Modulation of genotoxic and cytotoxic effects of aromatic amines in monolayers of rat hepatocytes

Holme, Jørn A.; Sønderland, Erik J.

doi:10.1007/bf00125568

Cited by 18 publications

(5 citation statements)

References 39 publications

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“…2-acetylaminofluorene) in lower concentra ons exhibit predominantly genotoxic proper es, as they work by introducing bulky adducts in DNA, which makes copying of the templates carrying those adducts difficult and more errorprone than copying undamaged DNA. In larger doses, however, aroma c amines may be directly cytotoxic [4]. Finally, cytotoxic effects may be exerted via genotoxic ac on.…”

Section: Cytotoxic and Genotoxic Agentsmentioning

confidence: 99%

DNA damage and mutation. Types of DNA damage

Chakarov¹,

Petkova²,

Russev³

et al. 2014

Biodiscovery

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This review outlines the basic types of DNA damage caused by exogenous and endogenous factors, analyses the possible consequences of each type of damage and discusses the need for different types of DNA repair. The mechanisms by which a minor damaging event to DNA may eventually result in the introduc on of heritable muta on/s are reviewed. The major features of the role of DNA damage in ageing and carcinogenesis are outlined and the role of iatrogenic DNA damage in human health and disease (with cura ve intent as well as a long-term adverse effect of genotoxic therapies) are discussed in detail.

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Section: Cytotoxic and Genotoxic Agentsmentioning

confidence: 99%

DNA damage and mutation. Types of DNA damage

Chakarov¹,

Petkova²,

Russev³

et al. 2014

Biodiscovery

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“…The nuclear fraction was obtained by the method of Holme and Soderlund (1984) as performed in UDS determinations (Denizeau et al, 1985b). Briefly, the cell suspension was treated with Nenidet P-40 (1% final concentration) in a buffer containing 0.25 M sucrose, 50 mM Tris-HC1, 25 mM KC1 and 15 mM MgC12, pH 8.0.…”

Section: Accumulation Of Metals In the Nuclear Fractionmentioning

confidence: 99%

“…[3H] TdR incorporation into DNA was measured as previously reported (Denizeau et al, 1985b); the method of Holme and Soderlund (1984), which involves the isolation of the nuclear fraction (prepared as described above) prior to the extraction of DNA, was applied because its sensitivity allows the detection of "short patch" DNA repair.…”

Section: Inductively Coupled Plasma~mass Spectrometry (Icp/ Ms) Analymentioning

confidence: 99%

Genotoxic effects of heavy metals in rat hepatocytes

Denizeau

Marion²

1989

Cell Biol Toxicol

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The genotoxic interaction of metals, which are common environmental contaminants, was studied in cultured hepatocytes. Freshly isolated rat hepatocytes were exposed to concentrations of cadmium, copper, silver and lead salts ranging from non-cytotoxic to moderately cytotoxic (as determined by LDH release), and the incorporation of [3H]thymidine into the DNA, as a measure of repair synthesis, was followed. In addition, the uptake of metals by the nuclear fraction was determined using Inductively Coupled Plasma/Mass Spectrometry or atomic absorption spectrophotometry. The evaluation of binding of 109Cd to the DNA in situ was also attempted. It was observed that after a 20 h exposure period, all the metals investigated were found in the nuclear fraction of hepatocytes, with Ag apparently being accumulated less efficiently. In parallel, Cd (0.18 to 1.8 microM) and Cu (7.9 to 78.5 microM) consistently produced a statistically significant stimulation of [3H]thymidine incorporation into the DNA, in the presence or absence of hydroxyurea while Ag was active only at the highest concentration tested (18.5 microM). In contrast, Pb failed to induce a UDS response at the levels used. Moreover, exposure of hepatocytes to 1.8 microM 109CdCl2 for 20 h led to a DNA binding ratio of 0.98 +/- 0.23 ng Cd/micrograms DNA. The present results support the view that the nucleus may be an important target organelle for metal toxicity.

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“…The reactive metabolites covalently bound to macromolecules represent only a minor fraction of the total amount of metabolites formed during the metabolism of AAF. They are thought to be formed via a cytochrome P-450 dependent N-hydroxylation, followed by sulfate transfer, deacetylation, N,O-acetyl transfer or a one electron oxidation (Thorgeirsson et al, 1984;Holme and S~derlund, 1984b).…”

Section: Holme Sp(derlund and Aunementioning

confidence: 99%

Effects of harman and norharman on the metabolism and genotoxicity of 2-acetylaminofluorene in cultured rat hepatocytes

Holme¹,

Søderlund²,

Aune³

1985

Cell Biol Toxicol

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Monolayers of rat hepatocytes metabolize 0.25 mM 2-acetylaminofluorene (AAF) to various ether-extractable, water-soluble as well as covalently bound products. The major ether-extractable metabolite formed is 2-aminofluorene (AF), followed by 7-OH-AAF and 9-OH-AAF. Pretreatment of rats with the inducer Aroclor 1254 (PCB) increased the metabolism of AAF and caused an increased DNA repair synthesis in hepatocytes exposed to AAF or AF. With N-OH-AAF, a decreased genotoxic response in PCB-treated cells compared to control cells was seen. The addition of harman and norharman decreased the metabolism of AAF to ether-extractable metabolites, water-soluble metabolites and metabolites covalently bound to macromolecules. In contrast, the DNA-repair synthesis caused by the same concentrations of AAF was increased by harman. One explanation for this apparent discrepancy could be that the aromatic amines changed the metabolism of harman and norharman in such a way that these compounds were converted into genotoxic metabolites.

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Modulation of genotoxic and cytotoxic effects of aromatic amines in monolayers of rat hepatocytes

Cited by 18 publications

References 39 publications

DNA damage and mutation. Types of DNA damage

DNA damage and mutation. Types of DNA damage

Genotoxic effects of heavy metals in rat hepatocytes

Effects of harman and norharman on the metabolism and genotoxicity of 2-acetylaminofluorene in cultured rat hepatocytes

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