Journal
MOLECULAR PHARMACEUTICS
Volume 5, Issue 1, Pages 77-91Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp700114j
Keywords
drug-metabolizing enzymes; transporters; ob/ob mice; obesity; diabetes; organic anion-transporting polypeptide; Oatp1a1; multidrug resistance-associated protein; Mrp4
Funding
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR016457] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK068039] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [K22ES013782] Funding Source: NIH RePORTER
- NCRR NIH HHS [P20RR016457] Funding Source: Medline
- NIDDK NIH HHS [R01 DK068039] Funding Source: Medline
- NIEHS NIH HHS [K22 ES013782, K22 ES013782-01] Funding Source: Medline
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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 pharmacokinetiGs 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, Nqol, 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 DIMES 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.
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