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World J Gastroenterol. Mar 21, 2009; 15(11): 1373-1380
Published online Mar 21, 2009. doi: 10.3748/wjg.15.1373
Progression of diethylnitrosamine-induced hepatic carcinogenesis in carnitine-depleted rats
Salim S Al-Rejaie, Abdulaziz M Aleisa, Abdulaziz A Al-Yahya, Saleh A Bakheet, Abdulmalik Alsheikh, Amal G Fatani, Othman A Al-Shabanah, Mohamed M Sayed-Ahmed
Salim S Al-Rejaie, Abdulaziz M Aleisa, Abdulaziz A Al-Yahya, Saleh A Bakheet, Amal G Fatani, Othman A Al-Shabanah, Mohamed M Sayed-Ahmed, Department of Pharmacology, College of Pharmacy, King Saud University, PO Box 2457, Kingdom of Saudi Arabia
Abdulmalik Alsheikh, Department of Pathology, College of Medicine, King Saud University, PO Box 2457, Kingdom of Saudi Arabia
Author contributions: Al-Rejaie SS and Aleisa AM designed the study and were involved in editing the manuscript; Al-Yahya AA and Bakheet SA performed the majority of experiments; Alsheikh A performed the histopathology; Fatani AG provided vital reagents and analyzed the data, Al-Shabanah OA and Sayed-Ahmed MM provided financial support for the study and wrote the manuscript.
Correspondence to: Dr. Mohamed M Sayed-Ahmed, Department of Pharmacology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Kingdom of Saudi Arabia. mmsayedahmed@hotmail.com
Telephone: +966-506065734
Fax: +966-1-14677200
Received: October 22, 2008
Revised: February 23, 2009
Accepted: March 1, 2009
Published online: March 21, 2009
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), 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.

Keywords: Carnitine deficiency; D-carnitine; L-carnitine; Diethylnitrosamine; Hepatic carcinogenesis