Hassan Hozeifa M, Yousef Bashir A, Guo Hongli, Xiaoxin Liu, Zhang Luyong, Jiang Zhenzhou
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
Department of Pharmacology, Faculty of Pharmacy, University of Gezira, Wad Medani, Sudan.
Front Pharmacol. 2018 Mar 7;9:198. doi: 10.3389/fphar.2018.00198. eCollection 2018.
Tuberculosis (TB) is one of the oldest infectious diseases that affected humankind and remains one of the world's deadliest communicable diseases that could be considered as global emergency, but the discovery and development of isoniazid (INH) in the 1950s paved the way to an effective single and/or combined first-line anti-TB therapy. However, administration of INH induces severe hepatic toxicity in some patients. Previously, we establish a rat model of INH hepatotoxicity utilizing the inflammatory stress theory, in which bacterial lipopolysaccharide (LPS) potentially enhanced INH toxicity. These enhancing activities ranged between augmenting the inflammatory stress, oxidative stress, alteration of bile acid homeostasis, and CYP2E1 over-expression. Although pre-treatment with dexamethasone (DEX) helped overcome both inflammatory and oxidative stress which ended-up in alleviation of LPS augmenting effects, but still minor toxicities were being detected, alongside with CYP2E1 over expression. This finding positively indicated the corner-stone role played by CYP2E1 in the pathogenesis of INH/LPS-induced liver damage. Therefore, we examined whether INH/LPS co-treatment with CYP2E1 inhibitor diallyl sulfide (DAS) and DEX can protect against the INH/LPS-induced hepatotoxicity. Our results showed that pre-administration of both DAS and DEX caused significant reduction in serum TBA, TBil, and gamma-glutamyl transferase levels. Furthermore, the histopathological analysis showed that DAS and DEX could effectively reverse the liver lesions seen following INH/LPS treatment and protect against hepatic steatosis as indicated by absence of lipid accumulation. Pre-treatment with DAS alone could not completely block the CYP2E1 protein expression following INH/LPS treatment, as appeared in the immunoblotting and immunohistochemistry results. This is probably due to the fact that the combined enhancement activities of both INH and LPS on CYP2E1 protein expression levels might resist the blocking probabilities of DAS. In the meantime, addition of DEX to the DAS/INH/LPS combination caused a significant reduction in CYP2E1 protein expression as revealed by the immunoblotting and fading coloration in immunohistochemistry results. Thus, addition of DEX and DAS together caused strong protection against INH/LPS-induced hepatic damage. These findings reveal the potential therapeutic value of combining DAS and DEX with INH in TB management for reducing the potential risk and incidences of hepatotoxicity.
结核病（TB）是影响人类最古老的传染病之一，至今仍是世界上最致命的传染病之一，可被视为全球紧急情况。但20世纪50年代异烟肼（INH）的发现和研发为有效的一线抗结核单一和/或联合治疗铺平了道路。然而，在一些患者中，服用INH会引发严重的肝毒性。此前，我们利用炎症应激理论建立了INH肝毒性大鼠模型，其中细菌脂多糖（LPS）可能增强INH毒性。这些增强作用包括加剧炎症应激、氧化应激、改变胆汁酸稳态以及CYP2E1过表达。虽然用地塞米松（DEX）预处理有助于克服炎症和氧化应激，最终减轻LPS的增强作用，但仍能检测到轻微毒性，同时伴有CYP2E1过表达。这一发现明确表明CYP2E1在INH/LPS诱导的肝损伤发病机制中起关键作用。因此，我们研究了INH/LPS与CYP2E1抑制剂二烯丙基硫醚（DAS）和DEX联合治疗是否能预防INH/LPS诱导的肝毒性。我们的结果表明，预先给予DAS和DEX可使血清总胆汁酸（TBA）、总胆红素（TBil）和γ-谷氨酰转移酶水平显著降低。此外，组织病理学分析表明，DAS和DEX可有效逆转INH/LPS治疗后出现 的肝脏病变，并预防肝脂肪变性，表现为无脂质蓄积。单独用DAS预处理不能完全阻断INH/LPS治疗后CYP2E1蛋白表达，免疫印迹和免疫组化结果均显示如此。这可能是由于INH和LPS对CYP2E1蛋白表达水平的联合增强作用可能抵抗了DAS的阻断作用。同时，免疫印迹和免疫组化结果褪色显示，在DAS/INH/LPS组合中加入DEX可使CYP2E1蛋白表达显著降低。因此，同时加入DEX和DAS可对INH/LPS诱导的肝损伤产生强大的保护作用。这些发现揭示了在结核病治疗中将DAS和DEX与INH联合使用以降低肝毒性潜在风险和发生率的潜在治疗价值。
