Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

Abstract

Isoniazid (INH) remains a cornerstone key constitute of the current tuberculosis management strategy, but its hepatotoxic potentiality remains a significant clinical problem. Our previous findings succeed to establish a rat model of INH hepatotoxicity employing the inflammatory stress theory in which non-injurious doses of inflammatory-mediating agent bacterial lipopolysaccharides (LPS) augmented the toxicity of INH that assist to uncover the mechanisms behind INH hepatotoxicity. Following LPS exposure, several inflammatory cells are activated and it is likely that the consequences of this activation rather than direct hepatocellular effects of LPS underlie the ability of LPS to augment toxic responses. In this study, we investigated the potential protective role of the anti-inflammatory agent dexamethasone (DEX), a potent synthetic glucocorticoid, in INH/LPS hepatotoxic rat model. DEX pre-treatment successfully eliminates the components of the inflammatory stress as shown through analysis of blood biochemistry and liver histopathology. DEX potentiated hepatic anti-oxidant mechanisms while serum and hepatic lipid profiles were reduced. However, DEX administration was not able to revoke the principal effects of cytochrome P450 2E1 (CYP2E1) in INH/LPS-induced liver damage. In conclusion, this study illustrated the DEX-preventive capabilities on INH/LPS-induced hepatotoxicity model through DEX-induced potent anti-inflammatory activity whereas the partial toxicity seen in the model could be attributed to the expression of hepatic CYP2E1. These findings potentiate the clinical applications of DEX co-administration with INH therapy in order to reduce the potential incidences of hepatotoxicity.

Investigating the CYP2E1 Potential Role in the Mechanisms Behind INH/LPS-Induced Hepatotoxicity

“…The gene expression profiles associated with INH/LPS hepatotoxicity with or without pre-administration of DAS and DEX were displayed in Figure 5 . As we suggested before, massive accumulation of bile acid in the hepatocytes could be one of the major pathways behind INH/LPS-induced severe liver damage which further support the overall reduction seen in bile acid-related genes ( Hassan et al, 2016 , 2017 ), in this part we extend our focusing to the effects of both DAS and DEX on those gene expressions. As shown in Figure 5A , the expression levels of the orphan nuclear receptor farnesoid X receptor (FXR) and the small heterodimer partner (SHP) were significantly repressed ( P < 0.01 and P < 0.001, respectively).…”

“…Our previous experimental data revealed that INH in a concentration of 400 mg/kg is associated with high incidence of liver toxicity ( Su et al, 2014 ; Hassan et al, 2016 , 2017 ). Therefore, in this study, we choose this dose in order to verify the role of CYP2E1 in INH/LPS-induced liver injury.…”

“…As we previously described that one reason for the struggles in identifying susceptibility factors for hepatotoxicity in patients receiving anti-tubercular medications (mainly INH) is the lack of a clear understanding of the molecular mechanisms underlying INH-induced liver injury ( Hassan et al, 2015 ). Despite these difficulties, our previous works ( Hassan et al, 2016 , 2017 ) achieved successfulness in establishing a 2-week INH hepatotoxic animal model implementing the inflammatory stress theory. In this model, implementation of endotoxic bacterial lipopolysaccharide (LPS), which are components from Gram-negative bacterial outer cell wall’s membrane, stimulates inflammatory response.…”

“…These enhancement activities ranged between augmenting the inflammatory stress, oxidative stress, alteration of bile acid homeostasis, elevated cytochrome P450 2E1 (CYP2E1) expression, and both macro- and micro-steatosis ( Hassan et al, 2016 ). Although pre-treatment with dexamethasone (DEX), a synthetic glucocorticoid that acts as a potent anti-inflammatory and immunosuppressive agent, helped overcome both inflammatory and oxidative stress which ended-up in alleviation of LPS augmenting effects, but still minor toxicities still being detected, alongside with CYP2E1 over expression ( Hassan et al, 2017 ). This finding positively indicated the corner-stone role played by CYP2E1 in the pathogenesis of INH/LPS-induced liver damage.…”

Hepatotoxicity Induced by Isoniazid-Lipopolysaccharide through Endoplasmic Reticulum Stress, Autophagy, and Apoptosis Pathways in Zebrafish

“…Clinical studies have shown that when tuberculosis patients also have hepatitis, their possibility of developing hepatotoxicity increases after being administered INH (4). Hepatocyte injury after administration of INH to patients with chronic hepatitis B viral (HBV) infection was shown to be more severe than that in patients without HBV infection.…”