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Hepatic CYP3A Expression is Attenuated in Obese Mice Fed a High-Fat Diet

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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.

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Abbreviations

CAR:

constitutive androstane receptor

COUP-TF:

chicken ovalbumin upstream promoter-transcription factor

DEX:

dexamethasone

GST-hPXR-LBD:

human PXR ligand-binding domain (amino acids 141–434) fused to glutathione S-transferase

GTG:

gold thioglucose

HNF:

hepatocyte nuclear factor

IL-6:

interleukin-6

PB:

phenobarbital

POR:

NADPH cytochrome P450 reductase

PXR:

pregnane X receptor

P450:

cytochrome P450

RPS9:

ribosomal protein S9

RT-PCR:

reverse transcription-polymerase chain reaction

RXR:

retinoid X receptor

STAT3:

signal transducers and activators of transcription 3

TNF-α:

tumor necrosis factor-α

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Acknowledgments

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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Authors and Affiliations

  1. Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Kouichi Yoshinari, Shunsuke Takagi, Teruyasu Yoshimasa, Junko Sugatani & Masao Miwa

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  1. Kouichi Yoshinari
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  2. Shunsuke Takagi
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  3. Teruyasu Yoshimasa
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  4. Junko Sugatani
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  5. Masao Miwa
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Correspondence to Masao Miwa.

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Yoshinari, K., Takagi, S., Yoshimasa, T. et al. Hepatic CYP3A Expression is Attenuated in Obese Mice Fed a High-Fat Diet. Pharm Res 23, 1188–1200 (2006). https://doi.org/10.1007/s11095-006-0071-6

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