Homopterocarpin alleviates methoxychlor-induced hepatotoxicity via modulating thioredoxin/peroxiredoxin and TLR4/MyD88 pathway: A comprehensive biochemical, histopathological, and computational analysis

Methoxychlor (MET) is a synthetic organo-chlorine Insecticide that is known to exert deleterious effects on hepatic tissues. Homopterocarpin (HTP) isa bioactive compound that possess highly valuable pharmacological effects. Thirty-six male albino Sprague Dawley rats were categorized into control, MET (150 mgkg^-1), MET (150 mgkg^-1) + HTP (25 mgkg^-1), and HTP (25 mgkg^-1) alone administered group. MET intoxication suppressed the expressions of Sulfiredoxin-1 (SRXN1), Thioredoxin (TXN), Thioredoxin reductase 1 (TXNRD1) and Peroxiredoxin 1 (PRDX1) while augmenting the expressions of nuclear factor-kappa B (NF-κB), myeloid differentiation primary response 88 (MyD88), interleukin-6 (IL-6), Toll-like Receptor 4 (TLR4), tumor necrosis factor-alpha (TNF-α), TNF receptor-associated factor 6 (TRAF6), interleukin-6 beta (IL-6) receptor-associated kinase 1 (IRAK1), cyclooxygenase-2 (COX-2) & interleukin-1 beta (IL-1β). MET therapy led to the upregulation of Reactive Oxygen Species (ROS) and malondialdehyde (MDA) while simultaneously inhibiting the catalytic activities of hem-oxygenase-1 (HO-1), Glutathione Peroxidase (GPx), Glutathione S-transferase (GST), glutathione reductase (GSR), catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) were reduced following the provision of MET. Besides, MET exposure exacerbated concentrations of gamma-glutamyl transferase (GGT), alanine transferase (ALT), hepcidin, Alkaline Phosphatase (ALP), and aspartate aminotransferase (AST) while lowering the concentrations of total proteins, hemojuvelin, and albumin in serum sample. Moreover, MET intoxication compromised apoptotic cascade via promoting the concentrations of cysteine-aspartic proteases-9 (Caspase-9), Bcl-2-associated X protein (Bax), and cysteine-aspartic proteases-3 (Caspase-3) while lowering the concentration of B-cell lymphoma (Bcl-2) in hepatic tissues. Severe histological disruptions were observed after MET administration. Nonetheless, HTP therapy alleviated hepatic damage via regulating redox profile, inflammatory and apoptotic indices, and histopathological alterations. Our findings were strengthened by computational analysis that revealed the strong binding affinity of HTP with key regulatory genes thereby showing its pivotal role in regulating gene expressions.

Apoptosis; Hepatotoxicity; Inflammation; Methoxychlor; Oxidative stress.