Eucalyptol Ameliorates Rifampicin-Induced Hepatotoxicity via Inhibiting Inflammation, Oxidant Stress and CYP2E1 Gene Expression in a Model of Modest Inflammation in Rats

Background and Objective: Host vulnerability may precipitate certain types of drug toxicity. Also, some concurrent events during drug therapy, such as mild inflammation, may precipitate drug-induced organ toxicity. This study was designed to investigate the ameliorative effect of eucalyptol, a natural component of many foodstuffs, on rifampicin-induced hepatotoxicity in lipopolysaccharide (LPS)-induced modest inflammation in rats. Materials and Methods: Sprague Dawley rats were divided into 6 groups (n = 8): Control, LPS (2 mg kg(-1) IV, non-hepatotoxic), low-dose rifampicin (LRIF, 20 mg kg(-1) IP, non-hepatotoxic), high-dose rifampicin (HRIF, 50 mg kg(-1) IP, hepatotoxic), LPS+LRIF (LRIF was given 2 hrs post LPS-administration) and EUC+LPS+LRIF (as LPS+LRIF but eucalyptol 1.0 mg kg(-1) IP, was given 1 hr before LPS administration). As 6 hrs after the last injection, blood Alanine Transaminase (ALT) and Aspartate Transaminase (AST) were measured. Moreover, hepatic Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-alpha), malondialdehyde (MDA), reduced Glutathione (GSH) and Cytochrome P450 2E1 (CYP2E1) mRNA expression were assessed in addition to histopathological analysis. Results: The LPS group showed small significant increases of ALT, AST, IL-6, TNF-alpha, MDA and CYP2E1 mRNA expression, a small significant decrease of GSH and mild hepatic injury. In contrast, the HRIF and LPS+LRIF groups showed large significant changes of all analytes and severe hepatic damage. The LRIF showed normal analyte values with normal hepatic architecture. Eucalyptol in the EUC+LPS+LRIF groups reversed the effects caused by LPS+LRIF resulting in normal analyte values with nearly-normal hepatic architecture. Conclusion: In a model of LPS-induced modest inflammation, non-hepatotoxic doses of rifampicin caused hepatotoxicity which was prevented with concurrent administration of eucalyptol. Therefore, eucalyptol supplementation could protect against hepatotoxicity in patients taking rifampicin and suffering simultaneously from systemic low-level inflammation such as in cases of aging, smoking, obesity and chronic diseases. The current data are novel and can help implement a safe, effective and economic protective tool against rifampicin-induced hepatotoxicity.