Differences in butadiene adduct formation between rats and mice not due to selective inhibition of CYP2E1 by butadiene metabolites

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• 作者：Kaila M. Pianalto ; Jessica H. Hartman ; Gunnar Boysen ; Grover P. Miller
• 关键词：CYP2E1 ; Butadiene ; Cooperativity ; Inactivation ; Mouse ; Rat
• 刊名：Toxicology Letters
• 出版年：25 November, 2013
• 年：2013
• 卷：223
• 期：2
• 页码：221-227
• 全文大小：1149 K

文摘

CYP2E1 metabolizes 1,3-butadiene (BD) into genotoxic and possibly carcinogenic 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 1,2-epoxy-3,4-butanediol (EB-diol). The dose response of DNA and protein adducts derived from BD metabolites increases linearly at low BD exposures and then saturates at higher exposures in rats, but not mice. It was hypothesized that differences in adduct formation between rodents reflect more efficient BD oxidation in mice than rats. Herein, we assessed whether BD-derived metabolites selectively inhibit rat but not mouse CYP2E1 activity using B6C3F1 mouse and Fisher 344 rat liver microsomes. Basal CYP2E1 activities toward 4-nitrophenol were similar between rodents. Through IC₅₀ studies, EB was the strongest inhibitor (IC₅₀ 54 渭M, mouse; 98 渭M, rat), BD-diol considerably weaker (IC₅₀ 1200 渭M, mouse; 1000 渭M, rat), and DEB inhibition nonexistent (IC₅₀ > 25 mM). Kinetic studies showed that in both species EB and BD-diol inhibited 4-nitrophenol oxidation through two-site mechanisms in which inhibition constants reflected trends observed in IC₅₀ studies. None of the reactive epoxide metabolites inactivated CYP2E1 irreversibly. Thus, there was no selective inhibition or inactivation of rat CYP2E1 by BD metabolites relative to mouse Cyp2e1, and it can be inferred that CYP2E1 activity toward BD between rodent species would similarly not be impacted by the presence of BD metabolites. Inhibition of CYP2E1 by BD metabolites is then not responsible for the reported species difference in BD metabolism, formation of BD-derived DNA and protein adducts, mutagenicity and tumorigenesis.