o-Phenanthroline protects mammalian cells from hydrogen peroxide-induced gene mutation and morphological transformation

Abstract

The radiomimetic agent hydrogen peroxide is known to produce DNA strand breaks, chromosome damage and cell death. It has also been identified as one of the cytotoxic agents formed during certain drug metabolism and by phagocytic cells in the respiratory burst. Our laboratory recently identified the ultimate reactive species responsible for the DNA-damaging and cytotoxic effect of H2O2 as being hydroxyl radical. This was achieved by the use of the specific iron chelator o-phenanthroline, which prevents the occurrence of a Fenton reaction between H2O2 and chromatin bound ferrous ions. In this paper we show that H2O2 is able to induce mutation at the HGPRT locus in V79 cells and morphological transformation of C3H/10T1/2 cells. o-Phenanthroline abolishes both effects, indicating that hydroxyl radical is directly involved in mutation and carcinogenesis.

Stimulated human leukocytes cause activating mutations in the K-ras proto-oncogene

“…Similarly, chronic in¯ammation of the skin, urinary bladder, gall bladder, stomach, esophagus, bone, etc, is associated with an increased incidence of malignancies in these tissues (Weitzman and Gordon, 1990). In addition to this well-known association between in¯ammation and human carcinogenesis, previous studies have also demonstrated that cultured mouse ®broblast cells can be transformed into malignant cells when exposed to in¯ammatory leukocytes (Weitzman et al, 1985;Nassi-Calo et al, 1989;Zimmerman and Cerutti, 1984).…”

Characterization of chromatin modified with reactive oxygen species: Recognition by autoantibodies in cancer

“…The damage leads to mutation, single-and double-strand breaks and generation of apurinic sites [11]. Hydroxyl radicals are also believed to be responsible for major damage to chromatin [32][33][34]. Superoxide anion radical is considered to be a highly toxic entity in many biological systems [16].…”

Danos ao DNA promovidos por ácido 5-aminolevulínico: possível associação com o desenvolvimento de carcinoma hepatocelular em portadores de porfiria aguda intermitente

“…25,No. 4 de HCC 62,64-67 uma vez que a produção de ROS tem sido constantemente relacionada à iniciação e à promoção do câncer 128,[244][245][246][247] . O ALA possui potencial pró-oxidante e é capaz de promover lesões ao DNA 248 , como quebras de fita em DNA plasmidial 106 , aumento dos níveis de várias bases oxidadas in vitro e in vivo 108,137 , além da formação de adutos entre a dGuo e o DOVA, produto final de oxidação do ALA 164 e das lesões promovidas pela dihidropirazina, produto da dimerização do ALA 196 .…”

“…Vários casos de câncer de fígado têm sido relatados em pacientes com acúmulo de ferro. Deste modo, o aumento da geração de ROS pode levar a danos oxidativos e ser potencialmente carcinogênico 128,225,244,245 64 propuseram duas hipóteses para explicar esta associação: primeiro, uma mutação de ponto no locus do gene da porfobilinogênio deaminase, presente no braço longo do cromossomo 11, pode estar ligada com a ativação do oncogene responsável pelo desenvolvimento do HCC. Segundo, as porfirinas por si próprias poderiam ser carcinogênicas.…”