Shayakhmetova Ganna M, Bondarenko Larysa B, Voronina Alla K, Anisimova Svitlana I, Matvienko Anatoliy V, Kovalenko Valentina M
General Toxicology Department, SI "Institute of Pharmacology & Toxicology NAMS of Ukraine", Eugene Pottier 14, Kyiv, Ukraine.
General Toxicology Department, SI "Institute of Pharmacology & Toxicology NAMS of Ukraine", Eugene Pottier 14, Kyiv, Ukraine.
Toxicol Lett. 2015 Apr 16;234(2):59-66. doi: 10.1016/j.toxlet.2015.02.008. Epub 2015 Feb 13.
Isoniazid is reported to be the most reliable and cost-effective remedy for tuberculosis treatment and prophylaxis among first line anti-tuberculosis drugs. Conventionally, the most common and best studied adverse effect of isoniazid is hepatotoxicity, but as for testicular toxicity the problem has not yet explored extensively. The aim of the study was to identify in vivo influence of isoniazid on induction of testicular cytochrome Р-450 2Е1 (CYP2E1) mRNA expression and enzymatic activity, testes DNA fragmentation, serum total testosterone level, and spermatogenesis indices. The significant induction of CYP2E1 was demonstrated in rat's testes following isoniazid administration, specifically CYP2E1 mRNA expression and p-nitrophenolhydroxylase activity was increased in 28 and 7 times as compared with control, respectively. These changes were accompanied by activating of testicular GST in 32%, changing in levels and character of DNA fragmentation, as well as damaging of the spermatogenic epithelium, decreasing in serum testosterone content (1.62 fold), sperm count (19%), and losing of fertility in comparison with untreated males. We assume that in testes of isoniazid-treated rats CYP2E1 may act as a trigger in generating of reactive oxygen species and other toxic metabolites which subsequently mediates DNA damage, spermatogenesis disturbances, and altered male fertilizing capacity.
据报道，在一线抗结核药物中，异烟肼是治疗和预防结核病最可靠且最具成本效益的药物。传统上，异烟肼最常见且研究最多的不良反应是肝毒性，但关于其睾丸毒性问题尚未进行广泛研究。本研究的目的是确定异烟肼对睾丸细胞色素P-450 2E1（CYP2E1）mRNA表达、酶活性、睾丸DNA片段化、血清总睾酮水平和精子发生指标的体内影响。异烟肼给药后，大鼠睾丸中CYP2E1有显著诱导，具体而言，CYP2E1 mRNA表达和对硝基苯酚羟化酶活性分别比对照组增加了28倍和7倍。这些变化伴随着32%的睾丸谷胱甘肽S-转移酶（GST）激活、DNA片段化水平和特征的改变，以及生精上皮的损伤、血清睾酮含量降低（1.62倍）、精子数量减少（19%），与未治疗的雄性相比生育能力丧失。我们假设，在异烟肼治疗的大鼠睾丸中，CYP2E1可能作为产生活性氧和其他有毒代谢物的触发因素，随后介导DNA损伤、精子发生紊乱和雄性受精能力改变。
