Pharmaceutical Research

, Volume 23, Issue 6, pp 1188–1200 | Cite as

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

  • Kouichi Yoshinari
  • Shunsuke Takagi
  • Teruyasu Yoshimasa
  • Junko Sugatani
  • Masao Miwa
Research Paper

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.

Key Words

CYP3A cytochrome P450 high-fat diet nuclear receptor obesity 

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

References

  1. 1.
    Nagata, K., Yamazoe, Y. 2002Genetic polymorphism of human cytochrome P450 involved in drug metabolismDrug Metab. Pharmacokinet.17167189PubMedCrossRefGoogle Scholar
  2. 2.
    Sugatani, J., Yamakawa, K., Yoshinari, K., Machida, T., Takagi, H., Mori, M., Kakizaki, S., Sueyoshi, T., Negishi, M., Miwa, M. 2002Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemiaBiochem. Biophys. Res. Commun.292492497PubMedCrossRefGoogle Scholar
  3. 3.
    Willson, T. M., Kliewer, S. A. 2002PXR, CAR and drug metabolismNat. Rev., Drug Discov.1259266CrossRefGoogle Scholar
  4. 4.
    Cheng, P. Y., Morgan, E. T. 2001Hepatic cytochrome P450 regulation in disease statesCurr. Drug Metab.2165183PubMedCrossRefGoogle Scholar
  5. 5.
    Blouin, R. A., Bandyopadhyay, A. M., Chaudhary, I., Robertson, L. W., Gemzik, B., Parkinson, A. 1993Cytochrome P450 2B enzyme (CYP2B) induction defect following phenobarbital treatment in the fa/fa Zucker rat: molecular characterizationArch. Biochem. Biophys.303313320PubMedCrossRefGoogle Scholar
  6. 6.
    Xiong, H., Yoshinari, K., Brouwer, K. L. R., Negishi, M. 2002Role of constitutive androstane receptor in the in vivo induction of Mrp3 and CYP2B1/2 by phenobarbitalDrug Metab. Dispos.30918923PubMedCrossRefGoogle Scholar
  7. 7.
    Roe, A. L., Howard, G., Blouin, R., Snawder, J. E. 1999Characterization of cytochrome P450 and glutathione S-transferase activity and expression in male and female ob/ob miceInt. J. Obes. Relat. Metab. Disord.234853PubMedCrossRefGoogle Scholar
  8. 8.
    Watson, A. M., Poloyac, S. M., Howard, G., Blouin, R. A. 1999Effect of leptin on cytochrome P-450, conjugation, and antioxidant enzymes in the ob/ob mouseDrug Metab. Dispos.27695700PubMedGoogle Scholar
  9. 9.
    Dong, Z. G., Hong, J. Y., Ma, Q. A., Li, D. C., Bullock, J., Gonzalez, F. J., Park, S. S., Gelboin, H. V., Yang, C. S. 1988Mechanism of induction of cytochrome P-450ac (P-450j) in chemically induced and spontaneously diabetic ratsArch. Biochem. Biophys.2632935PubMedCrossRefGoogle Scholar
  10. 10.
    O’Shea, D., Davis, S. N., Kim, R. B., Wilkinson, G. R. 1994Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of CYP2E1 activityClin. Pharmacol. Ther.56359367PubMedCrossRefGoogle Scholar
  11. 11.
    Lucas, D., Farez, C., Bardou, L. G., Vaisse, J., Attali, J. R., Valensi, P. 1998Cytochrome P450 2E1 activity in diabetic and obese patients as assessed by chlorzoxazone hydroxylationFundam. Clin. Pharmacol.12553558PubMedCrossRefGoogle Scholar
  12. 12.
    Irizar, A., Barnett, C. R., Flatt, P. R., Ioannides, C. 1995Defective expression of cytochrome P450 proteins in the liver of the genetically obese Zucker ratEur. J. Pharmacol.293385393PubMedCrossRefGoogle Scholar
  13. 13.
    Yoshinari, K., Sato, T., Okino, N., Sugatani, J., Miwa, M. 2004Expression and induction of cytochromes P450 in rat white adipose tissueJ. Pharmacol. Exp. Ther.311147154PubMedCrossRefGoogle Scholar
  14. 14.
    Omura, T., Sato, R. 1964The carbon monoxide-binding pigment of liver misrosomes. I. Evidence for its hemoprotein natureJ. Biol. Chem.23923702378PubMedGoogle Scholar
  15. 15.
    Nash, T. 1953The colorimetric estimation of formaldehyde by means of the Hantzsch reactionBiochem. J.55416421PubMedGoogle Scholar
  16. 16.
    Yoshinari, K., Sueyoshi, T., Moore, R., Negishi, M. 2001Nuclear receptor CAR as a regulatory factor for the sexually dimorphic induction of CYB2B1 gene by phenobarbital in rat liversMol. Pharmacol.59278284PubMedGoogle Scholar
  17. 17.
    Sonoda, J., Xie, W., Rosenfeld, J. M., Barwick, J. L., Guzelian, P. S., Evans, R. M. 2002Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR)Proc. Natl. Acad. Sci. USA991380113806PubMedCrossRefGoogle Scholar
  18. 18.
    Staudinger, J. L., Madan, A., Carol, K. M., Parkinson, A. 2003Regulation of drug transporter gene expression by nuclear receptorsDrug Metab. Dispos.31523527PubMedCrossRefGoogle Scholar
  19. 19.
    Watkins, P. B., Wrighton, S. A., Schuetz, E. G., Molowa, D. T., Guzelian, P. S. 1987Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and manJ. Clin. Invest.8010291036PubMedGoogle Scholar
  20. 20.
