Announcements

Seminar In Medicine, 10.08.2018, Dr. Abdo Mahli

Author: KUSOM
Time: 15:30
Location: MED 176

KOÇ UNIVERSITY

SCHOOL OF MEDICINE

 
SEMINAR IN MEDICINE
Friday, August 10th,
 2018

 ******************************************************************
Speaker         :  Dr. Abdo Mahli, Friedrich‐Alexander University Erlangen‐Nürnberg (FAU), Departmant of Biochemistry

Title               : Hepatic Steatosis Potentiates Irinotecan-Induced Hepatocellular Injury Via Dysregulation of Irinotecan-Metabolizing Enzymes

Time              : 15.30 (Refreshments will be served at 15:15)

Place              : MED 176

TelePresence   : AH 5th floor Chief Medical Officer / KUH 9th floor Meeting Room

******************************************************************

HEPATIC STEATOSIS POTENTIATES IRINOTECAN-INDUCED HEPATOCELLULAR INJURY VIA DYSREGULATION OF IRINOTECAN-METABOLIZING ENZYMES

 

Background and Aims: 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. Observational clinical studies indicate that obese patients have a higher risk for developing CASH. However, the underlying mechanisms are elusive.

The aim of this study was to analyze the impact of hepatic steatosis on the hepatotoxicity of irinotecan.

Methods and Results: Lipid accumulation in primary human hepatocytes (PHH) was induced by incubation with the fatty acid oleate. Subsequently, steatotic and control hepatocytes were incubated with up to 50 µM irinotecan (IX). In this dose range, IX alone had only minimal hepatotoxic effects but lipid accumulation enhanced synergistically the hepatotoxic effects of IX. 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. Furthermore, the expression CYP3A4 as well as the expression of UDPglucuronosyltransferase UGT1A1 (the main hepatic enzymes responsible for IX-inactivation) were significantly reduced in fat-loaded hepatocytes. Next, we applied IX to mice with hepatic steatosis (induced by feeding a high-fat diet for 10 weeks) and control mice. In mice with fatty livers, IX treatment further increased hepatocellular lipid accumulation and induced a significantly higher increase of serum transaminases and hepatic oxidative stress, ERK-activation and inflammation compared to control mice. Furthermore, hepatic expression of CYP3A4 and UGT1A1-expression were reduced in steatotic murine livers. This altered hepatic CYPEA4 and UGT1A1 expression pattern was confirmed in patients with non-alcoholic fatty livers.

Conclusion: Our data indicate 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.