Glutathione conjugation and bacterial mutagenicity of racemic and enantiomerically pure cis-and trans-methyl epoxycinnamates

Abstract

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.

Anti-mutagenicity Effects of Vitamin E on Oncology and Non-oncology Hospital Nurses by Ames Assay

“…Several prior studies indicate that drugs congaing thiol group decrease the activity of mutagenic compounds in urine [23,24], so our results are in line with these studies and we tried to confirming of anti-mutagenic effect of oral Vitamin E on study population. The purpose of our study was to evaluate the anti-mutagenic effect of Vitamin E on possible mutagenic risk associated with antinoeplastic drugs.…”

Flavouring Group Evaluation 82 (FGE.82) - Consideration of Epoxides evaluated by JECFA (65th meeting) - Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (AFC)

“…With metabolic activation, no significant increases in mutagenic activity were observed in any of the tester strains. When the individual diastereomers of cis-(V and VI; see Figure 1) and trans-methyl epoxycinnamate (III and VI; see Figure 1) were incubated at 1,500 or 3,000 µg/plate with S. typhimurium TA100 in the absence of metabolic activation, the trans isomers showed the greatest mutagenicity, compound IV being the most active (IV < III < VI < V) (Rietveld et al, 1988). The authors correlated these results with the increased N-alkylating potential of trans isomers discussed above.…”

Scientific Opinion on Flavouring Group Evaluation 82, Revision 1 (FGE.82Rev1): Consideration of Epoxides evaluated by the JECFA (65th meeting)

“…With metabolic activation, no significant increases in mutagenic activity were observed in any of the tester strains. When the individual diastereomers of cis-(V and VI; see Figure 1) and transmethyl epoxycinnamate (III and VI; see Figure 1) were incubated at 1,500 or 3,000 µg/plate with S. typhimurium TA100 in the absence of metabolic activation, the trans isomers showed the greatest mutagenicity, compound IV being the most active (IV < III < VI < V) (Rietveld et al, 1988). The authors correlated these results with the increased N-alkylating potential of trans isomers discussed above.…”

“…Although aberrations also occurred in the presence of S9, the results were considered equivocal owing to the lack of statistical significance in the Dunnett test (Galloway et al, 1987). (Rietveld et al, 1988)) In order to assess further the potential mutagenicity and genotoxicity of the epoxides, the results of a number of assays performed with structurally related glycidic and cycloaliphatic epoxide compounds were reviewed. The structurally related glycidic ester, racemic cis-methyl epoxycinnamate (II; see Figure 1) at ≤ 15,000 µg/plate was not mutagenic to S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 with or without metabolic activation in the plate incorporation test.…”