The online version of this article (doi:10.1186/1476-5926-11-1) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
VRM performed all experiments with mRNA and protein expression and immunohistochemistry, and drafted the manuscript. XW analyzed urine samples for APAP and metabolites. PET developed method for APAP analysis by HPLC. ALS, LMA and VRM designed the experiment, and contributed to writing of manuscript. All authors read and approved the final manuscript.
Type-2 Diabetes is a major health concern in the United States and other Westernized countries, with prevalence increasing yearly. There is a need to better model and predict adverse drug reactions, drug-induced liver injury, and drug efficacy in this population. Because transporters significantly contribute to drug clearance and disposition, it is highly significant to determine whether a severe diabetes phenotype alters drug transporter expression, and whether diabetic mouse models have altered disposition of acetaminophen (APAP) metabolites.
Transporter mRNA and protein expression were quantified in livers and kidneys of adult C57BKS and db/db mice, which have a severe diabetes phenotype due to a lack of a functional leptin receptor. The urinary excretion of acetaminophen-glucuronide, a substrate for multidrug resistance-associated proteins transporters was also determined. The mRNA expression of major uptake transporters, such as organic anion transporting polypeptide Slco1a1 in liver and kidney, 1a4 in liver, and Slc22a7 in kidney was decreased in db/db mice. In contrast, Abcc3 and 4 mRNA and protein expression was more than 2 fold higher in db/db male mouse livers as compared to C57BKS controls. Urine levels of APAP-glucuronide, -sulfate, and N-acetyl cysteine metabolites were higher in db/db mice.
A severe diabetes phenotype/presentation significantly altered drug transporter expression in liver and kidney, which corresponded with urinary APAP metabolite levels.
Additional file 1: Figure S1. Title of data: Moderate steatosis db/db mice. Description of data: Hematoxylin and eosin staining showing mild to moderate steatosis in female and male db/db mice as compared to C57BKS mice livers. (PDF 20 MB)12946_2011_144_MOESM1_ESM.pdf
Additional file 2: Table S1. Title of data: Primary antibodies for western blot. Description of data: Type, dilution, molecular weight and sources of primary antibodies for western blot. (DOCX 16 KB)12946_2011_144_MOESM2_ESM.docx
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- Severe diabetes and leptin resistance cause differential hepatic and renal transporter expression in mice
Vijay R More
Paul E Thomas
Lauren M Aleksunes
Angela L Slitt
- BioMed Central
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