Metabolism and molecular toxicology of isoprene.
Isoprene (2-methylbuta-1,3-diene) is a large-scale petrochemical used principally in the manufacture of synthetic rubbers. It is also produced by plants and trees and is the major endogenous hydrocarbon formed by mammals, probably from mevalonic acid. Isoprene is metabolised by mammals in processes that involve epoxidation by cytochrome P450-dependent monooxygenases to the isomeric mono-epoxides, (1-methylethenyl)-oxirane and 2-ethenyl-2-methyloxirane. Further metabolism of the mono-epoxides to mutagenic isoprene di-epoxides, (2, 2')-2-methylbioxiranes, can also occur. The oxidations to the mono- and di-epoxides occur enantioselectively and diastereoselectively. The mono-epoxides are hydrolysed enantioselectively to vicinal diols under catalysis by epoxide hydrolase. 2-Ethenyl-2-methyloxirane is also readily hydrolysed non-enzymatically. Because of the stereochemical possibilities for metabolites, the metabolism of isoprene is complex. The metabolism of isoprene by liver microsomes in vitro from a range of species including rat, mouse and human shows significant differences between species, strains and gender in respect of the diastereoselectivity and enantioselectivity of the metabolic oxidation and hydrolysis reactions. The impact of the extra methyl in isoprene on di-epoxide reactivity also appears to be critically important for the resulting biological effects. Isoprene di-epoxides may exhibit a lower cross-linking potential in vivo compared to butadiene di-epoxides. Differences in metabolism and reactivity of metabolites may be factors contributing to the significant differences in toxicological response to isoprene observed between species.
Watson
W P
WP
Syngenta, Alderley Park, Macclesfield SK10 4TJ, UK. william.watson@syngenta.com
Cottrell
L
L
Zhang
D
D
Golding
B T
BT
D000818:Animals; D002070:Butadienes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D005260:Female; D045782:Hemiterpenes; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010420:Pentanes; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism
D002070:Butadienes; D002273:Carcinogens; D004852:Epoxy Compounds; D045782:Hemiterpenes; D010420:Pentanes; C005059:isoprene; C031763:1,3-butadiene