In vitro and in vivo models for irinotecan induced steatohepatitis

Irinotecan induced steatohepatitis is a risk for perioperative morbidity and mortality, however, the underlying mechanisms are still unknown.

The aim of this study was to establish in vitro and in vivo models of for irinotecan induced steatohepatitis to unravel the molecular mechanisms of this phenomenon.

Methods and Results: Initially, we determined the dose-range in which irinotecan treatment did not affect the viability of hepatoma cells and primary human hepatocytes. In this dose-range (of up to 50µM) irinotecan induced a dose-dependent lipid accumulation as assessed by oil-red o staining and analysis of the triglyceride content, and expression of pro-inflammatory genes (IL-8 and ICAM-1). Moreover, irinotecan induced the accumulation of free fatty acids, the formation of reactive oxygen species (ROS) and ERK-activation. Preincubation with ROS-scavangers or ERK-inhibition diminished both irinotecan induced lipid accumulation and inflammatory gene expression. Of note, timecourse experiments indicated that ERK-activation and pro-inflammatory gene expression proceed hepatocellular lipid accumulation. To establish an in vivo CASH model, we injected mice with a dose of 50mg/kg irinotecan for 2 weeks, and detected significant hepatic steatosis and inflammatory gene expression, and also in vivo we detected increased hepatic ERK-activation in response to irinotecan treatment.

Conclusion: Our novel in vitro and vivo models indicate ERK-activation as critical pathways of irinotecan induced steatohepatitis, in which hepatic inflammation seems to proceed steatosis.