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Plasma exosomes exacerbate alcohol- and acetaminophen-induced toxicity via CYP2E1 pathway.
Scientific Reports ( IF 3.8 ) Pub Date : 2019-04-25 , DOI: 10.1038/s41598-019-43064-2
Mohammad A Rahman 1 , Sunitha Kodidela 1 , Namita Sinha 1 , Sanjana Haque 1 , Pradeep K Shukla 2 , Radhakrishna Rao 2 , Santosh Kumar 1
Scientific Reports ( IF 3.8 ) Pub Date : 2019-04-25 , DOI: 10.1038/s41598-019-43064-2
Mohammad A Rahman 1 , Sunitha Kodidela 1 , Namita Sinha 1 , Sanjana Haque 1 , Pradeep K Shukla 2 , Radhakrishna Rao 2 , Santosh Kumar 1
Affiliation
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Cellular CYP2E1 is well-known to mediate alcohol- (ALC) and acetaminophen- (APAP) induced toxicity in hepatic and extra-hepatic cells. Although exosomes have been gaining importance in understanding mechanism of intra- and inter-cellular communication, the functional role of drug metabolizing cytochrome P450 (CYP) enzymes in human plasma exosomes are yet to be explored. In our previous study, we reported that human plasma-derived exosomes contain substantial level of functional CYP2E1. In the current project, we investigated the potential role of plasma exosomal CYP2E1 in mediating ALC- and APAP-induced toxicity. We treated hepatic and extra-hepatic (monocytic) cells with exosomes ± ALC/APAP. We observed that the plasma exosomes containing CYP2E1 cargo further exacerbate ALC- and APAP-induced toxicity in both hepatic and monocytic cells. Further, both exosomes- and ALC/APAP-induced toxicity was reduced/abolished by a selective inhibitor of CYP2E1 enzyme activity (diallyl ether). However, only ALC-, but not exosome-induced toxicity was reduced/abolished by CYP2E1 siRNA. These findings suggest that ALC/APAP-induced toxicity in the presence of exosomes are mediated, at least in part, by CYP2E1 enzyme. To validate these in vitro findings, we characterized plasma exosomal contents in a binge-drinking animal model and their effect on ALC/APAP-induced toxicity in monocytic cells. Our results showed that ALC exposure caused a significant induction of the plasma exosomal CYP2E1 level in a binge drinking murine model. These exosomes containing increased levels of CYP2E1 caused significant toxicity in monocytic cells compared to exosomes derived from control mice. Overall, our results showed an important role of exosomal CYP2E1 in exacerbating ALC- and APAP-induced toxicity. The study is significant in terms of understanding the role of exosomal CYP2E1 in cell-cell interactions, and their effects on drug-induced toxicity.
中文翻译：
血浆外来体通过CYP2E1途径加重了乙醇和对乙酰氨基酚的毒性。
众所周知，细胞CYP2E1在肝细胞和肝外细胞中介导酒精（ALC）和对乙酰氨基酚（APAP）诱导的毒性。尽管外泌体在了解细胞内和细胞间通讯的机制方面已变得越来越重要，但仍需探索药物代谢细胞色素P450（CYP）酶在人血浆外泌体中的功能作用。在我们先前的研究中，我们报道了人血浆来源的外泌体含有大量的功能性CYP2E1。在当前项目中，我们研究了血浆外泌体CYP2E1在介导ALC和APAP诱导的毒性中的潜在作用。我们用外泌体±ALC / APAP处理了肝和肝外（单核）细胞。我们观察到，含有CYP2E1货物的血浆外泌体在肝细胞和单核细胞中进一步加剧了ALC和APAP诱导的毒性。进一步，外来体和ALC / APAP诱导的毒性均通过CYP2E1酶活性的选择性抑制剂（二烯丙基醚）降低/消除。但是，CYP2E1 siRNA仅降低/消除了ALC诱导的毒性，而没有消除由外来体诱导的毒性。这些发现表明，在外来体存在下ALC / APAP诱导的毒性至少部分地由CYP2E1酶介导。为了验证这些体外发现，我们表征了暴饮动物模型中血浆外泌体的含量及其对单核细胞中ALC / APAP诱导的毒性的影响。我们的结果表明，在暴饮暴饮的小鼠模型中，ALC暴露引起血浆外泌体CYP2E1水平的显着诱导。与衍生自对照小鼠的外泌体相比，这些含有增加的CYP2E1水平的外泌体在单核细胞中引起了显着的毒性。全面的，我们的研究结果表明，外泌体CYP2E1在加剧ALC和APAP诱导的毒性中具有重要作用。该研究对于理解外泌体CYP2E1在细胞-细胞相互作用中的作用及其对药物诱导的毒性的影响方面具有重要意义。
更新日期：2019-04-25
中文翻译：
血浆外来体通过CYP2E1途径加重了乙醇和对乙酰氨基酚的毒性。
众所周知，细胞CYP2E1在肝细胞和肝外细胞中介导酒精（ALC）和对乙酰氨基酚（APAP）诱导的毒性。尽管外泌体在了解细胞内和细胞间通讯的机制方面已变得越来越重要，但仍需探索药物代谢细胞色素P450（CYP）酶在人血浆外泌体中的功能作用。在我们先前的研究中，我们报道了人血浆来源的外泌体含有大量的功能性CYP2E1。在当前项目中，我们研究了血浆外泌体CYP2E1在介导ALC和APAP诱导的毒性中的潜在作用。我们用外泌体±ALC / APAP处理了肝和肝外（单核）细胞。我们观察到，含有CYP2E1货物的血浆外泌体在肝细胞和单核细胞中进一步加剧了ALC和APAP诱导的毒性。进一步，外来体和ALC / APAP诱导的毒性均通过CYP2E1酶活性的选择性抑制剂（二烯丙基醚）降低/消除。但是，CYP2E1 siRNA仅降低/消除了ALC诱导的毒性，而没有消除由外来体诱导的毒性。这些发现表明，在外来体存在下ALC / APAP诱导的毒性至少部分地由CYP2E1酶介导。为了验证这些体外发现，我们表征了暴饮动物模型中血浆外泌体的含量及其对单核细胞中ALC / APAP诱导的毒性的影响。我们的结果表明，在暴饮暴饮的小鼠模型中，ALC暴露引起血浆外泌体CYP2E1水平的显着诱导。与衍生自对照小鼠的外泌体相比，这些含有增加的CYP2E1水平的外泌体在单核细胞中引起了显着的毒性。全面的，我们的研究结果表明，外泌体CYP2E1在加剧ALC和APAP诱导的毒性中具有重要作用。该研究对于理解外泌体CYP2E1在细胞-细胞相互作用中的作用及其对药物诱导的毒性的影响方面具有重要意义。
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