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PubMed1978

Carcinogen-induced DNA repair in nucleotide-permeable Escherichia coli cells. Analysis of DNA repair induced by carcinogenic K-region epoxides and 1,2,3,4-diepoxybutane.

Ether-permeabilized (nucleotide-permeable) Escherichia coli cells exhibited DNA excision repair when exposed to the following carcinogenic K-region epoxides: 7-methyl- and 7,12-dimethyl-benz[a]anthracene-5,6-oxide, chrysene-5,6-oxide and benzo[a]pyrene-4,5-oxide. This DNA excision repair was missing in uvr A and uvr B mutant cells. The K-region epoxide phenanthrene-9,10-oxide was ineffective in all E. coli strains tested. In contrast to the K-region epoxides which where found active only in wild type cells, 1,2,3,4-diepoxybutane and the 6,7-epoxides of the tumor promoter TPA (12-O-tetradecanoyl-phorbol-13-acetate) elicited DNA repair in uvrA, uvrB mutant cells as well. Enzymic activities catalyzing particular repair steps were identified by determining a) repair polymerization and b) size reduction of denatured DNA. A) An easily quantifiable effect in E. coli wild type cells was epoxide-induced repair polymerization. None of the K-region epoxides tested stimulated DNA repair synthesis in uvrA, uvrB mutant cells, indicating that the uvrA-, uvrB-controlled UV-endonuclease initiated excision repair by cleaving epoxide-damaged DNA. 1,2,3,4-Diepoxybutane and the TPA-6,7-oxides induced DNA repair polymerization in uvr-deficient cells, although to a lesser extent than in wild type cells, suggesting the involvement of uvr-independent incision steps. None of the epoxides induced repair polymerization in a mutant (polA107) lacking the 5'--3'exonucleolytic activity of DNA polymerase I (exonuclease VI). The absence of any repair polymerization in the polA107 mutant indicates that the exonuclease VI plays a central role in removing epoxide-damaged nucleotides. As evidenced by greatly reduced levels of repair polymerization measured in polA1 cells, DNA polymerase I was the main polymerizing enzyme. b) As a consequence of treatment with 7-methyl-benz[a]anthracene-5,6-oxide, DNA from wild type cells, contrary to uvrA mutant cells, showed size reduction after denaturation and sedimentation in alkaline sucrose gradients. This is explained by repair-specific endonucleolytic cleavage of damaged DNA. The incision required the presence of ATP indicating that functional UV-endonuclease needs ATP as a cofactor.

Carcinogens↗

PubMed1976

Cell cycle-related hormone carcinogen interaction during chemical carcinogen induction of nodule-like mammary lesions in organ culture.

The immature mammary glands of BALB/c female mice were treated with 7,12-dimethylbenz[a]anthracene (DMBA), 2 micrograms/ml, or 3-methylcholanthrene (10 micrograms/ml) for a 24-hr period at different times during the inital six days of lobuloalveolar growth in hormone-supplemented organ culture. Nodule-like alveolar lesions (NLAL) were detectable in 80% of the glands treated with DMBA (40% in 3-methylcholanthrene-treated glands) in the presence of insulin + prolactin + aldosterone + cortisol in the medium. No NLAL were present in dimethyl sulfoxide-treated control glands cultivated with the same hormones. The hormone combination insulin + prolactin + cortisol was unfavorable for NLAL induction by DMBA, and the combination of aldosterone + insulin + prolactin was only moderately conducive. Thus, the presence of cortisol with insulin + prolactin + aldosterone enhances NLAL incidence of mammary cells by DMBA. The highest incidence was found in glands that were treated with DMBA for 24 hr between the third and fourth day of culture, the period corresponding to the onset of the second wave of DNA synthesis in the gland. Cytotoxicity of DMBA was pronounced between 24 and 48 hr, when a high frequency of cells were in DNA synthesis, and survival of the cells after the cytotoxic effect of DMBA appeared to play a role in NLAL incidence. This suggests that DMBA-induction of NLAL in mammary glands in organ culture involves a complex carcinogen-hormone-cell cycle interaction. We emphasize that, although NLAL morphologically resembles the hyperplastic alveolar nodules of mouse mammary gland in vivo, the abilitity of NLAL to produce typical hyperactive alveolar outgrowth and mammary tumor after transplantation iv vivo remains to be determined.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1978

Detection of mutagenicity of the colon carcinogen 1,2-dimethylhydrazine by the host-mediated assay and its correlation to carcinogenicity.

