title: Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters.
abstract: OBJECTIVE
  Our aim is to investigate the molecular mechanism of regulation of gene expression of drug metabolizing enzymes (DMEs) and transporters in diet-induced obesity.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 1441 Moursund Street, Houston, TX 77030, USA. rghose@uh.edu
authors.forename: Romi
authors.initials: R
authors.lastname: Ghose
authors.forename: Ozozoma
authors.initials: O
authors.lastname: Omoluabi
authors.forename: Adarsh
authors.initials: A
authors.lastname: Gandhi
authors.forename: Pranav
authors.initials: P
authors.lastname: Shah
authors.forename: Kelley
authors.initials: K
authors.lastname: Strohacker
authors.forename: Katie C
authors.initials: KC
authors.lastname: Carpenter
authors.forename: Brian
authors.initials: B
authors.lastname: McFarlin
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D015239:Arylsulfotransferase / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D004798:Enzymes / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000378:metabolism; D015151:Immunoblotting; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012890:Sleep / Q000187:drug effects; D013250:Steroid Hydroxylases / Q000378:metabolism; D015049:Zoxazolamine / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000090702:Constitutive Androstane Receptor; D016207:Cytokines; D004041:Dietary Fats; D004798:Enzymes; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D016328:NF-kappa B; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015049:Zoxazolamine; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C460223:Cyp2a4 protein, mouse; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D014453:Glucuronosyltransferase; D015239:Arylsulfotransferase; C513291:Sult1a1 protein, mouse; D008874:Midazolam