TitleHigh-Fat Diets Alter the Modulatory Effects of Xenobiotics on Cytochrome P450 Activities.
Publication TypeJournal Article
Year of Publication2018
AuthorsSadler, NC, Webb-Robertson, B-J, Clauss, TR, Pounds, JG, Corley, RA, Wright, AT
JournalChem Res Toxicol
Volume31
Issue5
Pagination308-318
Date Published2018 May 21
ISSN1520-5010
Abstract

Cytochrome P450 monooxygenase (P450) enzymes metabolize critical endogenous chemicals and oxidize nearly all xenobiotics. Dysregulated P450 activities lead to altered capacity for drug metabolism and cellular stress. The effects of mixed exposures on P450 expression and activity are variable and elusive. A high-fat diet (HFD) is a common exposure that results in obesity and associated pathologies including hepatotoxicity. Herein, we report the effects of cigarette smoke on P450 activities of normal weight and HFD induced obese mice. Activity-based protein profiling results indicate that HFD mice had significantly decreased P450 activity, likely instigated by proinflammatory chemicals, and that P450 enzymes involved in detoxification, xenobiotic metabolism, and bile acid synthesis were effected by HFD and smoke interaction. Smoking increased activity of all lung P450 and coexposure to diet effected P450 2s1. We need to expand our understanding of common exposures coupled to altered P450 metabolism to enhance the safety and efficacy of therapeutic drug dosing.

DOI10.1021/acs.chemrestox.8b00008
Alternate JournalChem. Res. Toxicol.
PubMed ID29688711