Effects of species of origin and mode of induction of microsomes on carbamazepine-induced cell toxicity

IF 1.3 4区医学 Q4 PHARMACOLOGY & PHARMACY

Journal of pharmacological and toxicological methods Pub Date : 2024-07-01 DOI:10.1016/j.vascn.2024.107536

Abdelbaset A. Elzagallaai , Awatif M. Abuzgaia , Michael J. Rieder

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引用次数: 0

Abstract

Standardization and validation of in vitro drug metabolism is essential for pre-clinical drug development as well as for in vitro toxicity assays including the lymphocyte toxicity assay (LTA) and the in vitro platelet toxicity assay (iPTA). Use of isolated liver microsomes (MIC) in in vitro testing has been utilized for a long time; however, the effect of species of origin and induction agents on the metabolic capacities of MIC is not adequately evaluated. In this study we investigated the impact of species of origin and induction agent on the capacity of MICs to bioactivate carbamazepine (CBZ) using cytotoxicity as a gross endpoint to measure the levels of cytotoxic metabolites generated by each type of MICs. Jurkat E6.1 cell line was used and MICs from human, rat, mouse, minipig and rabbit origin as well as rat MICs that is either non-induced or induced by phenobarbitone (PHB), dexamethasone (DEXA), 3-methylcholanthrene (3MC), clofibrate (CLOF) and isoniazid (INH) were investigated. MICs from minipig and rat MICs induced with 3MC exhibited the highest capacity to produce cytotoxic metabolites of CBZ. These findings will help optimize and standardize in vitro toxicity assays and provide guidance to pre-clinical investigation of drugs.

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微粒体的来源种类和诱导方式对卡马西平诱导的细胞毒性的影响

体外药物代谢的标准化和验证对于临床前药物开发以及体外毒性检测（包括淋巴细胞毒性检测（LTA）和体外血小板毒性检测（iPTA））至关重要。在体外测试中使用分离的肝脏微粒体（MIC）由来已久，但尚未充分评估来源物种和诱导剂对 MIC 代谢能力的影响。在本研究中，我们以细胞毒性为总终点，测量了各类 MIC 产生的细胞毒性代谢物的水平，从而研究了来源种类和诱导剂对 MIC 生物活化卡马西平（CBZ）能力的影响。我们使用了 Jurkat E6.1 细胞系，并研究了来自人、大鼠、小鼠、迷你猪和兔子的 MICs，以及未被苯巴比妥（PHB）、地塞米松（DEXA）、3-甲基胆蒽（3MC）、氯贝特（CLOF）和异烟肼（INH）诱导或诱导的大鼠 MICs。用 3MC 诱导的小鼠和大鼠 MICs 产生 CBZ 细胞毒性代谢物的能力最强。这些发现将有助于优化和规范体外毒性试验，并为药物的临床前研究提供指导。

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来源期刊

Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY

CiteScore

3.60

自引率

10.50%

发文量

审稿时长

26 days

期刊介绍： Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.