Drug-Metabolizing Enzyme and Transporter Expression in a Mouse Model of Diabetes and Obesity

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.

Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice

“…A notable difference in the data presented in this study compared with the results of Cheng et al (2008) is the lack of alterations observed in kidney transporter expression in DIO mice. Cheng et al (2008) reported multiple changes in renal expression of slco1a1 and abcc4 transporters in kidneys of ob/ob mice.…”

“…Transporter expression in ob/ob mice has been described previously (Cheng et al, 2008). ob/ob mice, in general, exhibited decreased uptake of transporter and increased efflux of transporter expression in liver compared with that in C57BL/6 mice (Cheng et al, 2008).…”

“…ob/ob mice, in general, exhibited decreased uptake of transporter and increased efflux of transporter expression in liver compared with that in C57BL/6 mice (Cheng et al, 2008). Because transporters are responsible for a significant phase of chemical handling, this observed change in transporter expression implies that obese mice should have differential patterns of chemical absorption and elimination.…”

“…Cheng et al (2008) reported multiple changes in renal expression of slco1a1 and abcc4 transporters in kidneys of ob/ob mice. However, in the current study, we observed a single slight decrease in one transporter (oat2) in kidneys of DIO mice.…”

Altered Drug Metabolism and Transport in Pathophysiological Conditions

“…Another study also showed that the hepatic expression of uptake transporters (Oatp1a1, 1a4, 1b2, 1a6, 2b1, and Ntcp) in diabetic mice decreased significantly compared to the wild type controls (Cheng et al, 2008). Our recent study showed no effect of high fat in DIO mice on gene expression of hepatic transporters (Mrp2 and 3, and Mdr1b) (Ghose et al, 2011b).…”