Hepatoprotective Effects of Nigella sativa and Thymoquinone: Modulation of CYP450 Enzymes and Cytochrome c Reductase in CCl4-Induced Hepatotoxicity.

INTRODUCTION: Carbon tetrachloride (CCl4) is a potent hepatotoxin that disrupts mitochondrial function and alters cytochrome P450 (CYP450) enzyme activity. Nigella sativa (Ns) and its primary bioactive compound, thymoquinone (TQ), are known for their hepatoprotective properties, but their effects on CYP450 modulation in liver injury remain underexplored. This study aimed to evaluate the effects of Ns and TQ on CYP450 activity and expression in CCl4-induced liver injury. METHODS: Forty-two male albino rats were divided into six groups: control, Ns-treated (50 mg/kg), TQ-treated (5 mg/kg), CCl4-exposed (1 mL/kg, single i.p. injection), and two combination groups pretreated with Ns or TQ followed by CCl4 administration. Ns and TQ were administered orally for five days, with CCl4 given on day three. Serum ALT, total CYP450 content, cytochrome c reductase activity, and specific CYP isoform activities and expression were measured. Statistical significance was set at p < 0.05 using one-way ANOVA with Tukey's post hoc test. RESULTS: CCl4 exposure significantly elevated ALT levels, decreased total CYP450 activity by 61%, and reduced cytochrome c reductase activity by 50%. It suppressed the activities of CYP3A1, CYP2C9, and CYP2D6 while upregulating CYP1B1 and CYP2E1. Ns and TQ pretreatment attenuated these effects by reducing ALT levels, restoring cytochrome c reductase activity, and partially normalizing CYP3A1 and CYP2D6 activities. Ns produced stronger hepatoprotective effects than TQ. DISCUSSION: The observed effects indicate that CCl4-induced liver injury is accompanied by broad CYP450 dysregulation, and that Ns and TQ provide significant protection by restoring enzymatic balance and mitochondrial function. CONCLUSION: Ns and TQ mitigate CCl₄-induced hepatotoxicity through modulation of CYP450 enzymes and improvement of mitochondrial function, suggesting their potential therapeutic use in oxidative stress-related liver dysfunction.