Fructose diet decreases APAP‐induced hepatotoxicity in mice

Abstract

Acetaminophen (APAP) is a commonly used over‐the‐counter analgesic and antipyretic. APAP overdose can cause hepatotoxicity, and is responsible for ~50% of acute liver failure in US. However, risk factors for severe liver injury after APAP dose remain unclear. Previous studies have shown conflicting effects of fructose diet on the susceptibility to APAP‐induced hepatotoxicity (1, 2). The aims of the present study were to evaluate the role of fructose diet in modulating the extent of APAP‐induced liver injury and explore potential roles of differential gut microbiota in any effects. Male C57BL/6J mice (8 weeks old) were given 30% (w/v) fructose in water (or regular water) for 8 weeks, followed by oral administration of APAP (600 mg/kg) or vehicle control. The animals were sacrificed 24 h after APAP dosing, and tissues were collected. APAP‐induced liver injury (determined by serum levels of liver enzymes) was decreased by two‐fold in mice pretreated with fructose. Fructose‐treated group exhibited (~1.5 fold) higher basal glutathione levels and (~2 fold) lower basal (mRNA and activity) levels of CYP1A2 and CYP2E1, suggesting decreased bioactivation of APAP and increased detoxification of toxic metabolite in fructose‐treated mice. Also, mRNA expression levels of GCLC (glutamate‐cysteine ligase; a rate‐limiting enzyme in synthesis of glutathione) exhibited a trend of increase in fructose group. mRNA expression of HSP70 (heat shock protein 70; a chaperone protein previously known to have a protective effect against APAP hepatotoxicity) was also found increased in fructose group. High‐throughput, next‐generation sequence (NGS) analysis of bacterial 16S rRNA gene amplicons from the cecal samples of vehicle group showed that fructose diet altered the composition of gut microbiota, leading to increased α‐diversity (Mann‐Whitney, p=0.043) and a significant difference in overall bacterial community (Bray‐Curtis, ANOSIM: R = 0.581, p = 0.001). However, no bacteria taxa were found to be significantly correlated with hepatic mRNA level of CYP2E1 or CYP1A2, or glutathione levels. These findings suggest that fructose diet decreases APAP‐induced liver injury in mice, in part by reducing metabolic activation of APAP and inducing detoxification to toxic metabolites. Fructose diet also alters gut microbiota composition in mice although its role in modulation of APAP toxicity remains unclear.Support or Funding InformationThis study was supported by Chicago Biomedical Consortium.