Toxicogenomics and Predictive Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow 226 001, Uttar Pradesh, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
Protein Pept Lett. 2020;27(10):1038-1045. doi: 10.2174/0929866527666200403110036.
Combined maneb (MB) and paraquat (PQ), two widely used pesticides, increases oxidative stress leading to Parkinsonism. Xenobiotic metabolizing enzymes, cytochrome P450 (CYP) 2D6 and its mouse ortholog Cyp2d22 protect against Parkinsonism. Resveratrol, an antioxidant, restores antioxidant defense system through the activation of nuclear factor erythroid 2- related factor 2 (Nrf2). However, a crosstalk between Cyp2d22/CYP2D6-mediated protection and resveratrol-induced Nrf2 activation leading to neuroprotection is not yet elucidated.
The study aimed to decipher the effect of resveratrol on Nrf2 activation and expression of its downstream mediators, nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 (NQO1) and thioredoxin 1 (Trx1) along with Cyp2d22/CYP2D6 activity in combined MB and PQ mouse model of Parkinsonism and differentiated neuroblastoma cells.
MB and PQ reduced the dopamine content (mouse) and Cyp2d22/CYP2D6 activity (mouse/neuroblastoma cells) and increased the nuclear translocation of Nrf2 and expression of NQO1 and Trx1 (both). Resveratrol ameliorated pesticides-induced changes in dopamine content and Cyp2d22/CYP2D6 activity. It was found to promote nuclear translocation of Nrf2 and expression of NQO1 and Trx1 proteins. Since Cyp2d22/CYP2D6 inhibitor (ketoconazole/quinidine) per se reduced Cyp2d22/CYP2D6 activity and dopamine content, it was found to substantially increase the pesticides-induced reduction in Cyp2d22/CYP2D6 activity and dopamine content. Inhibitors normalized the pesticides induced changes in Nrf2 translocation and NQO1 and Trx1 levels in pesticides treated groups.
The results suggest that resveratrol promotes the catalytic activity of xenobiotic metabolizing enzyme, Cyp2d22/CYP2D6, which partially contributes to Nrf2 activation in pesticides- induced Parkinsonism.
联合使用两种广泛使用的农药——代森锰（MB）和百草枯（PQ）会导致氧化应激，从而引发帕金森病。细胞色素 P450（CYP）2D6 及其小鼠同源物 Cyp2d22 等外源代谢酶可预防帕金森病。白藜芦醇是一种抗氧化剂，通过激活核因子红细胞 2 相关因子 2（Nrf2）来恢复抗氧化防御系统。然而，Cyp2d22/CYP2D6 介导的保护作用与白藜芦醇诱导的 Nrf2 激活导致神经保护作用之间的相互作用尚不清楚。
本研究旨在阐明白藜芦醇对 Nrf2 激活及其下游介质——烟酰胺腺嘌呤二核苷酸磷酸醌氧化还原酶 1（NQO1）和硫氧还蛋白 1（Trx1）的表达以及帕金森病小鼠模型和分化的神经母细胞瘤细胞中 Cyp2d22/CYP2D6 活性的影响。
MB 和 PQ 降低了多巴胺含量（小鼠）和 Cyp2d22/CYP2D6 活性（小鼠/神经母细胞瘤细胞），并增加了 Nrf2 的核转位以及 NQO1 和 Trx1 的表达（两者均有）。白藜芦醇改善了农药诱导的多巴胺含量和 Cyp2d22/CYP2D6 活性变化。它被发现可以促进 Nrf2 的核转位以及 NQO1 和 Trx1 蛋白的表达。由于 Cyp2d22/CYP2D6 抑制剂（酮康唑/奎尼丁）本身降低了 Cyp2d22/CYP2D6 活性和多巴胺含量，因此它显著增加了农药诱导的 Cyp2d22/CYP2D6 活性和多巴胺含量的降低。抑制剂使 Nrf2 转位以及 NQO1 和 Trx1 水平在农药处理组中的变化正常化。
结果表明，白藜芦醇促进了外源代谢酶 Cyp2d22/CYP2D6 的催化活性，这部分有助于农药诱导的帕金森病中 Nrf2 的激活。