    Kliewer, S. A., Moore, J. T., Wade, L., Staudinger, J. L., Watson, M. A., Jones, S. A., McKee, D. D., Oliver, B. B., Willson, T. M., Zetterstrom, R. H., Perlmann, T., Lehmann, J. M. 1998An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathwayCell927382PubMedCrossRefGoogle Scholar
  21. 21.
    Miyata, M., Nagata, K., Yamazoe, Y., Kato, R. 1995Transcriptional elements directing a liver-specific expression of P450/6βA (CYP3A2) gene-encoding testosterone 6β-hydroxylaseArch. Biochem. Biophys.3187179PubMedCrossRefGoogle Scholar
  22. 22.
    Goodwin, B., Hodgson, E., Liddle, C. 1999The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer moduleMol. Pharmacol.5613291339PubMedGoogle Scholar
  23. 23.
    Huss, J. M., Wang, S. I., Kasper, C. B. 1999Differential glucocorticoid responses of CYP3A23 and CYP3A2 are mediated by selective binding of orphan nuclear receptorsArch. Biochem. Biophys.372321332PubMedCrossRefGoogle Scholar
  24. 24.
    Ogino, M., Nagata, K., Miyata, M., Yamazoe, Y. 1999Hepatocyte nuclear factor 4-mediated activation of rat CYP3A1 gene and its modes of modulation by apolipoprotein AI regulatory protein I and v-ErbA-related protein 3Arch. Biochem. Biophys.3623237PubMedCrossRefGoogle Scholar
  25. 25.
    Goodwin, B., Hodgson, E., D’Costa, D. J., Robertson, G. R., Liddle, C. 2002Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptorMol. Pharmacol.62359365PubMedCrossRefGoogle Scholar
  26. 26.
    Tirona, R. G., Lee, W., Leake, B. F., Lan, L. B., Cline, C. B., Lamba, V., Parviz, F., Duncan, S. A., Inoue, Y., Gonzalez, F. J., Schuetz, E. G., Kim, R. B. 2003The orphan nuclear receptor HNF4α determines PXR- and CAR-mediated xenobiotic induction of CYP3A4Nat. Med.9220224PubMedCrossRefGoogle Scholar
  27. 27.
    Hotamisligil, G. S., Shargill, N. S., Spiegelman, B. M. 1993Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistanceScience2598791PubMedGoogle Scholar
  28. 28.
    Vozarova, B., Weyer, C., Hanson, K., Tataranni, P. A., Bogardus, C., Pratley, R. E. 2001Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretionObes. Res.9414417PubMedCrossRefGoogle Scholar
  29. 29.
    Abdel-Razzak, Z., Loyer, P., Fautrel, A., Gautier, J. C., Corcos, L., Turlin, B., Beaune, P., Guillouzo, A. 1993Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary cultureMol. Pharmacol.44707715PubMedGoogle Scholar
  30. 30.
    Morgan, E. T., Thomas, K. B., Swanson, R., Vales, T., Hwang, J., Wright, K. 1994Selective suppression of cytochrome P-450 gene expression by interleukins 1 and 6 in rat liverBiochim. Biophys. Acta1219475483PubMedGoogle Scholar
  31. 31.
    Nadin, L., Butler, A. M., Farrell, G. C., Murray, M. 1995Pretranslational down-regulation of cytochromes P450 2C11 and 3A2 in male rat liver by tumor necrosis factor alphaGastroenterology109198205PubMedCrossRefGoogle Scholar
  32. 32.
    Ishihara, K., Hirano, T. 2002Molecular basis of the cell specificity of cytokine actionBiochim. Biophys. Acta1592281296PubMedCrossRefGoogle Scholar
  33. 33.
    Marshall, N. B., Barrnett, R. J., Mayer, J. 1955Hypothalamic lesions in gold thioglucose injected miceProc. Soc. Exp. Biol. Med.90240244PubMedGoogle Scholar
  34. 34.
    Debons, A. F., Krimsky, I., Maayan, M. L., Fani, K., Jemenez, F. A. 1977Gold thioglucose obesity syndromeFed. Proc.36143147PubMedGoogle Scholar
  35. 35.
    Weltman, M. D., Farrell, G. C., Hall, P., Ingelman-Sundberg, M., Liddle, C. 1998Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitisHepatology27128133PubMedCrossRefGoogle Scholar
  36. 36.
    Leclercq, I., Horsmans, Y., Desager, J. P., Delzenne, N., Geubel, A. P. 1998Reduction in hepatic cytochrome P-450 is correlated to the degree of liver fat content in animal models of steatosis in the absence of inflammationJ. Hepatol.28410416PubMedCrossRefGoogle Scholar
  37. 37.
    Lin, J., Yang, R., Tarr, P. T., Wu, P. H., Handschin, C., Li, S., Yang, W., Pei, L., Uldry, M., Tontonoz, P., Newgard, C. B., Spiegelman, B. M. 2005Hyperlipidemic effects of dietary saturated fats mediated through PGC-1β coactivation of SREBPCell120261273PubMedCrossRefGoogle Scholar
  38. 38.
    Cheng, P. Y., Wang, M., Morgan, E. T. 2003Rapid transcriptional suppression of rat cytochrome P450 genes by endotoxin treatment and its inhibition by curcuminJ. Pharmacol. Exp. Ther.30712051212PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Kouichi Yoshinari
    • 1
  • Shunsuke Takagi
    • 1
  • Teruyasu Yoshimasa
    • 1
  • Junko Sugatani
    • 1
  • Masao Miwa
    • 1
  1. 1.Department of Pharmaco-Biochemistry, School of Pharmaceutical SciencesUniversity of ShizuokaShizuokaJapan

Personalised recommendations