNA damage in response to MOP treatment. When hamsters in which hepatic blood supply was interrupted by ligation were given 60 mg/kg MOP i.v. and sacrificed 15 min later, damage to pancreatic and liver DNA was comparable to that observed in ligated controls which had received saline only. Administration of MOP to sham-operated animals led to extensive DNA damage in both pancreas and liver at 15 min. Analysis by h.p.l.c. showed an almost Mold increase in the amount of MOP present in the pancreases of the liver-ligated animals as compared to the sham-operated unligated animals. MOP was absent from the liver of the ligated animals. These experiments strongly suggest that DNA damage by MOP to the pancreatic acinar cells and probably to other pancreatic cell types, as well, requires metabolic activation by the liver. [ABSTRACT FROM PUBLISHER]