Biochemistry of 1,3-butadiene metabolism and its relevance to 1,3-butadiene-induced carcinogenicity.
Recently, the roles of specific P450 isoforms, myeloperoxidase (MPO), GSH-S-transferase and epoxide hydrolase in the metabolism of 1,3-butadiene, and its major oxidative metabolite, butadiene monoxide (BM), were investigated. The results provided evidence for P450s 2A6 and 2E1 being major catalysts of 1,3-butadiene oxidation in human liver microsomes. cDNA-expressed human P450s 2E1, 2A6, and 2C9 catalyzed BM oxidation to meso- and (+/-)-diepoxybutane (DEB), but the rates of BM oxidation in mouse, rat, or human liver microsomes were much lower than the rates of 1,3-butadiene oxidation in these tissues. Human MPO catalyzed 1,3-butadiene oxidation to BM, but MPO incubations with BM did not yield DEB. Rates of BM formation in mouse and human liver microsomes were similar and were nearly 3.4-fold higher than that obtained with rat liver microsomes. However, rat liver epoxide hydrolase activity was nearly 2-fold higher than that of mouse liver microsomes. Rat and mouse liver GSH-S-transferases exhibited similar BM conjugation kinetics, but rats excreted more BM-mercapturic acids compared to mice given low equimolar doses of BM. BM reacted with guanosine and adenosine to yield N7-, N2-, and N1-guanosinyl and N6-adenosinyl adducts, respectively. These results may contribute to a better understanding of the biochemical basis of 1,3-butadiene-induced carcinogenicity.
Elfarra
A A
AA
Department of Comparative Biosciences, University of Wisconsin, Madison 53706-1102, USA.
Krause
R J
RJ
Selzer
R R
RR
D000818:Animals; D002070:Butadienes / Q000378:metabolism* / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009705:Nucleosides / Q000378:metabolism; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002070:Butadienes; D002273:Carcinogens; D004852:Epoxy Compounds; D009705:Nucleosides; C024370:3,4-epoxy-1-butene; D009195:Peroxidase; D005978:Glutathione; C031763:1,3-butadiene