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Western Diet Decreases Hepatic Drug Metabolism in Male LDLr-/-ApoB100/100 Mice
Markus Koponen1,2, Jaana Rysä1, Anna-Kaisa Ruotsalainen3
1School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1, 70210 Kuopio, Finland.
Abstract:
Consumption of a Western diet is an important risk factor for several chronic diseases including nonalcoholic fatty liver disease (NAFLD), but its effect on the xenobiotic metabolizing enzyme activities in the liver has been studied incompletely. In this study, male LDLr-/-ApoB100/100 mice were fed with Western diet (WD) or a standard diet for five months to reveal the effects on drug metabolism such as cytochrome P450 (CYP) oxidation and conjugation activities in the liver. Hepatic steatosis, lobular inflammation, and early fibrosis were observed in WD fed mice, but not in chow diet control mice. When compared to the controls, the WD-fed mice had significantly decreased protein-normalized CYP probe activities of 7-ethoxyresorufinO-deethylation (52%), coumarin 7-hydroxylation (26%), 7-hydroxylation of 3-(3-fluoro-4-hydroxyphenyl)-6-methoxycoumarin (70%), 7-hydroxylation of 3-(4-trifluoromethoxyphenyl)-6-methoxycoumarin (78%), 7-hydroxylation of 3-(3-methoxyphenyl)coumarin (81%), and pentoxyresorufin O-depentylation (66%). Increased activity was seen significantly in sulfonation of 3-(4-methylphenyl)-7-hydroxycoumarin (289%) and cytosol catechol O-methyltranferase (COMT, 148%) in the WD group when compared to the controls. In conclusion, the WD-induced steatosis in male LDLr-/-ApoB100/100 mice was associated with decreased CYP oxidation reactions but had no clear effects on conjugation reactions of glucuronidation, sulfonation, and cytosolic catechol O-methylation. Consequently, the WD may decrease the metabolic elimination of drugs compared to healthier low-fat diets.
Insights
A Western diet (WD) can cause nonalcoholic fatty liver disease (NAFLD) and impair drug metabolism in mice. This diet reduced cytochrome P450 (CYP) oxidation but did not affect most conjugation reactions, potentially slowing drug elimination.
Area of Science:
- Pharmacology and Toxicology
- Hepatology
- Nutritional Science
Background:
- Western diet (WD) consumption is a known risk factor for chronic diseases, including nonalcoholic fatty liver disease (NAFLD).
- The impact of WD on hepatic xenobiotic metabolism, particularly cytochrome P450 (CYP) enzyme activities, remains incompletely understood.
Purpose of the Study:
- To investigate the effects of a WD on drug-metabolizing enzyme activities in the liver of male LDLr-/-ApoB100/100 mice.
- To determine how WD-induced hepatic steatosis influences CYP oxidation and conjugation pathways.
Main Methods:
- Male LDLr-/-ApoB100/100 mice were fed either a WD or a standard diet for five months.
- Hepatic steatosis, inflammation, and fibrosis were assessed.
- Activities of specific CYP oxidation and conjugation enzymes were measured using probe substrates.
Main Results:
- WD-fed mice developed hepatic steatosis, lobular inflammation, and early fibrosis compared to controls.
- Significant decreases in protein-normalized CYP probe activities were observed in WD-fed mice (e.g., 52% decrease in 7-ethoxyresorufin O-deethylation).
- Increased sulfonation and cytosol catechol O-methyltransferase (COMT) activity were noted in the WD group.
Conclusions:
- WD-induced steatosis in mice is associated with reduced hepatic CYP oxidation activities.
- Conjugation reactions, including glucuronidation, sulfonation, and COMT, were not clearly affected by the WD.
- The WD may impair the metabolic elimination of drugs, suggesting potential drug-drug interactions or altered drug efficacy.
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