Hepatic CYP3A Expression is Attenuated in Obese Mice Fed a High-Fat Diet
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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.
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.
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.
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.
Key WordsCYP3A cytochrome P450 high-fat diet nuclear receptor obesity
constitutive androstane receptor
chicken ovalbumin upstream promoter-transcription factor
human PXR ligand-binding domain (amino acids 141–434) fused to glutathione S-transferase
hepatocyte nuclear factor
NADPH cytochrome P450 reductase
pregnane X receptor
ribosomal protein S9
reverse transcription-polymerase chain reaction
retinoid X receptor
signal transducers and activators of transcription 3
tumor necrosis factor-α
This work was supported in part by the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology, by a Goto Research Grant from University of Shizuoka, and The Mochida Memorial Foundation for Medical and Pharmaceutical Research. We are grateful to Dr. Yasushi Yamazoe (Tohoku University, Sendai, Japan) for his generous gift of the anti-CYP3A4 antibody.
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