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


CONCLUSIONS
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.
Al-Rejaie
Salim S
SS
Department of Pharmacology, College of Pharmacy, King Saud University, PO Box 2457, Kingdom of Saudi Arabia.
Aleisa
Abdulaziz M
AM
Al-Yahya
Abdulaziz A
AA
Bakheet
Saleh A
SA
Alsheikh
Abdulmalik
A
Fatani
Amal G
AG
Al-Shabanah
Othman A
OA
Sayed-Ahmed
Mohamed M
MM
D000410:Alanine Transaminase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D002331:Carnitine / Q000008:administration & dosage / Q000172:deficiency*; D002374:Catalase / Q000378:metabolism; D019587:Dietary Supplements; D004052:Diethylnitrosamine / Q000633:toxicity*; D018450:Disease Progression; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D015227:Lipid Peroxidation; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D017392:Thiobarbituric Acid Reactive Substances; D004052:Diethylnitrosamine; D002374:Catalase; D005979:Glutathione Peroxidase; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D005978:Glutathione; D001663:Bilirubin; D002331:Carnitine