Oxcarbazepine-induced cytotoxicity and genotoxicity in human lymphocyte cultures with or without metabolic activation

IF 2.8 4区医学 Q2 TOXICOLOGY

Toxicology Mechanisms and Methods Pub Date : 2017-01-11 DOI:10.1080/15376516.2016.1273430

Zülal Atlı Şekeroğlu, H. Kefeli̇oğlu, Seval Kontaş Yedier, V. Şekeroğlu, Berrin Delmecioğlu

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引用次数: 5

Abstract

Abstract There has been considerable debate about the relationship between epilepsy and cancer. Oxcarbazepine (OXC) is used for treating certain types of seizures in patients with epilepsy. There have been no detailed investigations about genotoxicity of OXC and its metabolites. Therefore, the aim of this study is to investigate the cytotoxic and genotoxic effects of OXC and its metabolites on cultured human lymphocytes. The cytotoxicity and genotoxicity of OXC on human peripheral blood lymphocytes were examined in vitro by sister chromatid exchange (SCE), chromosomal aberration (CA) and micronucleus (MN) tests. Cultures were treated with 125, 250 and 500 μg/ml of OXC in the presence (3 h treatment) and absence (24 h and 48 h treatment) of a metabolic activator (S9 mix). Dimethyl sulfoxide (DMSO) was used as a solvent control. OXC showed cytotoxic activities due to significant decreases in mitotic index (MI), proliferation index (PI) and nuclear division index (NDI) in the absence of S9 mix when compared with solvent control. Metabolites of OXC also significantly reduced MI and PI in cultures with S9 mix. OXC significantly increased the CAs, aberrant cells, SCE and MN values in the presence and absence of S9 mix. Our results indicated that both OXC and its metabolites have cytotoxic, cytostatic and genotoxic potential on human peripheral blood lymphocyte cultures under the experimental conditions. Further studies are necessary to elucidate the relationship between cytotoxic, cytostatic and genotoxic effects, and to make a possible risk assessment in patients receiving therapy with this drug.

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奥卡西平在有或无代谢激活的人类淋巴细胞培养中诱导的细胞毒性和遗传毒性

摘要关于癫痫与癌症之间的关系一直存在着相当大的争论。奥卡西平（OXC）用于治疗癫痫患者的某些类型的癫痫发作。目前还没有关于OXC及其代谢产物的遗传毒性的详细研究。因此，本研究的目的是研究OXC及其代谢产物对培养的人淋巴细胞的细胞毒性和遗传毒性作用。通过姐妹染色单体交换（SCE）、染色体畸变（CA）和微核（MN）试验，研究了OXC对人外周血淋巴细胞的细胞毒性和遗传毒性。用125、250和500处理培养物 μg/ml OXC（3 h治疗）和缺席（24 h和48 h处理）的代谢活化剂（S9混合物）。使用二甲基亚砜（DMSO）作为溶剂对照。OXC显示出细胞毒性活性，因为与溶剂对照相比，在没有S9混合物的情况下，有丝分裂指数（MI）、增殖指数（PI）和核分裂指数（NDI）显著降低。OXC的代谢产物也显著降低了S9混合物培养物中的MI和PI。OXC在存在和不存在S9混合物的情况下显著增加了CA、异常细胞、SCE和MN值。我们的结果表明，在实验条件下，OXC及其代谢产物对人外周血淋巴细胞培养具有细胞毒性、细胞抑制和遗传毒性潜力。需要进一步的研究来阐明细胞毒性、细胞抑制和基因毒性作用之间的关系，并对接受该药物治疗的患者进行可能的风险评估。

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来源期刊

Toxicology Mechanisms and Methods TOXICOLOGY-

自引率

3.10%

发文量

期刊介绍： Toxicology Mechanisms and Methods is a peer-reviewed journal whose aim is twofold. Firstly, the journal contains original research on subjects dealing with the mechanisms by which foreign chemicals cause toxic tissue injury. Chemical substances of interest include industrial compounds, environmental pollutants, hazardous wastes, drugs, pesticides, and chemical warfare agents. The scope of the journal spans from molecular and cellular mechanisms of action to the consideration of mechanistic evidence in establishing regulatory policy. Secondly, the journal addresses aspects of the development, validation, and application of new and existing laboratory methods, techniques, and equipment. A variety of research methods are discussed, including: In vivo studies with standard and alternative species In vitro studies and alternative methodologies Molecular, biochemical, and cellular techniques Pharmacokinetics and pharmacodynamics Mathematical modeling and computer programs Forensic analyses Risk assessment Data collection and analysis.