The molecular mechanism underlining the preventive effect of vitamin D against hepatic and renal acute toxicity through the NrF2/ BACH1/ HO-1 pathway.

ABSTRACT

AIM: Drug-induced liver and kidney injuries are worldwide problems that cause restrictions in the use of drugs. The injury is highly mediated by oxidative stress and inflammation pathways. So, demonstrating the role of the natural compound (Vit.D) on the prevention of acetaminophen (APAP) overdose toxicity and the molecular mechanism through NrF2/BACH1/HO-1 pathway is promising. EXPERIMENTAL Male Sprague Dawley rats (40 rats) were divided randomly into 4 groups Normal, APAP, APAP+Vit.D (500 IU/kg) and APAP+Vit.D (1000 IU/kg). The APAP toxicity caused by 2 g/kg (orally) on day 7. KEY FINDINGS: Vit D decreased significantly liver and kidney functions serum ALT and AST activities (P < 0.0005); creatinine and urea (P < 0.0005) concentrations; liver and kidney histopathological scores. Furthermore, Vit.D ameliorated APAP-caused oxidative stress through the liver malondialdehyde concentration's decrease and the total antioxidant capacity's increase (P < 0.0005). The molecular mechanism of Vit.D may include the prevention of high deteriorating increase of oxidative stress mediators hepatic and renal NrF2 and BACH1 tissue expression in addition to serum HO-1 (P < 0.0005); the increase of inflammatory mediators; hepatic and renal NF-κB tissue expression, serum interleukin-10 (P < 0.0005) and TNF-α (P < 0.05). The 500 IU/kg Vit.D administration caused better protection results especially on the histopathological and immunohistochemical results than the 1000 IU/kg Vit.D administration. SIGNIFICANCE: Vit.D ameliorates APAP-induced liver and kidney injury that may be attributed to its ability to moderately increase antioxidant status to counteract the toxicity without the massive destructive increase in the anti-oxidant pathway (NrF2/HO-1/BACH1). So, this work represents a great prophylactic role of Vit.D against drug-induced liver and kidney injury.