Methacrylonitrile (MAN) is structurally similar to the known carcinogen, acrylonitrile (AN), has similar industrial uses, and is used as its replacement. In contrast to AN, minimal information is available on the toxicity, carcinogenicity, and metabolism of MAN. Earlier work in this laboratory demonstrated that, in rats, MAN is primarily eliminated in the expired air as unchanged MAN, acetone, and CO2. Two mercapturic acids were identified in urine of rats and mice treated with MAN. In the present work, the common bile duct of anesthetized rats was cannulated. Animals received a single gavage dose of 58 mg/kg 2-14C-MAN. Bile was collected prior to and following MAN administration. Bile flow and MAN- derived radioactivity were determined at each time point. MAN had minimal effect on bile flow and 4-6% of the administered MAN dose was excreted in the bile within 6 hrs after dosing. HPLC analysis of bile showed two major metabolites which were identified as 1-(S-glutathionyl)-2-propanone and 1-(S-glutathionyl)-2-cyanopropane using NMR spectra and chemical synthesis. The ratio of the two metabolites in MAN-treated rats was approximately 2:1. Pretreatment of rats with sodium phenobarbital (PB) caused minimal quantitative or qualitative changes on the biliary metabolism or excretion of MAN. In contrast, pretreatment of rats with SKF 525-A (SKF) prior to MAN administration resulted in a reversal of the ratio of 1-(S-glutathionyl)-2-propanone to 1-(S-glutathionyl)-2- cyanopropane (1:2).
