Impact of acute streptozotocin-induced diabetes on ABC transporter expression in rats.
Hepatic ABC efflux transporters control the cellular uptake (in basolateral membranes) and excretion (in apical membranes) of many substrates. Since type-1 diabetes mellitus (T1DM) is associated with altered hepatobiliary excretion of many endogenous and exogenous substances, we examined key hepatic ABC transporters and levels of the endogenous substrate glutathione in rats with acute streptozotocin-induced T1DM. Renal transporters and inflammatory markers were also examined. Abcb1, Abcc1-4, and Abcg2 were measured using qRT-PCR. Glutathione was measured in liver tissue, plasma, and urine. Inflammatory markers, including C-reactive protein (CRP), were measured in plasma via ELISA. In diabetic rats, Abcb1a, Abcc2, and Abcg2 (apical) were decreased, while Abcc4 (basolateral) was increased. Abcb1a and Abcc2 inversely correlated with plasma CRP. Diabetic and control rats exhibited similar hepatic glutathione, but levels in diabetic plasma were lower. When standardized to urinary output, diabetic rats excreted 6.7-fold more glutathione in urine than controls. Renal transporter levels were normal in diabetic rats. Results show apical transporters involved in hepatobiliary excretion are downregulated in T1DM, possibly through an inflammation-mediated process. Findings suggest that there may be a vectorial shift from hepatic to renal excretion for some substrates in T1DM.
Anger
Gregory J
GJ
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
Magomedova
Lilia
L
Piquette-Miller
Micheline
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000208:Acute Disease; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001646:Bile / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; D015850:Interleukin-6; D004364:Pharmaceutical Preparations; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione