Effect of nutrition on drug-induced liver injury: insights from a high-fat diet mouse model

INTRODUCTION: 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 is 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 APAP-induced hepatotoxicity at different time intervals.
METHODS: Female Balb/c mice after weaning period separated into two different groups normal diet (ND) & high fat diet (HFD) receiving groups, after 15 weeks they were dosed with single dose (300 mg/kg p.o.) of acetaminophen (APAP). Blood samples were collected at different time intervals (0, 6 & 24hour), liver sample at the end time point. Liver injury parameters (ALT and AST), anti-oxidant assay (SOD, GSH & Catalase), and histopathology study was conducted. Pharmacokinetic analysis was done using RP-HPLC system and Phoenix WinNonlin 8.3 software.
RESULTS: APAP-induced liver injury decreased AST, ALT in HFD group compared to normal diet (ND) group. Antioxidant enzyme levels remained constant in HFD group, while histopathology showed remarkable changes. Pharmacokinetics of APAP in HFD indicates, it had lower plasma concentrations of APAP, with two-fold higher clearance and volume of distribution.
DISCUSSION AND CONCLUSION: HFD reduces susceptibility to APAP-mediated liver injury in Balb/C mice compared to those on ND. 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 an individual’s nutritional state in a clinical scenario.