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首页> 外文期刊>Archives of Toxicology >Inhibition of rat hepatic CYP2E1 by quinacrine: molecular modeling investigation and effects on 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mutagenicity
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Inhibition of rat hepatic CYP2E1 by quinacrine: molecular modeling investigation and effects on 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mutagenicity

机译：奎纳克林抑制大鼠肝CYP2E1的分子模型研究及其对4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）致突变性的影响

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Increased activity of CYP2E1 has been associated with increased risk of chemically-mediated cancers, through enhanced activation of a variety of procarcinogens. In this context, inhibition of CYP2E1 is potentially of significance in xenobiotic toxicity. The aim of the present study was to test the hypothesis that quinacrine inhibits hepatic CYP2E1. For this purpose, disulfiram (75 mg/kg i.p) as an inhibitor and isoniazid (100 mg/kg i.p) as an inducer of CYP2E1, as well as quinacrine (50 mg/kg i.p) were administered to Wistar rats and the hepatic activity of CYP2E1 was measured. The expression of CYP2E1 was further assessed by Western blot analysis. As expected, disulfiram inhibited, while isoniazid induced the activity and expression of the enzyme. Interestingly, treatment with quinacrine resulted in a significant decrease of CYP2E1 activity and expression. To investigate any similarities in the inhibition of CYP2E1 by quinacrine and disulfiram, molecular modeling techniques were adopted and revealed that quinacrine molecule anchors inside the same binding pocket of the protein where disulfiram is also attached. Finally, as assessed by the sister chromatid exchanges (SCE) assay, quinacrine was demonstrated to reduce the mutagenic effects of the tobacco-specific N-nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is known to be converted to active mutagen in the liver principally through CYP2E1. We suggest that these antimutagenic effects of quinacrine could be possibly attributed, at least in part, to its ability to block the bioactivation of NNK, mainly by the inhibition of CYP2E1. Our results, even preliminary, indicate that quinacrine as an inhibitor of CYP2E1 might be protective against chemically-induced toxicities such as NNK-induced mutagenicity.
机译：CYP2E1的活性增加通过增强多种致癌物的活化而与化学介导的癌症风险增加相关。在这种情况下，CYP2E1的抑制可能在异源生物毒性中具有重要意义。本研究的目的是检验奎纳克林抑制肝CYP2E1的假说。为此目的，向Wistar大鼠施用双硫仑（75 mg / kg ip）作为抑制剂，异烟肼（100 mg / kg ip）作为CYP2E1的诱导剂，以及奎纳克林（50 mg / kg ip ip）给予Wistar大鼠，并进行肝活动测定CYP2E1的值。通过蛋白质印迹分析进一步评估CYP2E1的表达。如预期的那样，双硫仑抑制，而异烟肼诱导酶的活性和表达。有趣的是，奎纳克林治疗导致CYP2E1活性和表达显着降低。为了研究奎纳克林和双硫仑对CYP2E1抑制的任何相似性，采用了分子建模技术，并揭示了奎纳克林分子锚定在蛋白质的相同结合口袋中，双硫仑也与之结合。最后，通过姐妹染色单体交换（SCE）分析评估，奎纳克林被证明可减少烟草特有的N-亚硝胺4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）的诱变作用。 ），已知主要通过CYP2E1在肝脏中转化为活性诱变剂。我们认为，奎纳克林的这些抗诱变作用可能至少部分归因于其阻断NNK生物活化的能力，主要是通过抑制CYP2E1。我们的结果，甚至是初步的，都表明奎纳克林作为CYP2E1的抑制剂可能对化学诱导的毒性（如NNK诱变）具有保护作用。

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