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

Abstract

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), g a m m a -g l u t a my l t ra n s fe ra s e ( G -G T ) , a l k a l i n e 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 DENAinduced 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.

Preventive Effect of Hydrazinocurcumin on Carcinogenesis of Diethylnitrosamine-induced Hepatocarcinoma in Male SD Rats

“…Generally, liver damage induced by DEN is related to the disruption of liver cell metabolism and membrane instability and subsequently causes distinctive changes in the activities of serum enzyme. The elevation of ALT activity is credited to hepatocellular damage and is usually accompanied by a rise in AST (Al-Rejaie et al, 2009). ALP as one of the liver function enzymes is closely connected with lipid membrane in the canalicular zone.…”

Metabolomics Study of Stepwise Hepatocarcinogenesis From the Model Rats to Patients: Potential Biomarkers Effective for Small Hepatocellular Carcinoma Diagnosis

“…The deregulation of PUFA has been considered as the early events in the liver carcinogenesis (39). L-carnitine acts as a protector from liver carcinogenesis by decreasing free fatty acid in blood and lower the oxidative damage from lipids peroxidation (40,41). Phospholipids take part in the metabolism of lipids.…”

Sequential analysis of diethylnitrosamine-induced hepatocarcinogenesis in rats

“…DEN is an established powerful hepatocarcinogen in rats, which possibly works by altering the DNA structure, forming alkyl DNA adducts, and inducing chromosomal aberrations and micronuclei in the liver (9,10). It has also been reported that oxidative stress plays a pivotal role during carcinogenesis (11).…”