Coenzyme Q10 protects against atorvastatin-induced hepatotoxicity via attenuation of oxidative stress and functional modulation of CYP3A1

Abstract Background Atorvastatin (ATO) is a widely prescribed lipid-lowering drug, but its use can be limited by hepatotoxicity, potentially linked to metabolism-related mechanisms. The cellular pathways connecting ATO metabolism to oxidative imbalance and apoptotic alterations remain incompletely defined. This study examined the roles of oxidative stress, mitochondrial-associated apoptosis, and the pregnane X receptor (PXR)–CYP3A4 axis in ATO-induced hepatic changes, and evaluated whether coenzyme Q10 (CoQ10) could modulate these effects depending on administration timing. Methods Forty male albino rats were randomly assigned to four groups ( n = 10). Group I received vehicle (5% DMSO + olive oil), Group II received atorvastatin (ATO, 80 mg/kg), Group III received ATO (80 mg/kg) plus CoQ10 (10 mg/kg), and Group IV received ATO for 21 days followed by CoQ10 for 21 days. All treatments were administered orally once daily. Hepatic outcomes were assessed using biochemical markers, histopathology, and Bcl-2 immunohistochemistry. Microsomal CYP3A1 (rat ortholog of human CYP3A4) catalytic activity was determined using a testosterone 6β-hydroxylation assay. Molecular docking evaluated interactions of ATO, its lactone metabolite, and CoQ10 with CYP3A4 and PXR. Results ATO induced oxidative imbalance, evidenced by increased lipid peroxidation and nitric oxide alongside depleted antioxidant defenses, accompanied by liver structural alterations and reduced Bcl-2 expression. ATO significantly reduced hepatic microsomal CYP3A1 activity to ~ 29% of vehicle control (~ 71% decrease). CoQ10 co-administration markedly attenuated these effects, restoring redox homeostasis and increasing Bcl-2 expression, while co-treatment restored CYP3A1 activity (~ 90% of vehicle control). Post-treatment with CoQ10 partially restored CYP3A1 activity (~ 60% of vehicle control). Docking analysis indicated favorable binding of ATO and its lactone to CYP3A4 and PXR, supporting metabolism-linked bioactivation, while CoQ10 exhibited lower affinity, suggesting indirect modulation. Conclusion ATO-induced hepatic injury is associated with oxidative stress and mitochondrial-related apoptotic processes linked to metabolism-dependent mechanisms. Functional impairment of CYP3A1 activity accompanied ATO-induced oxidative damage, whereas CoQ10 preserved enzymatic activity, consistent with hepatocellular protection. Early CoQ10 intervention provided superior protection, highlighting the importance of timing in mitigating metabolism-related hepatic damage. These findings provide mechanistic insight into statin-induced hepatotoxicity and support further investigation of CoQ10 as a complementary strategy to enhance statin safety.