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.
Rietveld
E C
EC
Department of Pharmacology, University of Nÿmegen, The Netherlands.
Engels
W J
WJ
Smit
R
R
Seutter-Berlage
F
F
D000179:Acrylates / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002934:Cinnamates / Q000378:metabolism* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D008689:Methacrylates / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000179:Acrylates; D002934:Cinnamates; D008689:Methacrylates; D013438:Sulfhydryl Compounds