An animal model for chemotherapy-associated steatohepatitis and its prevention by the oral administration of fatty acid bile acid conjugate.
BACKGROUND
Preoperative chemotherapy for hepatic resection of colorectal liver metastases is associated with the development of chemotherapy-associated steatohepatitis (CASH). This increases the risk of perioperative morbidity and mortality. To the authors' knowledge, an animal model for CASH has not been described previously. It has been established that fatty acid bile acid conjugates (FABACs) prevent the formation of diet-induced fatty liver. The current study was designed to establish an animal model of CASH and to use that model to study the effect of FABACs on its occurrence.


METHODS
C57BL/6 mice were given different doses of oxaliplatin and irinotecan. Oxaliplatin administered once weekly at a dose of 6 mg/kg for a total dose of 24 mg/kg was tolerated best and was associated most consistently with CASH. Thus, that dose was chosen as the induction model for CASH. Subsequently, mice were divided into a control group (no treatment), an oxaliplatin group, and a CASH-prevention group, which received oxaliplatin and C20-FABAC at a dose of 150 mg/kg daily. The animals were killed after 28 days.


RESULTS
Liver fat content was significantly lower (P < .0001) in the control group (51.63 mg/g) and the prevention group (62.13 mg/g) compared with the oxaliplatin group (95.35 mg/g). This difference was mainly because of the accumulation of liver triglycerides in the oxaliplatin group.


CONCLUSIONS
The current results indicated that C57BL/6 mice receiving weekly oxaliplatin can be used as a model for CASH. Oral FABAC therapy reduced the development of CASH in animals that received oxaliplatin. To the authors' knowledge, this report is the first description of a model and a potential preventive treatment for CASH.
Keizman
Daniel
D
Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. danielkeizman@gmail.com
Maimon
Natalie
N
Ish-Shalom
Maya
M
Buchbut
Dana
D
Inbar
Moshe
M
Klein
Baruch
B
Bernheim
Joelle
J
Goldiner
Ilana
I
Leikin-Frenkel
Alicia
A
Konikoff
Fred
F
D000818:Animals; D001647:Bile Acids and Salts / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000633:toxicity; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000627:therapeutic use; D005234:Fatty Liver / Q000139:chemically induced* / Q000517:prevention & control*; D000077146:Irinotecan; D051379:Mice; D008810:Mice, Inbred C57BL; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin
D001647:Bile Acids and Salts; D005227:Fatty Acids; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002166:Camptothecin