Evaluation of the Effect of Uremic Serum on Hepatic Reductase Functional Expression.

Drug metabolism letters Pub Date : 2018-01-01 DOI:10.2174/1872312812666180416154436

Osama Y Alshogran, Esra A F Al-Obaidi, Belal A Al-Husein, Ashraf O Oweis

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Abstract

Background: The nonrenal clearance of drugs mediated by hepatic reduction is selectively altered by kidney disease. This study evaluated the influence of uremic serum on the expression and activity of reductase enzymes.

Methods: Human hepatocellular carcinoma cells (HepG2) were incubated with 5% pooled serum collected from patients with hemodialysis (pre- and post-dialysis session) or control subjects. The mRNA expression of various aldo-keto (AKR1C) and carbonyl (CBR) reductases were measured. Reductase metabolic activity was assessed in human liver cytosol or HepG2 cells using naltrexone as a substrate.

Results: Incubation of cells with pre-dialysis serum resulted in significant upregulation of AKR1C4 (by 63.2%) and CBR1 (by 34.6%) versus control serum. This increase was not observed for AKR1C1 and CBR1 with serum collected post-dialysis. While uremic serum had no effect on reductase activity, some instances with differences in metabolite formation among individual's pre- and post-dialysis samples were observed.

Conclusion: Although uremic serum can upregulate mRNA expression of several reductases, this effect was not observed at the activity level. Future studies are necessary to improve our understanding of the mechanistic effects of impaired kidney function on drug reduction.

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尿毒症血清对肝还原酶功能表达影响的评价。

背景:肾脏疾病选择性地改变了肝脏还原介导的药物非肾清除率。本研究评价了尿毒症血清对还原酶表达和活性的影响。方法:将人肝癌细胞(HepG2)与从血液透析患者(透析前和透析后)或对照组收集的5%混合血清孵育。测定各种醛酮(AKR1C)和羰基(CBR)还原酶的mRNA表达。使用纳曲酮作为底物评估人肝细胞质或HepG2细胞中的还原酶代谢活性。结果:与对照血清相比，透析前血清细胞孵育导致AKR1C4(63.2%)和CBR1(34.6%)显著上调。在透析后收集的血清中，AKR1C1和CBR1未观察到这种增加。虽然尿毒症血清对还原酶活性没有影响，但在某些情况下，个体透析前和透析后样品的代谢物形成存在差异。结论:尿毒症血清虽然可以上调几种还原酶mRNA的表达，但在活性水平上没有观察到这种作用。未来的研究有必要提高我们对肾功能受损对药物减少的机制影响的理解。

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Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.