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 analogs, 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.

Crystal Structure of a Putative Cytochrome P450 Alkane Hydroxylase (CYP153D17) from Sphingomonas sp. PAMC 26605 and Its Conformational Substrate Binding

“…The CYP2E, CYP4B, CYP52, CYP86, and CYP153 families are known to hydroxylate n-alkanes or fatty acids in both eukaryotes and prokaryotes [6,7,8,9,10]. Among them, CYP2E, CYP4B, CYP52, and CYP86 are eukaryotic CYPs; these enzymes are membrane-bound proteins, limiting their structural characterization and making it difficult to use them in engineered pathways.…”

1,3-Butadiene-induced mitochondrial dysfunction is correlated with mitochondrial CYP2E1 activity in Collaborative Cross mice

“…In this case, butadiene exposure may downregulate erCYP2E1 expression at the transcription or translational level leading to the observed lowered activities. Alternatively, the reactive metabolites might directly affect enzyme activity through inhibition as reported previously(Hartman et al 2014) or covalent binding to CYP2E1 at sites potentially important for enzyme activity(Boysen et al 2007b). …”

The genetic consequences of paternal acrylamide exposure and potential for amelioration

“…Resveratrol does demonstrate the potential for combatting acrylamide induced DNA damage via Cyp2e1 inhibition. A number of other CYP2E1 inhibitors have been identified using the human enzyme and these warrant further investigation (and potential modification) to assess their ability to inhibit the effects of acrylamide [100][101][102]. Future clinical application of natural or modified CYP2E1 inhibitors may be of benefit to those males ingesting acrylamide while attempting fertilisation.…”