Glutathione conjugation and bacterial mutagenicity of racemic and enantiomerically pure cis- and trans-methyl epoxycinnamates.
This paper describes the ability of racemic, and enantiomerically pure cis- and trans-methyl epoxycinnamates (methyl 3-phenyl-2,3-epoxy-propanoates) to undergo glutathione conjugation and subsequent excretion as mercapturic acid and on the mutagenicities of these epoxy esters in the Ames assay. In incubation mixtures containing rat liver cytosol (9,000 g), the decrease of glutathione due to the epoxy esters occurred enzymatically. The highest glutathione depletion was found for the cis-epoxy cinnamic esters. Adult male rats administered a single i.p. dose of racemic trans- and cis-epoxy cinnamates (0.7 mmol/kg, n = 4) excreted thioethers in urine. Higher urinary thioether excretion was found after the cis-epoxy ester dosing. The structures of the thioether metabolites isolated from the urinary extracts were identified by TLC and confirmed by synthesis and mass spectrometry (FAB+). The thioethers appeared to be hydroxy mercapturic acids. The N-alkylating potential of the racemic epoxy esters was determined using 4-(p-nitrobenzyl)pyridine (= NBP). The trans-epoxy ester appeared to react much better with NBP than the cis-compound. Mutagenic effects of racemic trans-epoxy cinnamate as well as the enantiomerically pure trans-epoxy cinnamates were observed in the Ames test with S. typhimurium strains TA1535, TA1537, TA1538 and TA100 without metabolic activation. No mutagenic responses were detected using any of the epoxy cinnamates with S9 activation. By comparing the mutagenicity and the enzymatically catalyzed glutathione conjugation it follows that the activity of the respective enantiomeric methyl cinnamates goes in the opposite order. Glutathione conjugation plays a protective role in the detoxication in living organism of the potentially toxic methyl epoxy cinnamates.
Rietveld
E C
EC
Department of Pharmacology, University of Nijmegen, The Netherlands.
van Gastel
F J
FJ
Seutter-Berlage
F
F
Zwanenburg
B
B
D000111:Acetylcysteine / Q000302:isolation & purification; D000478:Alkylation; D000818:Animals; D001711:Biotransformation; D002849:Chromatography, Gas; D002855:Chromatography, Thin Layer; D002934:Cinnamates / Q000378:metabolism* / Q000633:toxicity / Q000652:urine; D004852:Epoxy Compounds / Q000378:metabolism* / Q000633:toxicity / Q000652:urine; D004988:Ethers, Cyclic / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D009152:Mutagenicity Tests; D009153:Mutagens; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D002934:Cinnamates; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D009153:Mutagens; C056586:methyl 3-phenyl-2,3-epoxypropanoate; D005978:Glutathione; D000111:Acetylcysteine