Alpha-lipoic acid promotes the growth of rat hepatic pre-neoplastic lesions in the choline-deficient model.
alpha-lipoic acid (alpha-LA) is an antioxidant used in a number of conditions related to liver diseases. Herein, we investigated the effect of alpha-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 alpha-LA. Pre-neoplastic lesions were identified by their positivity to the placental form of glutathione S-transferase (GSTP) or to gamma glutamyl transpeptidase. alpha-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/cm(2) versus 7/cm(2)), the mean foci area (0.033 versus 0.008 mm(2)) 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 + alpha-LA also resulted in the enhancement of fat accumulation, lipid peroxidation and hepatocyte death; increased expression of tumor necrosis factor-alpha, 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 alpha-LA was added to a choline-supplemented diet. In conclusion, administration of alpha-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.
Perra
Andrea
A
Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy.
Pibiri
Monica
M
Sulas
Pia
P
Simbula
Gabriella
G
Ledda-Columbano
Giovanna Maria
GM
Columbano
Amedeo
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death; D002796:Choline Deficiency / Q000473:pathology*; D015227:Lipid Peroxidation; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011230:Precancerous Conditions / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D008063:Thioctic Acid / Q000494:pharmacology*
D000975:Antioxidants; D008063:Thioctic Acid