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Carcinogenesis Advance Access originally published online on September 24, 2007
Carcinogenesis 2008 29(1):161-168; 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 pre-neoplastic lesions in the choline-deficient model

Andrea Perra, Monica Pibiri, Pia Sulas, Gabriella Simbula, Giovanna Maria Ledda-Columbano and Amedeo Columbano*

Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy

* To whom correspondence should be addressed. Tel: +39 070 6758345; Fax: +39 070 666062; Email: columbano{at}unica.it

{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/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 + {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.

Abbreviations: {alpha}-LA, {alpha}-lipoic acid; BrdU, bromodeoxyuridine; CMD, choline–methionine deficient diet; CS, choline-supplemented diet; COX, cyclooxygenase; DENA, diethylnitrosamine; GGT, gamma glutamyl transpeptidase; GSTP, glutathione S-transferase; HCC, hepatocellular carcinoma; JNK, c-jun N-terminal kinase; LPO, lipid peroxidation; mRNA, messenger RNA; ROS, reactive oxygen species; STAT3, signal transducer activator of transcription 3; TNF-{alpha}, tumor necrosis factor-{alpha}

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


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