Progression of diethylnitrosamine-induced hepatic carcinogenesis in carnitine-depleted rats

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.