Pentoxifylline, as nonselective phosphodiesterase inhibitor, attenuate paraquat-induced hepatic damage: in vivo and molecular docking insights
Abstract Oxidative stress has a key role in paraquat (PQ)-mediated hepatic failure. Considering the known antioxidant and anti-inflammatory properties of nonselective phosphodiesterase inhibitors, this study investigated the potential of pentoxifylline (PTX) to counteract acute PQ-induced liver damage. The molecular interactions of PQ and PTX with key oxidative stress enzymes (NADPH oxidase, xanthine oxidase) were investigated by molecular docking using AutoDock 4.2.6. For in vivo studies, thirty-six mice were randomized into six groups: a normal saline control, a PQ-intoxicated group (20 mg/kg, single dose), a PTX control group (100 mg/kg for 3 days), and three treatment groups that received PTX (25, 50, or 100 mg/kg) for three consecutive days, starting one hour after PQ administration. Blood and liver tissues were collected 24 hours after the final dose for biochemical and histological analysis. The PQ administration resulted in a significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), hepatic lipid peroxidation (LPO), and nitric oxide (NO) levels, while concurrently decreasing antioxidant capacity (TAC), total thiol molecule (TTM), and superoxide dismutase (SOD) activity in liver tissue. PTX treatment effectively improved serum hepatic enzymes, LPO, TTM, and SOD levels, as corroborated by histological findings. Moreover, molecular docking analysis suggests that PTX may reduce PQ-induced oxidative stress by competitively inhibiting the FAD-binding site of xanthine oxidase, and by engaging a non-active-site region of NADPH oxidase. This study indicates PTX administration may prevent PQ-induced hepatic damage in mice, potentially by inhibiting free radical formation. Further research is needed to validate the proposed enzymes inhibition mechanisms and assess PTX’s potential in acute PQ poisoning.