α-Lipoic acid promotes preneoplastic growth in rat liver

α-lipoic acid (α-LA) is a thiol containing antioxidant widely used in a number of conditions related to liver diseases. However, little is known about its effect on the hepatocarcinogenic process. Herein, we investigated the effect of α-LA on the development of rat preneoplastic enzyme-altered foci generated by a model of hepatocarcinogenesis consisting of initiation with a single dose of diethylnitrosamine (DENA) and promotion by feeding a choline-methionine deficient (CMD) diet. The results showed that α-LA administered in drinking water at concentration of 0.05, 0.1 and 0.2% for 6 weeks significantly increased the number of preneoplastic foci positive for the placental form of glutathione S-transferase (GSTP). Further experiments where α-LA was administered in the diet at the final concentration of 0.2% for 6 weeks dramatically increased the number of GSTP-positive foci as compared to rats fed a CMD diet alone (104/cm2 vs. 7/cm2), the mean foci area (0.033 mm2 vs. 0.008 mm2) and the percentage of GSTP-positive liver tissue (3.01% vs. 0.07%). Very few GSTP-positive foci were observed in DENA-treated rats fed a choline supplemented (CS) diet with or without α-LA. The increased number and size of preneoplastic lesions caused by α-LA was associated with enhanced fatty accumulation, elevated levels of serum transaminases, increased expression of CYP2E1 and COX–2, activation of JNK, and chronic hepatocyte proliferation, indicating that α-LA addition to CMD diet aggravates, rather than ameliorating, the hepatic accumulation of triglycerides and liver injury caused by the CMD diet. None of these effects were observed when α-LA was added to the CS diet. In conclusion, these results indicate that α-LA acts as a strong co-promoting agent in the process of liver carcinogenesis, and suggest extreme caution in the use of α-LA for conditions associated with liver damage.