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Effect of experimental kidney disease on the functional expression of hepatic reductases
Osama Y Alshogran1, Judith Naud1, Andrew J Ocque1
1Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada.
Abstract:
Chronic kidney disease (CKD) affects the nonrenal clearance of drugs by modulating the functional expression of hepatic drug-metabolizing enzymes and transporters. The impact of CKD on oxidative and conjugative metabolism has been extensively studied. However, its effect on hepatic drug reduction, an important phase I drug-metabolism pathway, has not been investigated. We aimed to assess the effect of experimental CKD on hepatic reduction using warfarin as a pharmacological probe substrate. Cytosolic and microsomal cellular fractions were isolated from liver tissue harvested from five-sixths-nephrectomized and control rats (n = 10 per group). The enzyme kinetics for warfarin reduction were evaluated in both fractions, and formation of warfarin alcohols was used as an indicator of hepatic reductase activity. Selective inhibitors were employed to identify reductases involved in warfarin reduction. Gene and protein expression of reductases were determined using quantitative real-time polymerase chain reaction and Western blotting, respectively. Formation of RS/SR-warfarin alcohol was decreased by 39% (P < 0.001) and 43% (P < 0.01) in cytosol and microsomes, respectively, in CKD rats versus controls. However, RR/SS-warfarin alcohol formation was unchanged in the cytosol, and a trend toward its decreased production was observed in microsomes. Gene and protein expression of cytosolic carbonyl reductase 1 and aldo-keto reductase 1C3/18, and microsomal 11β-hydroxysteroid dehydrogenase type 1 were significantly reduced by >30% (P < 0.05) in CKD rats compared with controls. Collectively, these results suggest that the functional expression of hepatic reductases is selectively decreased in kidney disease. Our findings may explain one mechanism for altered nonrenal clearance, exposure, and response of drugs in CKD patients.
Insights
Chronic kidney disease (CKD) selectively reduces hepatic drug-reducing enzymes, impacting drug metabolism and exposure. This study investigated the effect of CKD on hepatic reduction using warfarin in rats.
Area of Science:
- Pharmacology
- Drug Metabolism
- Nephrology
Background:
- Chronic kidney disease (CKD) alters drug clearance by affecting liver enzymes and transporters.
- While oxidative and conjugative metabolism in CKD are studied, hepatic drug reduction remains unexplored.
- Hepatic reduction is a crucial Phase I drug metabolism pathway.
Purpose of the Study:
- To investigate the impact of experimental chronic kidney disease (CKD) on hepatic drug reduction.
- To assess changes in warfarin reduction, a marker for hepatic reductase activity, in CKD.
- To identify specific reductases affected by CKD.
Main Methods:
- Experimental CKD was induced in rats via five-sixths nephrectomy.
- Warfarin reduction was measured in liver cytosolic and microsomal fractions.
- Enzyme kinetics, selective inhibitors, gene expression (RT-PCR), and protein expression (Western blotting) were used.
Main Results:
- Warfarin alcohol formation (RS/SR isomers) significantly decreased in both cytosol (39%) and microsomes (43%) in CKD rats.
- RR/SS-warfarin alcohol formation showed no significant change in cytosol and a trend toward decrease in microsomes.
- Expression of key reductases (Carbonyl reductase 1, Aldo-keto reductase 1C3/18, 11β-hydroxysteroid dehydrogenase type 1) was reduced by over 30% in CKD.
Conclusions:
- Experimental CKD selectively impairs the functional expression of hepatic drug-reducing enzymes.
- Reduced hepatic reductase activity may explain altered drug clearance, exposure, and response in CKD patients.
- This study highlights a novel mechanism of drug metabolism alteration in kidney disease.
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