Mutagenic potential of 1,2-dimethylhydrazine (DMH) was investigated in the host-mediated assay with mice used as hosts. This assay revealed potent mutagenicity of this colon carcinogen for Salmonella typhimurium G46. The mutagenicity of DMH was inhibited by pretreatment of mice with disulfiram. In addition, mouse strain and sex differences influenced the mutation induction by DMH: Mutation induction was significantly lower in C57BL/6 mice than in outbred ICR mice of either sex and was generally higher in male than in females of either C57BL/6 or ICR mice.

Animals↗

PubMed1976

The metabolic activation of the carcinogen 1'-hydroxysafrole in vivo and in vitro and the electrophilic reactivities of possible ultimate carcinogens.

Administration of [2',3'-3H]-1'-hydroxysafrole to rats or mice resulted in the formation of hepatic DNA-, ribosomal RNA-, and protein-bound 3H derivatives. Alkaline digestion of the 3H-protein released 0.1 to 0.3% of the 3H as a derivative that was identified as 3'-methylmercaptoisosafrole by its cochromatography in five solvent systems with the synthetic compound. 1'-Hydroxysafrole was metabolized at a low rate by rat and mouse liver cytosols in a 3'-phosphoadenosine 5'-phosphosulfate-dependent reaction to a derivative (presumably the sulfuric acid ester) that was captured by its reaction with RNA. Likewise, 1'-hydroxysafrole was oxidized at a low rate by rat and mouse liver microsomes to 1'-hydroxysafrole-2',3'-oxide in a reduced nicotinamide adenine dinucleotide phosphate-dependent reaction. Both of these electrophilic metabolites are candidate ultimate carcinogenic derivatives of 1'-hydroxysafrole. The electrophilic reactivities of various safrole derivatives with nucleosides were determined to be in the order of 1'-oxosafrole greater than 1'-acetoxysafrole greater than 1'-acetoxysafrole-2',3'-oxide greater than 1'-hydroxysafrole-2',3'-oxide greater than safrole-2',3'-oxide greater than or equal to 1'-oxosafrole-2',3'-oxide. The major reactions were generally observed with guanosine. A major reaction product of 1'-acetoxysafrole and guanosine 5'-monophosphate yielded 3'-hydroxyisosafrole under very mild acidic conditions. These data further substantiate the previous characterization of this reaction product as O-6-(isosafrol-3'-yl)guanylic acid. The syntheses of 1'-oxosafrole, 2',3'-dehydrosafrole, [2',3'-3H]-1'-hydroxysafrole, and the 2',3'-oxed.

Acetyltransferases↗

PubMed1975

Investigations on the carcinogenic burden by air pollution in man. XIII. Assessment of the contribution of passenger cars to air pollution by carcinogenic polycylic hydrocarbons.

A total of 100 passenger cars were tested with regard to the amount of polycyclic aromatic hydrocarbons (PAH) emitted during the EUROPA-Test (E.-Test, simulate city driving; 4 times 195 s). As determined by frequency of registration, the 20 most common car models were chosen. Each model was represented by 5 cars. The total amount of selected 14 PAH emitted by all test vehicles during an E.-test is in the range of 1-16 mg. As can be seen from the average of fuel consumption (409.4 g/E.-test) and benzo(a)pyrene emission (41.6 mug/E.-test), 1000 kg of burned fuel yield 101 mg of benzo(a)pyrene. Based on the consumption of gasoline in 1973 in West Germany (18508200 tons), an annual amount of 1.85 tons of benzo(a)pyrene is produced by gas engine vehicles. However, the biological effect of the automobile exhaust is still larger because it contains additional carcinogenic PAH. - A statistical evaluation of the results shows that different car models can not be distinguish by their PAH emission. When evaluating individual vehicles after 5 repeated E.-tests, the margin of error for any single PAH is between 6.3-10.9% (variation coefficient) for this car. A larger margin of error is obtained by pooling 5 different vehicles of the same model.

