Hepatic CYP3A expression is attenuated in obese mice fed a high-fat diet

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

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1188-1200
Number of pages13
JournalPharmaceutical research
Volume23
Issue number6
DOIs
Publication statusPublished - 2006 Jun

Keywords

  • CYP3A
  • Cytochrome P450
  • High-fat diet
  • Nuclear receptor
  • Obesity

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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