Metabolism of some methyl 2-cyano-3-phenyl-acrylates (methyl alpha-cyanocinnamates) in rats.

1. The metabolism of 2-cyano-3-phenylacrylic acid (CPA) and some methyl 2-cyano-3-phenylacrylates (methyl alpha-cyanocinnamates) after i.p. administration to rats, was investigated. 2. The conjugation of CPA and methyl alpha-cyanocinnamates with L-cysteine, N-acetylcysteine and glutathione (GSH) in vitro was studied and the rate of hydrolysis of the double bond of the methyl alpha-cyanocinnamates determined. 3. CPA and the methyl alpha-cyanocinnamates caused a significant increase in urinary (24 h) thioether excretion, with no increase in SCN- excretion. 4. No thioethers, such as possible addition products of N-acetylcysteine with CPA or methyl alpha-cyanocinnamates, were isolated; such thioether compounds appeared to be very unstable. 5. Administration of the carboxylesterase inhibitor, tri-ortho tolyl phosphate, to rats resulted in increased urinary excretion of SCN- but no significant excretion of thioethers, after a single i.p. injection of methyl alpha-cyanocinnamates. 6. Following incubation of methyl alpha-cyanocinnamates with GSH under non-enzymic and enzymic conditions, the GSH was 100% recovered. However, incubation of CPA depleted GSH and N-acetylcysteine (non-enzymic). 7. A metabolic pathway for the metabolism of methyl alpha-cyanocinnamates to thioether adducts is proposed, which proceeds via the corresponding CPA. Ester hydrolysis and the carbon-carbon double bond hydrolysis are probably in vivo reactions of some importance.