Mutagenicity of chloroolefins in the Salmonella/mammalian microsome test--II. Structural requirements for the metabolic activation of non-allylic chloropropenes and methylated derivatives via epoxide formation.
Non-allylic chloropropenes and their methyl-homologues, being chloro-substituted exclusively in vinylic position, are mutagenic in the presence of metabolizing rat liver homogenate fraction (S9 mix). This can be interpreted as the result of polarizing inductive (I-) and mesomeric (M-) effects exerted by Cl- as well as by CH3-substituents on the olefinic double bond. The extent of their mutagenic activity increases with longer preincubation time and/or a higher concentration of rat liver homogenate fraction (S9) in the S9 mix. The only exception from this rule of a qualitative correlation of C = C-bond polarization due to asymmetric substitution and mutagenic activity is 1-chloro-2-methyl-1-propene which is non-mutagenic. In this case effects of a steric hindrance of two voluminous CH3-substituents attached to one C-atom of the C = C-bond might inhibit enzymatic attack of the double bond by microsomal oxygenase. Mutagenic activity is invariably decreased in the presence of SKF525, inhibitor of microsomal oxygenase, and increased when 1,1,1-trichloropropene-2,3-oxide (TCPO), inhibitor of epoxide hydrolase, is added to the test system. This is a strong argument for metabolic activation of these substances occurring via epoxide formation.
D000475:Alkenes / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D006846:Hydrocarbons, Halogenated / Q000378:metabolism / Q000633:toxicity*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009154:Mutation / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship
D000475:Alkenes; D006846:Hydrocarbons, Halogenated