Metabolism and mutagenicity of isoprene.
Liver microsomes of various rodents (mouse, rat, rabbit, and hamster) metabolize isoprene (2-methyl-1,3-butadiene) to the corresponding monoepoxides 3,4-epoxy-3-methyl-1-butene and 3,4-epoxy-2-methyl-1-butene. 3,4-Epoxy-3-methyl-1-butene (half-life 85 min) was found to be the main metabolite, although the stable 3,4-epoxy-2-methyl-1-butene was also formed (about 14-25% with respect to the main epoxide). The kinetic constants (Km and Vmax) for the formation of the major epoxide metabolite of isoprene were determined by gas-liquid chromatography. The minor epoxide was further epoxidized to the isoprene dioxide by the microsomes of all rodents studied. The Km and Vmax were determined and phenobarbital was found to be a good inducer for this epoxidation in all species. The mutagenic activity, using Salmonella typhimurium, and the chemical reactivity (alkylating power and half-life) of the epoxide metabolites of isoprene were investigated and compared to those of other structurally related epoxides. Isoprene and the monoepoxide intermediates of the isoprene biotransformation were not mutagenic in Salmonella typhimurium. However, the isoprene dioxide (2-methyl-1,2,3,4-diepoxybutane) was found to be mutagenic and have alkylating power towards nicotinamide, similar to the structurally corresponding 1,2,3,4-diepoxybutane. In conclusion, the metabolism of isoprene does not lead to the formation of mutagenic monoepoxide (in contrast to butadiene) but the formation of mutagenic and presumably carcinogenic isoprene diepoxide is possible, thereby a genotoxic effect of isoprene in rodents or other species cannot be ruled out.
Gervasi
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PG
Istituto di Mutagenesi e Differenziamento C.N.R., Pisa, Italy.
Longo
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V
D000478:Alkylation; D000818:Animals; D001711:Biotransformation; D002070:Butadienes / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D006224:Cricetinae; D045782:Hemiterpenes; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D010420:Pentanes; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
D002070:Butadienes; D045782:Hemiterpenes; D009153:Mutagens; D010420:Pentanes; C005059:isoprene