摘要
AIM:To investigate whether carnitine deficiency is a risk factor during the development of diethylnitrosamine (DENA)-induced hepatic carcinogenesis. METHODS:A total of 60 male Wistar albino rats were divided into six groups with 10 animals in each group.Rats in group 1(control group)received a single intraperitoneal(i.p.)injection of normal saline. Animals in group 2(carnitine-supplemented group) were given L-carnitine(200 mg/kg per day)in drinking water for 8 wk.Animals in group 3(carnitine-depleted group)were given D-carnitine(200 mg/kg per day)and mildronate(200 mg/kg per day)in drinking water for 8 wk.Rats in group 4(DENA group)were injected with a single dose of DENA(200 mg/kg,i.p.)and 2 wk later received a single dose of carbon tetrachloride(2 mL/kg) by gavage as 1:1 dilution in corn oil.Animals in group 5(DENA-carnitine depleted group)received the same treatment as group 3 and group 4.Rats in group 6 (DENA-carnitine supplemented group)received the same treatment as group 2 and group 4.RESULTS:Administration of DENA resulted in a significant increase in alanine transaminase(ALT), gamma-glutamyl transferase(G-GT),alkaline phosphatase(ALP),total bilirubin,thiobarbituric acid reactive substances(TBARS)and total nitrate/ nitrite(NOx)and a significant decrease in reduced glutathione(GSH),glutathione peroxidase(GSHPx), catalase(CAT)and total carnitine content in liver tissues.In the carnitine-depleted rat model,DENA induced a dramatic increase in serum ALT,G-GT,ALP and total bilirubin,as well as a progressive reduction in total carnitine content in liver tissues.Interestingly, L-carnitine supplementation resulted in a complete reversal of the increase in liver enzymes,TBARS and NOx,and a decrease in total carnitine,GSH,GSHPx, and CAT induced by DENA,compared with the control values.Histopathological examination of liver tissues confirmed the biochemical data,where L-carnitine prevented DENA-induced hepatic carcinogenesis while D-carnitine-mildronate aggravated DENA-induced hepatic damage. CONCLUSION:Data from this study suggest for the first time that:(1)carnitine deficiency is a risk factor and should be viewed as a mechanism in DENA- induced hepatic carcinogenesis;(2)oxidative stress plays an important role but is not the only cause of DENA-induced hepatic carcinogenesis;and(3) long-term L-carnitine supplementation prevents the development of DENA-induced liver cancer.
AIM： To investigate whether carnitine deficiency is a risk factor during the development of diethylnitrosamine （DENA）-induced hepatic carcinogenesis. METHODS： A total of 60 male Wistar albino rats were divided into six groups with 10 animals in each group. Rats in group 1 （control group） received a single intraperitoneal （i.p.） injection of normal saline. Animals in group 2 （carnitine-supplemented group） were given L-carnitine （200 mg/kg per day） in drinking water for 8 wk. Animals in group 3 （carnitine-depleted group） were given D-carnitine （200 mg/kg per day） and mildronate （200 mg/kg per day） in drinking water for 8 wk. Rats in group 4 （DENA group） were injected with a single dose of DENA （200 mg/kg, i.p.） and 2 wk later received a single dose of carbon tetrachloride （2 mL/kg） by gavage as 1：1 dilution in corn oil. Animals in group 5 （DENA-carnitine depleted group） received the same treatment as group 3 and group 4. Rats in group 6 （DENA-carnitine supplemented group） received the same treatment as group 2 and group 4.RESULTS： Administration of DENA resulted in a significant increase in alanine transaminase （ALT）, gamma-glutamyl transferase （G-GT）, alkaline phosphatase （ALP）, total bilirubin, thiobarbituric acid reactive substances （TBARS） and total nitrate/ nitrite （NOx） and a significant decrease in reduced glutathione （GSH）, glutathione peroxidase （GSHPx）, catalase （CAT） and total carnitine content in liver tissues. In the carnitine-depleted rat model, DENA induced a dramatic increase in serum ALT, G-GT, ALP and total bilirubin, as well as a progressive reduction in total carnitine content in liver tissues. Interestingly, L-carnitine supplementation resulted in a complete reversal of the increase in liver enzymes, TBARS and NOx, and a decrease in total carnitine, GSH, GSHPx, and CAT induced by DENA, compared with the control values. Histopathological examination of liver tissues confirmed the biochemical data, where L-carnitine prevented DENA-induced hepatic carcinogenesis while D-carnitine-mildronate aggravated DENA-induced hepatic damage. CONCLUSION： Data from this study suggest for the first time that： （1） carnitine deficiency is a risk factor and should be viewed as a mechanism in DENA-induced hepatic carcinogenesis; （2） oxidative stress plays an important role but is not the only cause of DENA-induced hepatic carcinogenesis; and （3） long-term L-carnitine supplementation prevents the development of DENA-induced liver cancer.
基金
Supported by Operating grant from Research Center,Collegeof Pharmacy,King Saud University(CPRC 207)
