Metabolism and molecular toxicology of isoprene

Isoprene (2-methylbuta-1,3-diene) is a large-scale petrochemical used princ ipally in the manufacture of synthetic rubbers. It is also produced by plan ts and trees and is the major endogenous hydrocarbon formed by mammals., pr obably from mevalonic acid. Isoprene is metabolised by mammals in processes that involve epoxidation by cytochrome P450-dependent monooxygenases to th e isomeric mono-epoxides, (1-methylethenyl)-oxirane and 2-ethenyl-2-methylo xirane. Further metabolism of the mono-epoxides to mutagenic isoprene di-ep oxides, (2, 2')-2-methylbioxiranes, can also occur. The oxidations to the m ono- and di-epoxides occur enantioselectively and diastereoselectively. The mono-epoxides are hydrolysed enantioselectively to vicinal diols under cat alysis by epoxide hydrolase. 2-Ethenyl-2-methyloxirane is also readily hydr olysed non-enzymatically. Because of the stereochemical possibilities for m etabolites, the metabolism of isoprene is complex. The metabolism of isopre ne by liver microsomes in vitro from a range of species including rat, mous e and human shows significant differences between species, strains and gend er in respect of the diastereoselectivity and enantioselectivity of the met abolic oxidation and hydrolysis reactions. The impact of the extra methyl i n isoprene on di-epoxide reactivity also appears to be critically important for the resulting biological effects. Isoprene di-epoxides may exhibit a l ower cross-linking potential in vivo compared to butadiene di-epoxides. Dif ferences in metabolism and reactivity of metabolites may be factors contrib uting to the significant differences in toxicological response to isoprene observed between species. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.