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High-Fat Diet Feeding Alters Expression of Hepatic Drug-Metabolizing Enzymes in Mice
Miaoran Ning1, Hyunyoung Jeong2
1Department of Pharmacy Practice (H.J.) and Department of Biopharmaceutical Sciences (M.N., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
Abstract:
Medical conditions accompanying obesity often require drug therapy, but whether and how obesity alters the expression of drug-metabolizing enzymes and thus drug pharmacokinetics is poorly defined. Previous studies have shown that high-fat diet (HFD) feeding and subsequent obesity in mice lead to altered expression of transcriptional regulators for cytochrome P450 CYP2D6, including hepatocyte nuclear factor 4α (HNF4α, a transcriptional activator of CYP2D6) and small heterodimer partner (SHP, a transcriptional repressor of CYP2D6). The objective of this study was to examine whether diet-induced obesity alters CYP2D6 expression by modulating HNF4α and SHP expression. Male CYP2D6-humanized transgenic (Tg-CYP2D6) mice were fed with HFD or matching control diet for 18 weeks. Hepatic mRNA expression of CYP2D6 decreased to a small extent in the HFD group (by 31%), but the differences in CYP2D6 protein and activity levels in hepatic S9 fractions were found insignificant between the groups. Although hepatic SHP expression did not differ between the groups, HNF4α mRNA and protein levels decreased by ∼30% in the HFD group. Among major mouse endogenous cytochrome P450 genes, Cyp1a2 and Cyp2c37 showed significant decreases in the HFD group, whereas Cyp2e1 expression did not differ between groups. Cyp2b10 and Cyp3a11 expression was higher in the HFD group, with corresponding 2.9-fold increases in hepatic CYP3A activities in HFD-fed mice. Together, these results suggest that obesity has minimal effects on CYP2D6-mediated drug metabolism, although it modulates the expression of mouse endogenous P450s in a gene-specific manner.
Insights
Obesity minimally impacts drug metabolism via CYP2D6. Diet-induced obesity in mice altered expression of some drug-metabolizing enzymes, but not CYP2D6 significantly.
Area of Science:
- Pharmacology and Toxicology
- Metabolism and Drug Interactions
- Obesity Research
Background:
- Obesity often necessitates drug therapy, yet its impact on drug-metabolizing enzymes and pharmacokinetics remains unclear.
- Previous research indicates high-fat diet (HFD)-induced obesity alters expression of transcriptional regulators for cytochrome P450 CYP2D6, namely HNF4α and SHP.
- Understanding these alterations is crucial for optimizing drug efficacy and safety in obese individuals.
Purpose of the Study:
- To investigate if diet-induced obesity modifies CYP2D6 expression by affecting HNF4α and SHP levels.
- To assess the impact of obesity on the expression and activity of drug-metabolizing enzymes, particularly CYP2D6.
- To determine gene-specific effects of obesity on endogenous cytochrome P450 enzymes.
Main Methods:
- Male CYP2D6-humanized transgenic mice were fed either an HFD or a control diet for 18 weeks.
- Hepatic mRNA and protein levels of CYP2D6, HNF4α, and SHP were quantified.
- Cytochrome P450 activity and expression of endogenous mouse P450 genes were analyzed.
Main Results:
- Hepatic CYP2D6 mRNA decreased slightly (31%) in the HFD group, but protein and activity levels remained insignificant.
- HNF4α mRNA and protein levels decreased by approximately 30% in HFD-fed mice, while SHP expression showed no significant difference.
- Expression of mouse Cyp1a2 and Cyp2c37 decreased, whereas Cyp2b10 and Cyp3a11 increased, leading to a 2.9-fold rise in hepatic CYP3A activities.
Conclusions:
- Obesity exerts minimal influence on CYP2D6-mediated drug metabolism.
- Diet-induced obesity modulates the expression of endogenous mouse P450s in a gene-specific manner.
- These findings suggest that while overall CYP2D6 function is largely preserved, other drug-metabolizing pathways may be significantly altered in obesity.
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