Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters

Romi Ghose, Ozozoma Omoluabi, Adarsh Gandhi, Pranav Shah, Kelley Strohacker, Katie C Carpenter, Brian McFarlin, Tao Guo

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Aim: Our aim is to investigate the molecular mechanism of regulation of gene expression of drug metabolizing enzymes (DMEs) and transporters in diet-induced obesity. Main methods: Adult male CD1 mice were fed diets containing 60% kcal fat (HFD) or 10% kcal fat (LFD) for 14 weeks. RNA levels of hepatic DMEs, transporters and their regulatory nuclear receptors (NRs) were analyzed by real-time PCR. Activation of cell-signaling components (JNK and NF-κΒ) and pro-inflammatory cytokines (IL-1β, IL-6 and TNFα) were measured in the liver. Finally, the pharmacodynamics of drugs metabolized by DMEs was measured to determine the clinical relevance of our findings. Key findings: RNA levels of the hepatic phase I (Cyp3a11, Cyp2b10, Cyp2a4) and phase II (Ugt1a1, Sult1a1, Sultn) enzymes were reduced ~ 30-60% in HFD compared to LFD mice. RNA levels of Cyp2e1, Cyp1a2 and the drug transporters, multidrug resistance proteins, (Mrp)2, Mrp3 and multidrug resistant gene (Mdr)1b were unaltered in HFD mice. Gene expression of the NRs, PXR and CAR and nuclear protein levels of RXRα was reduced in HFD mice. Cytokines, JNK and NF-κΒ were induced in HFD mice. Thus reduction in hepatic gene expression in obesity may be modulated by cross-talk between NRs and inflammation-induced cell-signaling. Sleep time of Midazolam (Cyp3a substrate) was prolonged in HFD mice, while Zoxazolamine (Cyp1a2 and Cyp2e1 substrate)-induced sleep time was unaltered. Significance: This study demonstrates that gene-specific reductions in DMEs can affect specific drugs metabolized by these enzymes, thus providing a rationale to monitor the effectiveness of drug therapy in obese individuals.

Original languageEnglish (US)
Pages (from-to)57-64
Number of pages8
JournalLife Sciences
Volume89
Issue number1-2
DOIs
StatePublished - Jul 4 2011

Fingerprint

Gene Expression Regulation
High Fat Diet
Nutrition
Gene expression
Fats
Enzymes
Pharmaceutical Preparations
Cell signaling
Liver
RNA
Cytoplasmic and Nuclear Receptors
Zoxazolamine
Sleep
Obesity
Genes
Pharmacodynamics
Cytokines
Diet
Drug therapy
Gene Expression

Keywords

  • Drug metabolism
  • Nuclear receptors
  • Obesity

Cite this

Ghose, R., Omoluabi, O., Gandhi, A., Shah, P., Strohacker, K., Carpenter, K. C., ... Guo, T. (2011). Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters. Life Sciences, 89(1-2), 57-64. https://doi.org/10.1016/j.lfs.2011.05.005

Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters. / Ghose, Romi; Omoluabi, Ozozoma; Gandhi, Adarsh; Shah, Pranav; Strohacker, Kelley; Carpenter, Katie C; McFarlin, Brian; Guo, Tao.

In: Life Sciences, Vol. 89, No. 1-2, 04.07.2011, p. 57-64.

Research output: Contribution to journalArticle

Ghose, R, Omoluabi, O, Gandhi, A, Shah, P, Strohacker, K, Carpenter, KC, McFarlin, B & Guo, T 2011, 'Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters', Life Sciences, vol. 89, no. 1-2, pp. 57-64. https://doi.org/10.1016/j.lfs.2011.05.005
Ghose R, Omoluabi O, Gandhi A, Shah P, Strohacker K, Carpenter KC et al. Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters. Life Sciences. 2011 Jul 4;89(1-2):57-64. https://doi.org/10.1016/j.lfs.2011.05.005
Ghose, Romi ; Omoluabi, Ozozoma ; Gandhi, Adarsh ; Shah, Pranav ; Strohacker, Kelley ; Carpenter, Katie C ; McFarlin, Brian ; Guo, Tao. / Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters. In: Life Sciences. 2011 ; Vol. 89, No. 1-2. pp. 57-64.
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