PARP-1抑制剂减轻可卡因引起的肝毒性

J. McCluskey, Stephen C Harbison, D. Sava, G. Johnson, R. Harbison
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引用次数: 2

摘要

可卡因滥用与多种健康问题有关,包括偶尔的肝功能衰竭和死亡。可卡因诱导肝毒性(CIH)的机制尚不清楚,尽管小鼠研究表明,可卡因诱导的肝损伤可能是由一氧化氮和活性氧介导的。最近,我们发现可卡因增加了肝脏中聚(adp -核糖)聚合酶(PARP)的活性。因此,抑制PARP可能会阻断CIH。PARP抑制剂3,4-二氢-5-(4-(1-哌啶基)丁氧基)-1(2H)-异喹啉酮(DPQ)在ICR小鼠中的初步评估未能减轻CIH。然而,PARP抑制剂1,5-二羟基异喹啉(DIQ)成功地减弱了CIH。单独使用可卡因引起的平均ALT活性为569 IU,而同时使用DIQ (10 mg/kg, ip)治疗的ICR小鼠的ALT活性限制为79 IU。DIQ的保护作用还与预防肝组织脂质过氧化的发展、减少谷胱甘肽(GSH)的消耗和减少亚硝酸盐的产生有关。可卡因诱导的TBARS通过DIQ显著降低,从平均5.7 nmol/mg蛋白质降低到平均2.5 nmol/mg蛋白质,与未处理的小鼠相似。可卡因给药后肝脏GSH降低了2倍以上,但DIQ治疗使GSH保持在未治疗小鼠的水平。DIQ对CIH的保护作用可能是由DIQ的双重抑制作用来解释的,DIQ可以减少PARP和诱导型一氧化氮合成酶(iNOS)的诱导。CIH的DIQ衰减为PARP和iNOS调节这种肝细胞病理的作用机制提供了证据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
PARP-1 Inhibitor Attenuates Cocaine-Induced Hepatotoxicity
Cocaine abuse is associated with multiple health problems including occasional hepatic failure and death. The mechanism of cocaine-induced hepatotoxicity (CIH) is not clear, although studies in mice have demonstrated that cocaine-induced liver injury may be mediated by nitric oxide and reactive oxygen species. Recently, we have found that cocaine increases poly (ADP-ribose) polymerase (PARP) activity in the liver. Therefore, inhibition of PARP may block CIH. A preliminary assessment of the PARP inhibitor 3,4-Dihydro-5-(4-(1-piperidinyl)butoxyl)-1(2H)-isoquinolinone (DPQ) in ICR mice failed to attenuate CIH. However, the PARP inhibitor 1,5-dihydroxyisoquinoline (DIQ) successfully attenuated CIH. Mean ALT activity of 569 IU caused by cocaine treatment alone, was limited to 79 IU in ICR mice concomitantly treated with DIQ (10 mg/kg, ip). The protective effect of DIQ was also associated with prevention of development of lipid peroxidation in liver tissue, reduced depletion of glutathione (GSH), and a reduced production of nitrites. Cocaine-induced TBARS was significantly decreased by DIQ from a mean of 5.7 nmol/mg protein to a mean of 2.5 nmol/mg protein, similar to untreated mice. Hepatic GSH was reduced more than 2 fold following cocaine administration but treatment with DIQ conserved GSH at the level of untreated mice. The protective effect of DIQ in attenuating CIH can potentially be explained by the dual inhibitory effect of DIQ that reduces induction of PARP and inducible nitric oxide synthetase (iNOS). The DIQ attenuation of CIH provides evidence for a PARP and iNOS modulated mechanism of action for this hepatocellular pathology.
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