Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612722
Poster Visit Session II Clinical Hepatology – Friday, January 26, 2018, 2:35pm – 3:20pm, Room 120
Georg Thieme Verlag KG Stuttgart · New York

Hepatic steatosis potentiates irinotecan-induced hepatocellular injury

A Mahli
1   Friedrich-Alexander University Erlangen-Nürnberg, Institute of Biochemistry, Erlangen
,
A Koch
1   Friedrich-Alexander University Erlangen-Nürnberg, Institute of Biochemistry, Erlangen
,
W Thasler
2   Ludwig-Maximilians-University Munich, Biobank o.b. HTCR, Department of General Visceral- and Transplantation Surgery, Munich
,
C Hellerbrand
1   Friedrich-Alexander University Erlangen-Nürnberg, Institute of Biochemistry, Erlangen
3   Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2018 (online)

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Inclusion of irinotecan (IX) in preoperative chemotherapy regimens is associated with the risk to develop steatohepatitis known as chemotherapy-associated steatohepatitis (CASH) which increases the risk of perioperative morbidity and mortality. However, several observational clinical studies have reported that the obese patients had a higher risk for developing irinotecan-induced steatohepatitis. Moreover, IX could aggravate the pre-existing NAFLD, particularly in obese and diabetic patients, and sometimes hasten the progression into CASH and severe fibrosis.

The aim of this study was to analyze the impact of hepatic steatosis on the hepatotoxicity of IX by analyzing of the effects of IX on fat-loaded (steatotic) hepatocytes compared to control cells.

Methods and Results:

Lipid accumulation in primary human hepatocytes (PHH) was induced by incubation with the fatty acid oleate (0.2 mM). Subsequently, steatotic and control hepatocytes were incubated with up to 50µM irinotecan (IX). In this dose range, IX alone had only minimal hepatotoxic effects but lipid accumulation enhanced synergistically the hepatotoxic effects of IX as revealed by AST and ALT leakage to the cultured supernatants. Moreover, the effects of IX on cellular triglyceride content, as well as lipid peroxidation, oxidative stress and ERK-mediated pro-inflammatory gene expression were significantly enhanced in fat-loaded hepatocytes compared to control cells. Moreover, under the used experimental conditions, the expression of carboxylesterase 2 (CE2), which metabolizes IX to its active metabolite SN38, was significantly induced in fat-loaded hepatocytes while the expression of UDP-glucuronosyltransferase UGT1A1 (the main hepatic enzyme responsible for IX-inactivation) was significantly reduced in fat-loaded hepatocytes.

Conclusion:

Our model indicates that irinotecan and steatosis synergistically induce pathological mechanisms in hepatocytes via dysregulation of IX-metabolizing enzymes which lead to higher hepatic levels of its toxic metabolite SN38. These findings may have important implications for prediction, prevention and treatment of irinotecan-induced CASH particularly in obese individuals.