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Autonomous regulation of inducible nitric oxide synthase and cytochrome P450 2E1-mediated oxidative stress in maneb- and paraquat-treated rat polymorphs.
Pestic Biochem Physiol. 2021 Oct; 178:104944.PB

Abstract

Maneb (MB)- and paraquat (PQ)-induced oxidative stress in rat polymorphonuclear leukocytes (PMNs) is regulated in parallel by cytochrome P450 2E1 (CYP2E1) and inducible nitric oxide synthase (iNOS). However, mechanism underlying their regulation is not yet understood. The study investigated the role of nuclear factor- kappa B (NF-κB) and mitogen-activated protein kinase/extracellular signal regulated kinase/protein kinase C (MEK/ERK/PKC) pathway in the regulation of iNOS- and CYP2E1-induced oxidative stress in PMNs. MB + PQ-induced changes in nitrite content, lipid peroxidation (LPO), iNOS expression/activity and inflammatory mediators were alleviated by aminoguanidine (AG), an iNOS inhibitor, without any change in CYP2E1. Alternatively, diallyl sulphide (DAS), a CYP2E1 inhibitor, rescued from MB + PQ-induced changes in CYP2E1 activity/expression, free radical generation, superoxide dismutase (SOD) activity, LPO and pro-inflammatory cytokines without any alterations in nitrite content and iNOS activity/expression. Pyrrolidine dithiocarbamate (PDTC), NF-κB inhibitor, did not alter CYP2E1 but mitigated free radical generation, SOD activity, LPO, nitrite content, iNOS activity/expression and levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukine-1β and interleukine-4). Ex-vivo treatment with MEK inhibitor (PD98059), ERK1/2 inhibitor (AG126) or PKC inhibitor (rottlerin) ameliorated MB + PQ-induced increase in free radical generation and CYP2E1 activity/expression in PMNs. While PD98059 and AG126 abated MB + PQ-induced increase in ERK1/2, PKC-α/δ and CYP2E1 levels, rottlerin restored PKC-α/δ and CYP2E1 towards normalcy without affecting ERK1/2 level in MB + PQ-treated group. The results suggest that iNOS and CYP2E1 contributing to MB + PQ-induced oxidative stress in rat PMNs exhibit differential regulatory mechanisms. The inflammatory mediators regulate iNOS expression while CYP2E1 expression is triggered via MEK-ERK1/2-PKC pathway.

Authors+Show Affiliations

Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow 226 001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, Uttar Pradesh, India.Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow 226 001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, Uttar Pradesh, India.Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow 226 001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, Uttar Pradesh, India. Electronic address: chetna@iitr.res.in.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34446210

Citation

Singh, Deepali, et al. "Autonomous Regulation of Inducible Nitric Oxide Synthase and Cytochrome P450 2E1-mediated Oxidative Stress in Maneb- and Paraquat-treated Rat Polymorphs." Pesticide Biochemistry and Physiology, vol. 178, 2021, p. 104944.
Singh D, Yadav A, Singh C. Autonomous regulation of inducible nitric oxide synthase and cytochrome P450 2E1-mediated oxidative stress in maneb- and paraquat-treated rat polymorphs. Pestic Biochem Physiol. 2021;178:104944.
Singh, D., Yadav, A., & Singh, C. (2021). Autonomous regulation of inducible nitric oxide synthase and cytochrome P450 2E1-mediated oxidative stress in maneb- and paraquat-treated rat polymorphs. Pesticide Biochemistry and Physiology, 178, 104944. https://doi.org/10.1016/j.pestbp.2021.104944
Singh D, Yadav A, Singh C. Autonomous Regulation of Inducible Nitric Oxide Synthase and Cytochrome P450 2E1-mediated Oxidative Stress in Maneb- and Paraquat-treated Rat Polymorphs. Pestic Biochem Physiol. 2021;178:104944. PubMed PMID: 34446210.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Autonomous regulation of inducible nitric oxide synthase and cytochrome P450 2E1-mediated oxidative stress in maneb- and paraquat-treated rat polymorphs. AU - Singh,Deepali, AU - Yadav,Archana, AU - Singh,Chetna, Y1 - 2021/07/31/ PY - 2021/04/07/received PY - 2021/07/28/revised PY - 2021/07/28/accepted PY - 2021/8/27/entrez PY - 2021/8/28/pubmed PY - 2021/9/1/medline KW - Cytochrome P450 2E1 KW - Inducible nitric oxide synthase KW - Maneb KW - Oxidative stress KW - Paraquat SP - 104944 EP - 104944 JF - Pesticide biochemistry and physiology JO - Pestic Biochem Physiol VL - 178 N2 - Maneb (MB)- and paraquat (PQ)-induced oxidative stress in rat polymorphonuclear leukocytes (PMNs) is regulated in parallel by cytochrome P450 2E1 (CYP2E1) and inducible nitric oxide synthase (iNOS). However, mechanism underlying their regulation is not yet understood. The study investigated the role of nuclear factor- kappa B (NF-κB) and mitogen-activated protein kinase/extracellular signal regulated kinase/protein kinase C (MEK/ERK/PKC) pathway in the regulation of iNOS- and CYP2E1-induced oxidative stress in PMNs. MB + PQ-induced changes in nitrite content, lipid peroxidation (LPO), iNOS expression/activity and inflammatory mediators were alleviated by aminoguanidine (AG), an iNOS inhibitor, without any change in CYP2E1. Alternatively, diallyl sulphide (DAS), a CYP2E1 inhibitor, rescued from MB + PQ-induced changes in CYP2E1 activity/expression, free radical generation, superoxide dismutase (SOD) activity, LPO and pro-inflammatory cytokines without any alterations in nitrite content and iNOS activity/expression. Pyrrolidine dithiocarbamate (PDTC), NF-κB inhibitor, did not alter CYP2E1 but mitigated free radical generation, SOD activity, LPO, nitrite content, iNOS activity/expression and levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukine-1β and interleukine-4). Ex-vivo treatment with MEK inhibitor (PD98059), ERK1/2 inhibitor (AG126) or PKC inhibitor (rottlerin) ameliorated MB + PQ-induced increase in free radical generation and CYP2E1 activity/expression in PMNs. While PD98059 and AG126 abated MB + PQ-induced increase in ERK1/2, PKC-α/δ and CYP2E1 levels, rottlerin restored PKC-α/δ and CYP2E1 towards normalcy without affecting ERK1/2 level in MB + PQ-treated group. The results suggest that iNOS and CYP2E1 contributing to MB + PQ-induced oxidative stress in rat PMNs exhibit differential regulatory mechanisms. The inflammatory mediators regulate iNOS expression while CYP2E1 expression is triggered via MEK-ERK1/2-PKC pathway. SN - 1095-9939 UR - https://www.unboundmedicine.com/medline/citation/34446210/Autonomous_regulation_of_inducible_nitric_oxide_synthase_and_cytochrome_P450_2E1_mediated_oxidative_stress_in_maneb__and_paraquat_treated_rat_polymorphs_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0048-3575(21)00175-9 DB - PRIME DP - Unbound Medicine ER -