1,3-Dichloropropene epoxides: intermediates in bioactivation of the promutagen 1,3-dichloropropene.
1,3-Dichloropropene (1,3-D), a major soil fumigant nematicide, is genotoxic in many types of assays, leading to its classification as possibly carcinogenic in humans. This study tests in three steps the hypothesis that 1,3-D is a promutagen activated by epoxidation and further reaction of the 1,3-D-epoxides. Stereospecific epoxidation of 1,3-D (examined as the cis/trans mixture and as individual isomers) to the corresponding cis- and trans-1,3-D-epoxides is demonstrated here for the first time, both in vitro in a mouse liver microsome-NADPH system and in vivo in the liver of ip-treated mice, using GC/MS for product identification and quantitation. The cis epoxide is observed in higher yield than the trans epoxide, both in vitro and in vivo, and the cis isomer also reacts slower than the trans isomer with GSH alone or catalyzed by GSH S-transferase. cis- and trans-1,3-D-Epoxides are stable in acetone or chloroform but degrade completely in Me2SO exclusively to 2-chloroacrolein (30 min at 40 degrees C). Epoxide decomposition is slower in pH 7.4 phosphate buffer (t1/2 = 116 and 64 min for cis and trans, respectively, at 41 degrees C) with a >99% yield of 3-chloro-2-hydroxypropanal (and its dimer) and <0.5% formation of 2-chloroacrolein (for which the t1/2 is 248 min at 41 degrees C). Mutagenicity assays in Salmonella typhimurium TA100 (standard plate incorporation) establish high potencies of 37, 17, and 150 revertants/nmol for cis- and trans-1, 3-D-epoxides and 2-chloroacrolein, respectively. The mutagenicity of the epoxides is due either to their direct action or to a degradation product formed at physiological pH, i.e., 3-chloro-2-hydroxypropanal or its dehydrochlorination products. The candidate mutagens methylglyoxal and glycidaldehyde are not detected as breakdown products of 3-chloro-2-hydroxypropanal at pH 7.4 and also have low mutagenic activity in TA100. It is therefore proposed that the penultimate and ultimate mutagens of 1,3-D metabolism are the corresponding epoxides and their direct hydrolysis product 3-chloro-2-hydroxypropanal, respectively.
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
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Schneider
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Quistad
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Casida
D000498:Allyl Compounds / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism*; D006843:Hydrocarbons, Chlorinated; D006863:Hydrogen-Ion Concentration; D007306:Insecticides / Q000378:metabolism*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism*
D000498:Allyl Compounds; D004852:Epoxy Compounds; D006843:Hydrocarbons, Chlorinated; D007306:Insecticides; D009153:Mutagens; C023891:1,3-dichloro-1-propene; D004851:Epoxide Hydrolases