α-lipoic acid promotes the growth of rat hepatic pre-neoplastic lesions in the choline-deficient model

Abstract

α-lipoic acid (α-LA) is an antioxidant used in a number of conditions related to liver diseases. Herein, we investigated the effect of α-LA on the development of rat pre-neoplastic lesions generated by a model of hepatocarcinogenesis, which has similarities in its histopathological sequence to human hepatocellular carcinoma development with cirrhosis. Initiation of hepatocytes was achieved by treatment with a single dose of diethylnitrosamine and promotion by feeding a choline-methionine-deficient diet (CMD), with or without α-LA. Pre-neoplastic lesions were identified by their positivity to the placental form of glutathione S -transferase (GSTP) or to gamma glutamyl transpeptidase. α-LA given to rats fed a CMD for 6 weeks dramatically increased the number of GSTP-positive foci as compared with rats fed a CMD alone (96/cm2 versus 7/cm2), the mean foci area (0.033 versus 0.008 mm2) and the percentage of GSTP-positive liver tissue (3.01 versus 0.07%). Essentially similar results were obtained after 10 weeks of treatment. Co-treatment with CMD + α-LA also resulted in the enhancement of fat accumulation, lipid peroxidation and hepatocyte death; increased expression of tumor necrosis factor-α, cytochrome 2E1 and cyclooxygenase-2, enhanced activation of c-jun N-terminal kinase and signal transducer activator of transcription 3, and chronic hepatocyte proliferation was also observed. No such effects were observed when α-LA was added to a choline-supplemented diet. In conclusion, administration of α-LA in conditions associated with hepatic damage aggravates liver injury and stimulates the development of pre-neoplastic lesions; the results also suggest caution in its use in the presence of chronic liver injury. © The Author 2007. Published by Oxford University Press. All rights reserved.