Gemfibrozil's cytotoxicity and DNA protection: PPAR-α agonism overrides genotoxicity in lymphocytes

Fibrates, carboxylic acid derivatives used in hypercholesterolemia treatment, are classified as non-genotoxic carcinogens. However, induce oxidative stress and DNA damage. This study investigates the genotoxic effects of gemfibrozil (GMF), a hypolipidemic agent, on human peripheral blood lymphocytes through cytokinesis-block micronucleus (CBMN) and alkaline comet assays. Plasmid DNA (pBR322) assessed GMF's DNA protective effects, while total oxidant (TOS) and antioxidant (TAS) status quantified oxidative stress modulation. Molecular docking simulations evaluated non-covalent interactions of GMF against DNA and peroxisome proliferator-activated receptor alpha (PPAR-α). At 25-250 µg/mL, GMF did not induce micronuclei (24-48 h) but triggered significant DNA fragmentation at 250 µg/mL (p < 0.01). GMF significantly reduced cytokinesis-block proliferation index (CBPI) across all concentrations and durations (p < 0.001), except 25 µg/mL (48 h). In a cell-free system, GMF exhibited a complex, bimodal protective effect against H₂O₂-induced plasmid damage, offering protection at 25 and 175 µg/mL but not at 100 µg/mL. However, TOS/TAS levels remained unaltered. Molecular docking demonstrated weak DNA binding (ΔG =  -5.93 kcal/mol) compared to mitomycin C (ΔG =  -7.25 kcal/mol), but strong PPAR-α affinity (ΔG =  -7.40 kcal/mol). These findings suggest GMF exerts cytotoxicity via disrupted cell division kinetics rather than direct DNA damage or oxidative stress. Despite a low genotoxic risk of GMF in vitro. In vivo studies are critical to confirm safety.