Oxidative stress in carcinogenesis. Correlation between lipid peroxidation and induction of preneoplastic lesions in rat hepatocarcinogenesis.
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.
Sánchez-Pérez
Yesennia
Y
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.
Carrasco-Legleu
Claudia
C
García-Cuellar
Claudia
C
Pérez-Carreón
Julio
J
Hernández-García
Sergio
S
Salcido-Neyoy
Martha
M
Alemán-Lazarini
Leticia
L
Villa-Treviño
Saúl
S
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D004052:Diethylnitrosamine / Q000633:toxicity; D005038:Ethylnitrosourea / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000473:pathology; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000187:drug effects
D000477:Alkylating Agents; D000975:Antioxidants; D017392:Thiobarbituric Acid Reactive Substances; D004052:Diethylnitrosamine; D011794:Quercetin; D005723:gamma-Glutamyltransferase; D005038:Ethylnitrosourea