Effect of Experimental Kidney Disease on the Functional Expression of Hepatic Reductases

Abstract

Chronic kidney disease (CKD) affects the nonrenal clearance of drugs by modulating the functional expression of hepatic drugmetabolizing 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 11b-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.

Comparative pharmacokinetics of three alkaloids in normal and acute hepatitis rats after oral administration of Yanhuanglian total alkaloids extract

“…It is associated with the development of multiple organ dysfunction syndromes, such as those in the kidney and intestinal tract. GalN‐induced acute hepatitis may affect renal function via oxidative stress (Ghosh, Das, & Sil, ), which is associated with multiple physiological changes that affect the disposition of therapeutic drugs (Alshogran et al, ). Finally, renal impairment influences the excretion of the alkaloids and leads to the drug accumulation in blood.…”

Decreased Kidney Function Is Associated with Enhanced Hepatic Flavin Monooxygenase Activity and Increased Circulating Trimethylamine N-Oxide Concentrations in Mice

“…Hepatic FMO protein expression and activity was assessed in isolated liver microsomes. Microsomes were isolated from frozen liver tissue by differential ultracentrifugation, as previously described with slight modification (Alshogran et al, 2015). Briefly, mouse livers from the same group were pooled together in sets of three and homogenized in ice-cold buffer (50 mM Tris-HCl buffer, 150 mM KCl, 1 mM EDTA, 0.1 mM dithiothreitol, and 20% glycerol, pH 7.4) containing 0.1 mM phenylmethylsulfonyl fluoride and 0.113 mM butylated hydroxytoluene as protease inhibitors.…”

Comparative pharmacokinetics of the main compounds of Shanzhuyu extract after oral administration in normal and chronic kidney disease rats

“…The change may display the interplay between 2 major drug eliminating organs, the liver and the kidney. The down-regulation of liver CYP enzymes and transporters presumably by elevated levels of circulating inflammatory proteins, or direct inhibition of CYP enzymes and transporters by increased levels of circulating uremic toxins in patients with kidney disease have been postulated to describe the interrelationship between renal function and hepatic drug clearance (Dixon et al, 2014;Alshogran et al, 2015;).…”