Mutagenicity of hydrogen peroxide in V79 Chinese hamster cells

Ziegler‐Skylakakis, Kyriakoula; Andrae, U.

doi:10.1016/0165-7992(87)90127-8

Cited by 50 publications

(11 citation statements)

References 15 publications

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“…Under these specific conditions, we have shown that the frequency of mutants arising at the supF locus of the pZ 189 plasmid is enhanced by a factor of ~ 4 times over the spontaneous level when cells transfected with the plasmid are treated with H 2 O 2 and incubated for a suitable period (Figure 1). This is not only consistent with a recent report that H 2 O 2 is mutagenic to mammalian cells (15) but has also provided material for an analysis of such mutants at the DNA sequence level. The spectrum of deletion mutations induced by H 2 O 2 differs markedly from that arising spontaneously.…”

Section: Discussionsupporting

confidence: 78%

“…Despite several reports showing that treatment of mammalian cells in culture with H 2 O 2 results in DNA damage, sister chromatid exchange and chromosome aberrations (11)(12)(13), initial attempts to demonstrate the induction of gene mutations in mammalian cells were unsuccessful (12,14). However, in a recent study, Ziegler-Skylakakis and Andrae (15) have shown that if cells are treated at high cell density with concentrations of H 2 O 2 in the low millimolar range then mutations can be detected at the hypoxanthine guanine phosphoribosyl transferase locus. The increase in mutation frequency is dependent on the concentration of H 2 O 2 employed.…”

Section: Introductionmentioning

confidence: 97%

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Mutagenesis by hydrogen peroxide treatment of mammalian cells: a molecular analysis

Moraes¹,

Keyse²,

Tyrrell³

1990

Carcinogenesis

113

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Hydrogen peroxide is an oxidizing agent which can be generated intracellularly either during normal metabolism or by treatment with external agents including solar UV radiation. Simian cells (CV-1) transfected with the SV40-based shuttle vector plasmid pZ189 have been treated with H 2 O 2 and then incubated to allow repair and replication of the plasmid. The frequency of mutations at the supF locus of the recovered plasmid increases by a factor of up to four over the spontaneous value. The nucleotide changes associated with 100 spontaneous and 100 H 2 O 2 -induced mutants have been determined directly by sequencing a 150 bp fragment that includes the entire supF tRNA coding region. Deletions were observed in -45% of both the spontaneous and induced mutants, whereas single or multiple base changes arose in 68 and 57% of the induced and spontaneous mutants respectively. The spectrum of induced mutations is characterized by (i) the occurrence of deletions associated with base changes (16% of all mutants analysed) and (ii) small deletions of 3 bp and less (51% of all deletion mutants sequenced). Sixty-five per cent (15 out of 23) of all small deletions (spontaneous and induced) are associated with runs of between two and five identical bases and eight of them arise at a mutational 'hotspot' region of five cytosines between bp 172 and 176. The majority (19 out of 30) of completely sequenced deletions observed in the spontaneous spectrum contain either (i) small (2-10 bp) direct repeat sequences that lie immediately outside one deletion terminus and immediately inside the second deletion terminus or (ii) small (2-3 bp) inverted repeat sequences lying immediately inside the two deletion termini. Most deletions that we have observed are therefore likely to arise as a consequence of specific aspects of DNA structure. IntroductionOxygen radicals appear to be involved in both the ageing process and in the initiation and progression of many human diseases, including cancer. A knowledge of the nature of mutations arising in DNA as a result of oxygen radical attack should provide important clues to understanding the molecular events that underlie these pathological changes. The characterization of the genotoxic action of the oxidizing agent, hydrogen peroxide, is particularly relevant in this respect for several reasons. In addition

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 97%

Mutagenesis by hydrogen peroxide treatment of mammalian cells: a molecular analysis

Moraes¹,

Keyse²,

Tyrrell³

1990

Carcinogenesis

113

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“…Superoxide, for example, may disproportionate to hydrogen peroxide singlet oxygen. Mutagenic activity was observed with hydrogen peroxide, added at high concentrations (> 1 mM) to V79 cells (4). In this context, it is important to know that one molecule of quinone may give rise to the forrnation of numerous molecules of active oxygen, since transfer of the electron from semiquinone to another molecule results in reformation of the quinone, which is now available for new redox cycles with radical formation.…”

Section: Introductionmentioning

confidence: 99%

Genotoxicity of 1,4-benzoquinone and 1,4-naphthoquinone in relation to effects on glutathione and NAD(P)H levels in V79 cells.

