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Hepatic CYP3A expression is attenuated in obese mice fed a high-fat diet
Kouichi Yoshinari1, Shunsuke Takagi, Teruyasu Yoshimasa
1Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
Purpose:
Changes in physiological, pathophysiological, and/or nutritional conditions often alter the expression of drug-metabolizing enzymes. In this study, we investigated obesity-induced changes in hepatic cytochrome P450 (P450) levels using nutritionally obese mice.
Methods:
To induce obesity, mice were fed a high-fat diet or treated with gold thioglucose, which impairs ventromedial hypothalamus. Total RNAs and microsomal and nuclear proteins were prepared from the liver of these mice, and mRNA and protein levels of P450s and transcription factors were determined.
Results:
Among P450s examined, the constitutive expression of CYP3As was drastically reduced at both mRNA and protein levels by nutrition-induced obesity. One-week administration of a high-fat diet also reduced hepatic CYP3As. However, changes in nuclear receptors involved in the transcriptional regulation of CYP3A genes were not correlated with that of CYP3As. Obese mice induced by gold thioglucose exhibited a different expression profile of hepatic P450s with no significant change in CYP3As.
Conclusion:
High-fat diet-induced changes in energy metabolism, which eventually result in obesity, modulate the hepatic expression profile of P450s, particularly CYP3As. Alternatively, the accumulation of a certain component in a high-fat diet may directly attenuate the CYP3A expression, suggesting a clinically important drug-diet interaction.
Insights
Obesity induced by a high-fat diet significantly reduces hepatic CYP3A expression at both mRNA and protein levels. This highlights a potential drug-diet interaction impacting drug metabolism.
Area of Science:
- Pharmacology
- Biochemistry
- Metabolism
Background:
- Physiological and nutritional changes impact drug-metabolizing enzyme expression.
- Hepatic cytochrome P450 (P450) enzymes are crucial for drug metabolism.
- Understanding obesity's effect on P450s is vital for drug efficacy and safety.
Purpose of the Study:
- To investigate obesity-induced alterations in hepatic P450 enzyme levels.
- To examine the impact of different obesity induction methods on P450 expression.
Main Methods:
- Mice were made obese via high-fat diet or gold thioglucose treatment.
- Liver tissues were analyzed for mRNA and protein levels of P450s and associated transcription factors.
- Quantitative analysis of gene and protein expression was performed.
Main Results:
- Nutrition-induced obesity drastically reduced constitutive CYP3A mRNA and protein levels.
- A one-week high-fat diet also decreased hepatic CYP3A expression.
- Obesity induced by gold thioglucose showed a different P450 expression profile without significant CYP3A changes.
Conclusions:
- High-fat diet-induced obesity modulates hepatic P450 expression, particularly CYP3As.
- Dietary components in high-fat diets may directly reduce CYP3A expression.
- Findings suggest a clinically significant drug-diet interaction.
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