Drug-metabolizing enzyme and transporter expression in a mouse model of diabetes and obesity

Mol Pharm. Jan-Feb 2008;5(1):77-91. doi: 10.1021/mp700114j. Epub 2008 Jan 12.

Abstract

Obesity and type II diabetes pose a serious human health risk. Obese or diabetic patients usually take prescription drugs that require hepatic and renal metabolism and transport, and these patients sometimes display different pharmacokinetics of these drugs. Therefore, mRNA and protein expression of drug-metabolizing enzymes (DMEs) and transporters was measured in livers and kidneys of adult wild-type and ob/ob mice, which model obesity and diabetes. mRNA expression of numerous DMEs increased by at least 2-fold in livers of male ob/ob mice, including Cyp4a14, Cyp2b10, NAD(P)H:quinone oxidoreductase 1 (Nqo1), and sulfotransferase 2a1/2. In general, expression of uptake transporters was decreased in livers of ob/ob mice, namely organic anion-transporting polypeptides (Oatps) and sodium/taurocholate cotransporting polypeptide (Ntcp). In particular, Oatp1a1 mRNA and protein expression in livers of ob/ob mice was diminished to <5% and <15% of that in wild-types, respectively. Generally, the mRNA and protein expression of efflux transporters multidrug resistance-associated proteins (Mrps) was increased in livers of ob/ob mice, particularly with Mrp4 expression being elevated by at least 6-fold and Mrp2 expression at least 3-fold in livers of ob/ob mice. In kidney, Nqo1, Mrp3, 4, Oatp1a1, and organic anion transporter 2 (Oat2) showed significant alterations with mRNA expression levels in ob/ob mice, being increased for Nqo1 and Mrp4 and decreased for Mrp3, Oatp1a1, and Oat2. In summary, the expression of a number of DMEs and transporters was significantly altered in livers and kidneys of ob/ob mice. Since expression of some DMEs and transporters is regulated similarly between mouse and human, the data from this study suggest that transporter expression in liver and kidney may be changed in patients presenting with obesity and/or type II diabetes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Biological Transport
  • Blotting, Western
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Cytochrome P450 Family 2
  • Cytochrome P450 Family 4
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus / pathology
  • Disease Models, Animal*
  • Female
  • Kidney / metabolism*
  • Kidney / pathology
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / metabolism
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • NAD(P)H Dehydrogenase (Quinone)
  • NADPH Dehydrogenase / genetics
  • NADPH Dehydrogenase / metabolism
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism
  • Subcellular Fractions

Substances

  • Cyp4a14 protein, mouse
  • Multidrug Resistance-Associated Proteins
  • Organic Anion Transporters
  • RNA, Messenger
  • multidrug resistance-associated protein 3
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • Cyp2b10 protein, mouse
  • Cytochrome P450 Family 2
  • Cytochrome P450 Family 4
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse
  • NADPH Dehydrogenase