CYP2E1 hydroxylation of aniline involves negative cooperativity

Biochemical Pharmacology
Jessica H HartmanGrover P Miller

Abstract

CYP2E1 plays a role in the metabolic activation and elimination of aniline, yet there are conflicting reports on its mechanism of action, and hence relevance, in aniline metabolism. Based on our work with similar compounds, we hypothesized that aniline binds two CYP2E1 sites during metabolism resulting in cooperative reaction kinetics and tested this hypothesis through rigorous in vitro studies. The kinetic profile for recombinant CYP2E1 demonstrated significant negative cooperativity based on a fit of data to the Hill equation (n=0.56). Mechanistically, the data were best explained through a two-binding site cooperative model in which aniline binds with high affinity (K(s)=30 μM) followed by a second weaker binding event (K(ss)=1100 uM) resulting in a threefold increase in the oxidation rate. Binding sites for aniline were confirmed by inhibition studies with 4-methylpyrazole. Inhibitor phenotyping experiments with human liver microsomes validated the central role for CYP2E1 in aniline hydroxylation and indicated minor roles for CYP2A6 and CYP2C9. Importantly, inhibition of minor metabolic pathways resulted in a kinetic profile for microsomal CYP2E1 that replicated the preferred mechanism and parameters observed with the recom...Continue Reading

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Citations

Aug 1, 2015·Biochemical Pharmacology·Jessica H HartmanGrover P Miller
Dec 30, 2014·Journal of Molecular Graphics & Modelling·Joseph W LevyGrover P Miller
May 12, 2016·Drug Metabolism Reviews·Pramod C NairJohn O Miners
Oct 11, 2017·Toxicology Research·Jessica H HartmanJoel N Meyer
May 11, 2017·Biochemistry·Drew R TietzThomas C Pochapsky
Nov 5, 2021·Environmental Science. Processes & Impacts·Oluwadamilola Daramola, Amy A Rand

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