Selection of agents for prevention of cisplatin-induced hepatotoxicity.
The objective of this study was to explore the optimal combination of agents used along with cisplatin for protection of hepatotoxicity. Animal experiment was carried out based on the orthogonal design L(8) (2(7)) setting seven factors with two different levels of each, and eight groups of mice were needed. The agents tested in this study were zinc, selenium, fosfomycin, sodium thiosulfate (STS), N-acetyl-cysteine (NAC), methionine and taurine. Mice were supplemented by gavage with various combinations of agents as designed in the orthogonal table once a day for nine days beginning two days before cisplatin administration. 3.5mg/kg body weight of cisplatin was given intraperitoneally once a day for five days simultaneously. After cessation of cisplatin administration, the agents were supplemented continuously for two days. Activities of alanine aminotransferase (ALT) in serum, levels of glutathione (GSH) and malondialdehyde (MDA) in liver were analyzed after cessation of supplementation. Results showed zinc, fosfomycin and methionine were the effective factors for protection of weight loss; fosfomycin and methionine were the effective factors for prevention of decreased liver ratio; selenium, fosfomycin and STS were the effective factors for prevention of increased ALT activities in serum. On the other hand, methionine was the only effective factor for prevention of decreased GSH levels in liver; zinc, selenium and fosfomycin were the effective factors for prevention of increased MDA levels in liver. Based on the data observed in this study, the optimum combinations of agents were selenium, fosfomycin, methionine and taurine, and zinc, selenium, STS and methionine. In conclusion, each agent used in this study could play a beneficial role for prevention of cisplatin hepatotoxicity, however, none could play the crucial role. The potentiated actions for prevention of cisplatin hepatotoxicity could be achieved via combined use of these agents.
Liao
Yingjun
Y
Department of Physiology, School of Basic Medicine, China Medical University, Shenyang, Liaoning, PR China.
Lu
Xiuqiang
X
Lu
Chunwei
C
Li
Gexin
G
Jin
Yaping
Y
Tang
Hao
H
D000111:Acetylcysteine / Q000008:administration & dosage / Q000627:therapeutic use; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000517:prevention & control*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects*; D004359:Drug Therapy, Combination; D005578:Fosfomycin / Q000008:administration & dosage / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008715:Methionine / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D010865:Pilot Projects; D012643:Selenium / Q000008:administration & dosage / Q000627:therapeutic use; D013654:Taurine / Q000008:administration & dosage / Q000627:therapeutic use; D013885:Thiosulfates / Q000008:administration & dosage / Q000627:therapeutic use; D015032:Zinc / Q000008:administration & dosage / Q000627:therapeutic use
D000970:Antineoplastic Agents; D000975:Antioxidants; D013885:Thiosulfates; D013654:Taurine; D005578:Fosfomycin; D008315:Malondialdehyde; D008715:Methionine; D000410:Alanine Transaminase; D005978:Glutathione; D012643:Selenium; C017717:sodium thiosulfate; D015032:Zinc; D002945:Cisplatin; D000111:Acetylcysteine