Glycosphingolipids Prevent APAP and HMG-CoA Reductase Inhibitors-mediated Liver Damage:A Novel Method for'Safer Drug'Formulation that Prevents Drug-induced Liver Injury

摘要

Background and Aims: Acetaminophen (APAP) and HMG-CoA reductase inhibitors are common causes of drug-induced liver injury (DILI). This study aimed to determine the ability to reduce APAP- and statins-mediated liver injury by using formu-lations that combine glycosphingolipids and vitamin E. Meth-ods: Mice were injected with APAP or with statins and treated before and after with β-glucosylceramide (GC), with or without vitamin E. Mice were followed for changes in liver enzymes, liver his-tology, hepatic expression of JNK, STAT3 and caspase 3, as well as intrahepatic natural killer T cells (NKT) and the serum cytokine levels by flow cytometry. Results: Administration of GC before or after APAP alleviated the liver damage, as noted by a reduction of the liver enzymes, improvement in the liver histology and decreased hepatic caspase 3 expression. Beneficial effect was associated with a reduction of the intrahepatic NKT,JNK expression in the liver, and increased glutathione in the liver, and decreased TNF-α serum levels. Synergistic effect of co-administration of GC with vitamin E was observed. Similar protective effect of GC on statin-mediated liver damage was documented by a reduction in liver enzymes and improved liver histology, which was mediated by reduction of NKT, increased STAT3 expression in the liver, and reduced the TGF-β and IL17 levels. Conclusions: β-glycosphingolipids exert a hepatopro-tective effect on APAP- and statins-mediated liver damage. Vitamin E exerted a synergistic effect to that of GC. The gener-ation of "safer drug" formulations, which include an active mol-ecule combined with a hepatoprotective adjuvant, may provide an answer to the real unmet need of DILI.