Ludewig

Dogra

Glatt

1989

Environ Health Perspect

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,4-Benzoquinone is cytotoxic in V79 Chinese hamster cells and induces gene mutations and micronuclei. The cell-damaging effects of quinones are usually attributed to thiol depletion, oxidation of NAD(P)H, and redox-cycling involving the formation of semiquinone radicals and reactive oxygen species. To elucidate the role of these mechanisms in the genotoxicity of 1,4-benzoquinone, we measured various genotoxic effects, cytotoxicity, and the levels of glutathione, NADPH, NADH, and their oxidized forms all in the same experiment. 1,4-Naphthoquinone, which does not induce gene mutations in V79 cells, was investigated for comparative reasons. The quinones had a similar effect on the levels of cofactors. Total glutathione was depleted, but levels of oxidized glutathione were slightly increased. The levels of NADPH and NADH were reduced at high concentrations of the quinones with a simultaneous increase in the levels of NADP + and NAD +. Both compounds induced micronuclei, but neither increased the frequency of sister chromatid exchange. Only 1,4-benzoquinone induced gene mutations. This effect was observed at low concentrations, where none of the other parameters studied was affected. When the cells were depleted of glutathione prior to treatment with the quinones, the induction of gene mutations and micronuclei remained virtually unchanged. We conclude that a) induction of micronuclei and glutathione depletion by the two quinones are not linked causally, b) 1,4-benzoquinone induces gene mutations by a mechanism different from oxidative stress and glutathione depletion, and c) glutathione does not fully protect the cells against the genotoxicity of quinones.

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“…Some MPO substrates, such as hydrogen peroxide, have been shown to be mutagenic in various systems such as bacterial (Kensese and Smith, 1989), rodent (Ziegler-Skylakakis, 1987) and human (Oller and Thilly, 1992) cells. It is unclear whether and how a buildup of hydrogen peroxide or any other MPO substrates could lead to the observed increase in HPRT mutant frequency in cells in which the activities of MPO and potentially those of other heme proteins were downregulated.…”

Section: Discussionmentioning

confidence: 98%

Increased mutant frequencies in the HPRT gene locus of leukemia HL-60 cells treated with succinylacetone

et al. 2006

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Succinyl acetone (SA) was initially identified in the urine of patients with tyrosinemia type I, an autosomally recessive inherited disease. SA has been used to downregulate the activity of myeloperoxidase (MPO) through its specific inhibition of heme biosynthesis and to investigate the biological properties of MPO in the human myeloid leukemic (HL-60) cell line. The goal of this study is to evaluate the mutagenic potential of SA by determining the frequencies of somatic mutations in the hypoxanthine-guanine phosphoribosyl transferase (HPRT) reporter gene in HL-60 cells following treatment with the chemical. Treatments of HL-60 cells with 500 micromol/L SA for 72 h, a condition generally used to inhibit the MPO activity, resulted in a significantly increased HPRT mutant frequency (HPRT-Mf), compared with the control of untreated cells (47.25 x 10(-6) versus 7.5 x 10(-6), respectively, p <0.01). Treatment of the cells with lower doses of SA also led to an increase in HPRT-Mf but this was significant only with 200 micromol/L (28.67 x 10(-6), p<0.05) and not with doses lower than 100 micromol/L (p0.05), compared with the control of untreated cells (7.5 x 10(-6)). These data show a dose-response increase in HPRT-Mf in HL-60 cells treated with SA, suggesting that this chemical causes mutations in the HPRT locus in these cells either directly or indirectly through its inhibition of the MPO activity.

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Mutagenicity of hydrogen peroxide in V79 Chinese hamster cells

Cited by 50 publications

References 15 publications

Mutagenesis by hydrogen peroxide treatment of mammalian cells: a molecular analysis

Mutagenesis by hydrogen peroxide treatment of mammalian cells: a molecular analysis

Genotoxicity of 1,4-benzoquinone and 1,4-naphthoquinone in relation to effects on glutathione and NAD(P)H levels in V79 cells.

Increased mutant frequencies in the HPRT gene locus of leukemia HL-60 cells treated with succinylacetone

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