Effect of Nutrition on Drug-Induced Liver Injury: Insights from a High-Fat Diet Mouse Model.

Abstract

Literature suggests that a high-fat diet (HFD) potentially increases the risk of chemical/drug-induced toxicity after an acute overdose. Drug/chemical-induced hepatotoxicity has been well studied, and the mechanism that regulates this toxicity has been extensively examined using different experimental animal models. Our study focuses on drug-induced hepatotoxicity in HFD-fed female Balb/C mice. This study addresses the effect of nutrition on the magnitude of acetaminophen (APAP)-induced hepatotoxicity at different time intervals. Female Balb/C mice, after the weaning period separated into two different groups, normal diet (ND) and HFD receiving groups; after 15 weeks, they were dosed with a single dose (300 mg/kg per os (p.o.) of APAP. Blood samples were collected at different time intervals (0, 6 and 24 hours), and liver samples were collected at the end time point. Liver injury parameters [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)], antioxidant assay (sodium dismutase, glutathione, and catalase), and histopathology study were conducted. Pharmacokinetic (PK) analysis was done using the RP-HPLC system and Phoenix WinNonlin 8.3 software. APAP-induced liver injury decreased AST and ALT in the HFD group compared with the ND group at 6 and 24 hours (p < 0.01 and p < 0.001), respectively. Antioxidant enzyme levels remained constant in the HFD group, whereas histopathology showed remarkable changes. The PK's of APAP in HFD indicate lower plasma concentrations of APAP (p < 0.05), with two-fold higher clearance and volume of distribution. HFD significantly reduced susceptibility to APAP-mediated liver injury in Balb/C mice compared with ND mice. Our study mimics the clinical scenario where the same dose of the drug is prescribed to the normal and obese population. Our results suggest the potential need for dose titration to assess an individual's nutritional state in a clinical scenario.