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Cancer Lett. 2005 Jan 10;217(1):25-32.

Oxidative stress in carcinogenesis. Correlation between lipid peroxidation and induction of preneoplastic lesions in rat hepatocarcinogenesis.

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Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV), Av. IPN No. 2508 Col. San Pedro Zacatenco, México 14, DF, CP 07360, Mexico.


Oxidative stress during carcinogen metabolism seems to participate in liver tumor production in the rat. N-diethylnitrosamine is an important carcinogen used in liver cancer animal models. This indirect alkylating agent produces DNA-ethyl adducts and oxidative stress. In contrast, N-ethyl-N-nitrosourea, a direct mutagen, which generates DNA-ethyl adducts, does not produce liver tumors in rat unless it is given under oxidative stress conditions such as partial hepatectomy or phenobarbital treatment. To gain insight into the relation between oxidative stress and hepatocarcinogenicity, the induction of preneoplastic liver lesions was compared among three different initiation protocols related to the initiation-promotion-resistant hepatocyte model. In addition, liver lipid peroxidation levels, determined as thiobarituric acid reactive substances were studied early during the initiation stage. Rats initiated with N-ethyl-N-nitrosourea, 25 days after treatment developed fewer and smaller gamma-glutamyl transpeptidase positive preneoplastic lesions than rats initiated with N-diethylnitrosamine. A pre-treatment with the antioxidant quercetin 1 h before N-diethylnitrosamine initiation, significantly prevented development of gamma-glutamyl transpeptidase-positive lesions. Increased lipid peroxidation levels were induced with N-diethylnitrosamine from 3 to 24 h after initiation, while N-ethyl-N-nitrosourea did not induce increments, and importantly, pre-treatment with quercetin decreased lipid peroxidation induced by N-diethylnitrosamine. These results show correlation between lipid peroxidation and hepatocarcinogenicity and support the important role of oxidative stress on liver carcinogenesis.

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