CYP2E1-mediated oxidative stress regulates HO-1 and GST expression in maneb- and paraquat-treated rat polymorphonuclear leukocytes.
Cytochrome P4502E1 (CYP2E1), glutathione-S-transferase A4-4 (GSTA4-4), and inducible nitric oxide synthase (iNOS) are implicated in maneb- and paraquat-induced toxicity leading to various pathological conditions. The study aimed to investigate the role of CYP2E1 in maneb- and paraquat-induced oxidative stress in rat polymorphonuclear leukocytes (PMNs) and its crosstalk with iNOS-mediated nitrosative stress and GSTA4-4-linked protective effect, if any and their consequent links with the nuclear factor erythoid 2-related factor 2 (Nrf2) activation and heme oxygenase-1 (HO-1) expression. Rats were treated with/without maneb and/or paraquat for 1, 2, and 3 weeks along with vehicle controls. Subsets of rats were also treated with diallyl sulfide (DAS) or aminoguanidine (AG) along with the respective controls. Maneb and paraquat augmented the reactive oxygen species (ROS), lipid peroxidation (LPO) and 4-hydroxy nonenal (4-HNE) contents, and superoxide dismutase (SOD) activity in the PMNs. However, maneb and paraquat attenuated the reduced glutathione (GSH) level and the expression/activity of total GST and GST-pi. Maneb and paraquat increased the expression/activity of CYP2E1, GSTA4-4, iNOS, Nrf2 and HO-1, and nitrite content. CYP2E1 inhibitor, DAS noticeably alleviated maneb- and paraquat-induced ROS, LPO, 4-HNE, SOD, Nrf2 and HO-1, GST, GSH, and GST-pi while iNOS, nitrite content and GSTA4-4 levels were unchanged. Conversely, AG, an iNOS inhibitor, attenuated maneb- and paraquat-directed changes in nitrite, LPO, iNOS but it did not alter ROS, GSH, SOD, GST, GST-pi, Nrf2, HO-1, CYP2E1, and GSTA4-4. The results demonstrate that CYP2E1 induces iNOS-independent free radical generation and subsequently modulates the Nrf2-dependent HO-1 and 4-HNE-mediated GST expression in maneb- and paraquat-treated PMNs.
Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Mahatma Gandhi Marg, Post Box- 80, Lucknow, Uttar Pradesh, 226 001, India.
Israr
I
Ahmad
Smriti
S
Shukla
Deepali
D
Singh
Amit Kumar
AK
Chauhan
Vinod
V
Kumar
Brajesh Kumar
BK
Singh
Devendra Kumar
DK
Patel
Haushila Prasad
HP
Pandey
Chetna
C
Singh
D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008344:Maneb / Q000633:toxicity; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D010269:Paraquat / Q000633:toxicity; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D008344:Maneb; D019392:Cytochrome P-450 CYP2E1; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D005982:Glutathione Transferase; D010269:Paraquat