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Carcinogenesis Advance Access published online on September 24, 2007
Carcinogenesis, doi:10.1093/carcin/bgm205
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

{alpha}-LIPOIC ACID PROMOTES THE GROWTH OF RAT HEPATIC PRENEOPLASTIC LESIONS IN THE CHOLINE DEFICIENT MODEL

Andrea Perra, Monica Pibiri, Pia Sulas, Gabriella Simbula, Giovanna M. Ledda-Columbano and Amedeo Columbano

Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Italy

Send all correspondence to: Amedeo Columbano, Department of Toxicology, Oncology and Molecular Pathology Unit, Via Porcell 4, 09124 Cagliari, ITALY, Telephone: ++39-070-6758345, Fax: ++39-070-666062, e-mail: columbano{at}unica.it

{alpha}-lipoic acid is an antioxidant used in a number of conditions related to liver diseases. Herein, we investigated the effect of {alpha}-lipoic acid on the development of rat preneoplastic 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}-lipoic acid. Preneoplastic lesions were identified by their positivity to the placental form of glutathione S-transferase (GSTP) or to gamma-glutamyl transpeptidase (GGT). {alpha}-lipoic acid given to rats fed a CMD for 6 weeks dramatically increased the number of GSTP-positive foci as compared to rats fed a CMD diet alone (96/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%). Essentially similar results were obtained after 10 weeks of treatment. Co-treatment with CMD + {alpha}-lipoic acid also resulted in the enhancement of fat accumulation, lipid peroxidation, and hepatocyte death; increased expression of tumour necrosis factor-{alpha}, cytochrome 2E1, cyclooxygenase-2, enhanced activation of JNK and STAT3, and chronic hepatocyte proliferation was also observed. No such effects were observed when {alpha}-lipoic acid was added to a choline-supplemented diet. In conclusion, administration of {alpha}-lipoic acid in conditions associated with hepatic damage aggravates liver injury and stimulates the development of preneoplastic lesions; the results also suggest caution in its use in the presence of chronic liver injury.

Key Words: {alpha}-lipoic acid • choline deficient diet • preneoplastic hepatic foci • fatty liver • steatohepatitis

Received July 20, 2007; revised September 5, 2007; accepted September 6, 2007.


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