title: Inhibitory potency of 4-carbon alkanes and alkenes toward CYP2E1 activity.
abstract: CYP2E1 has been implicated in the bioactivation of many small molecules into reactive metabolites which form adducts with proteins and DNA, and thus a better understanding of the molecular determinants of its selectivity are critical for accurate toxicological predictions. In this study, we determined the potency of inhibition of human CYP2E1 for various 4-carbon alkanes, alkenes and alcohols. In addition, known CYP2E1 substrates and inhibitors including 4-methylpyrazole, aniline, and dimethylnitrosamine were included to determine their relative potencies. Of the 1,3-butadiene-derived metabolites studied, 3,4-epoxy-1-butene was the strongest inhibitor with an IC50 of 110 μM compared to 1700 μM and 6600 μM for 1,2-butenediol and 1,2:3,4-diepoxybutane, respectively. Compared to known inhibitors, inhibitory potency of 3,4-epoxy-1-butene is between 4-methylpyrazole (IC50 = 1.8 μM) and dimethylnitrosamine (IC50 = 230 μM). All three butadiene metabolites inhibit CYP2E1 activity through a simple competitive mechanism. Among the 4-carbon compounds studied, the presence and location of polar groups seems to influence inhibitory potency. To further examine this notion, the investigation was extended to include structurally and chemically similar analogues, including propylene oxide and various butane alcohols. Those results demonstrated preferential recognition of CYP2E1 toward the type and location of polar and hydrophobic structural elements. Taken together, CYP2E1 metabolism may be modified in vivo by exposure to 4-carbon compounds, such as drugs, and nutritional constituents, a finding that highlights the complexity of exposure to mixtures.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Hartman
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
authors.forename: Grover P
authors.initials: GP
authors.lastname: Miller
authors.affiliation: Department of Environmental and Occupational Health, College of Public Health, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 820. Little Rock, AR 72205, Unites States; The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States. Electronic address: gboysen@uams.edu.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Boysen
mesh_terms: D000473:Alkanes / Q000633:toxicity*; D002070:Butadienes / Q000633:toxicity*; D045424:Complex Mixtures / Q000633:toxicity; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects* / Q000378:metabolism*; D004785:Environmental Pollutants / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004852:Epoxy Compounds / Q000633:toxicity; D015386:Hazardous Substances / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000473:Alkanes; D002070:Butadienes; D045424:Complex Mixtures; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D015386:Hazardous Substances; C024370:3,4-epoxy-1-butene; D019392:Cytochrome P-450 CYP2E1
keywords: Butadiene; CYP2E1; Cytochrome P450; Epoxide