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  • 1980-1984  (2)
  • Carcinogens  (1)
  • DNA binding  (1)
  • 1
    Electronic Resource
    Electronic Resource
    Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro (1984)
    Springer
    Archives of toxicology 55 (1984), S. 97-103 
    Details
    ISSN: 1432-0738
    Keywords: Estrogen ; Hormone ; Carcinogenesis ; DNA binding ; Protein binding ; Estrone ; Estradiol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract [6,7-3H] Estrone (E) and [6,7-3H]estradiol-17β (E2) have been synthesized by reduction of 6-dehydroestrone and 6-dehydroestradiol with tritium gas. Tritiated E and E2 were administered by oral gavage to female rats and to male and female hamsters on a dose level of about 300 μg/kg (54 mCi/kg). After 8 h, the liver was excised from the rats; liver and kidneys were taken from the hamsters. DNA was purified either directly from an organ homogenate or via chromatin. The radioactivity in the DNA was expressed in the units of the Covalent Binding Index, CBI = (μmol chemical bound per mol DNA-P)/(mmol chemical administered per kg b.w.). Rat liver DNA isolated via chromatin exhibited the very low values of 0.08 and 0.09 for E and E2, respectively. The respective figures in hamster liver were 0.08 and 0.11 in females and 0.21 and 0.18 in the males. DNA isolated from the kidney revealed a detectable radioactivity only in the female, with values of 0.03 and 0.05 for E and E2, respectively. The values for male hamster kidney were 〈 0.01 for both hormones. The minute radioactivity detectable in the DNA samples does not represent covalent binding to DNA, however, as indicated by two sets of control experiments. (A) Analysis by HPLC of the nucleosides prepared by enzyme digest of liver DNA isolated directly or via chromatin did not reveal any consistent peak which could have been attributed to a nucleoside-steroid adduct. (B) All DNA radioactivity could be due to protein contaminations, because the specific activity of chromatin protein was determined to be more than 3,000 times higher than of DNA. The high affinity of the hormone to protein was also demonstrated by in vitro incubations, where it could be shown that the specific activity of DNA and protein was essentially proportional to the concentration of radiolabelled hormone in the organ homogenate, regardless of whether the animal was treated or whether the hormone was added in vitro to the homogenate. Carcinogens acting by covalent DNA binding can be classified according to potency on the basis of the Covalent Binding Index. Values of 103–104 have been found for potent, 102 for moderate, and 1–10 for weak carcinogens. Since estrone is moderately carcinogenic for the kidney of the male hamster, a CBI of about 100 would be expected. The actually measured limit of detection of 0.01 places covalent DNA binding among the highly unlikely mechanisms of action. Similar considerations can be made for the liver where any true covalent DNA binding must be below a level of 0.01. It is concluded that an observable tumor induction by estrone or estradiol is unlikely to be due to DNA binding.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00346046
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Tests for mutagenicity in salmonella and covalent binding to DNA and protein in the rat of the riot control agent o-chlorobenzylidene malononitrile (CS) (1981)
    Springer
    Archives of toxicology 49 (1981), S. 15-27 
    Details
    ISSN: 1432-0738
    Keywords: o-Chlorobenzylidene malononitrile ; Riot control agents ; DNA Binding ; Salmonella/microsome assay ; Carcinogens ; Mutagens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aim of this study was to determine whether o-chlorobenzylidene malononitrile (CS) exhibits any genotoxic activity towards Salmonella or mammalian DNA in vivo. CS was synthesized with a [14C]-label at the benzylic carbon atom. It was administered i.p. at a dose level of 13 mg/kg (1 mCi/kg) to young adult male rats. Liver and kidney DNA was isolated after 8,25, and 75 h. The radioactivity was at (liver, 8 and 75 h) or below (all other samples) the limit of detection of 3 dpm. Therefore, a possible binding of CS to DNA is at least 105 times lower than that of the strong hepatocarcinogen aflatoxin B1, and 4,000 times lower than that of vinyl chloride. In contrast to this lack of DNA binding, but in agreement with the chemical reactivity of CS, a binding to nuclear proteins could be detected with specific activities ranging between 50 and 121 dpm/mg for liver and between 3 and 41 dpm/mg for kidney. Protein binding could well be responsible for its pronounced cytotoxic effects. CS was also tested in the Ames Salmonella/microsome assay. Strains TA 1535, TA 1537, TA 1538, TA 98, and TA 100 were used with or without pre-incubation. Only with strain TA 100 and only without pre-incubation, a doubling of the number of revertants was detectable at the highest dose levels used, 1,000 and 2,000 μg CS per plate. With pre-incubation of TA 100 with CS, a slight increase of the number of revertants was seen at 100 and 500 μg per plate, and a subsequent fall below control values at 1,000 μg. A check for the number of surviving bacteria revealed a strong bacteriotoxicity of the higher doses of CS so that the calculated mutation frequencies, i.e., the number of revertants per number of surviving bacteria, increased with doses up to 500 μg. This toxicity could be counteracted in part by the addition of increasing amounts of rat liver microsomes. In the view of these results, and taking into account the rare and low exposure of man, it is concluded that CS will not create a risk for the induction of point mutations or of carcinogenic processes mediated by DNA binding.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00352067
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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