Z Gastroenterol 2019; 57(01): e47
DOI: 10.1055/s-0038-1677171
3. Metabolism (incl. NAFLD)
Georg Thieme Verlag KG Stuttgart · New York

Hepatic steatosis potentiates irinotecan-induced hepatocellular steatohepatitis via dysregulation of irinotecan-metabolizing enzymes

A Mahli
1   Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
,
A Koch
1   Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
,
S Lee
2   Biobank of the Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
,
WE Thasler
2   Biobank of the Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
,
AK Bosserhoff
1   Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
3   Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen, Germany
,
C Hellerbrand
1   Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
3   Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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Neoadjuvant chemotherapy with irinotecan is associated with the risk of developing a type of steatohepatitis known as chemotherapy-associated steatohepatitis (CASH) which increases the risk of perioperative morbidity and mortality. Observational studies indicate that obesity enhances the risk for irinotecan-induced CASH. However, the underlying mechanisms are elusive.

The aim of this study was to analyze the impact of hepatocellular lipid accumulation on irinotecan-induced hepatotoxicity.

Methods and Results:

Incubation with free fatty acids was used to induce dose-dependent lipid accumulation in primary human hepatocytes (PHH). Subsequently, steatotic and control hepatocytes were incubated with up to 50µM irinotecan. In this dose range, irinotecan alone had only minimal hepatotoxic effects but lipid accumulation synergistically enhanced the hepatotoxic effects of irinotecan. Moreover, the effects of irinotecan on cellular triglyceride content, as well as lipid peroxidation, oxidative stress and ERK-mediated pro-inflammatory gene expression, were significantly enhanced in steatotic cells compared to control cells. Enhanced ERK activation and autophagy impairment were identified as underlying mechanisms. Moreover, the expression of carboxylesterase 2 (CE2), which metabolizes irinotecan to its active metabolite SN38, was significantly induced in fat-loaded hepatocytes while the expression of UDP-glucuronosyltransferase (UGT1A1) and CYP3A4, the 2 main hepatic enzymes responsible for irinotecan-inactivation, were significantly reduced in fat-loaded hepatocytes. Accordingly, pre-incubation of the cells with rifampicin (an inducer of CYP3A4 and UGT1A1) abrogated the fat-enhanced irinotecan toxicity.

Conclusion:

Steatosis-induced dysregulation of irinotecan-metabolizing enzymes causes an accumulation of its toxic metabolite SN38. Consecutively, enhanced ERK activation and impairment of autophagy aggravate inflammation and cell death in steatotic livers. These findings may have important implications for the prediction, prevention and treatment of irinotecan-induced CASH particularly in obese individuals.