Air Pollutants↗

PubMed1977

Oncogenic interaction of carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons in mice.

To evaluate possible interactions between PAH occurring in automobile exhaust condensates with regard to their tumour forming potency, the following experiments were performed. Six different doses of benzo[a]pyrene (3-100 microgram) and of dibenzo]a,h]anthracene (2-75 microgram) and mixtures thereof were tested subcutaneously on female NMRI mice. In addition, mixtures of 10 non-carcinogenic hydrocarbons were applied: benzo[e]pyrene, benzo[a]anthracene, phenanthrene, anthracene, pyrene, fluoranthene, chrysene, perylene, benzo[ghi]perylene and coronene. Mixtures of all 12 PAH were also applied. The proportion of PAH in all mixtures used was the same as in automobile exhaust condensates; benzo[a]pyrene was used as reference substance. The most important results were as follows: 1. Small doses of dibenzo[a,h]anthracene have a greater tumour promoting effect than do comparable doses of benzo[a]pyrene. Increased doses increase the effect of benzo[a]pyrene more than that of dibenzo[a,h]anthracene. 2. The mixture of benzo[a]pyrene and dibenzo[a,h]anthracene is 1.4 time more active than dibenzo[a,h]anthracene alone. 3. The mixture of all PAH has a lower efficacy than dibenzo[a,h]anthracene alone, amounting to only 0.03 that of dibenzanthracene; however, the activity of dibenzo[a,h]anthracene within the mixture of the 12 PAH increases by a factor of 3.1. 4. The activity of a mixture of dibenzo[a,h]anthracene and benzo[a]pyrene depends to about 40% on dibenzo[a,h]anthracene; and that of 12 PAH to 30% on dibenzo[a,h]anthracene alone or to 80% on a mixture of dibenzo[a,h]anthracene and benzo[a]pyrene.

Animals↗

PubMed1976

Comparative study of the carcinogenic activities of nas and some chemical carcinogens when introduced into the buccal pouch of the Syrian hamster.

Studies were carried out on the carcinogenic effects of nas, 7,12-dimethylbenz-[a]anthracene (DMBA), DMBA+nas, dimethylnitrosamine (DMNA), diethylnitrosamine (DENA), and N-methyl-N-nitrosourea (MNU) when introduced into the buccal pouch of the Syrian hamster. Nas alone induced no tumours in the buccal pouch but tumours at other sites occurred in 18.8% of the treated animals, compared with 4.4% of the controls. Three of 11 hamsters treated with DMBA alone developed tumours. No tumours appeared in the buccal pouch following treatment with DMBA + nas but they developed at other sites in 6 of the 11 hamsters treated. DMNA and DENA induced no macroscopic changes in the mucous membrane of the buccal pouch. Following DMNA administration, tumours developed only in the liver; no tumours developed following the application of DENA. Tumours developed at various sites, including the buccal pouch, in 20 of the 25 hamsters treated with MNU.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1977

Chromosomal effects of carcinogens and non-carcinogens on WI-38 after short term exposures with and without metabolic activation.

The human diploid fibroblast culture, WI-38 was analyzed for chromosomal damage after 24 h exposures to benzo(a)pyrene (BP), 3-methylcholanthrene (MCA), n-methyl-n'-nitrosoguanidine (MNNG), 4-nitroquinoline-1-oxide (4NQO), pyrene and caffeine. A low concentration of 4NQO (0.15 micron) and MNNG (1.9 micron) produced breakage and exchange figures. A relatively high concentration of caffeine (1300 micron) caused breakage. The other compounds (BP, MCA and pyrene) caused little or no increase in damage above the control levels. A 1-h pulse exposure of WI-38 cells to BP (40 micron) in the presence of a rat liver homogenate supernate (S-9) resulted in damage significantly greater than the untreated cells or cells treated with BP alone. 4NQO (0.25 micron) produced exchange figures after a similar 1-h exposure, but this effect was eliminated by the S-9. A much higher concentration of caffeine (10,300 micron) was required to cause breakage greater than control levels after a one hour exposure. The results indicate a possible short term in vitro human cell system for distinguishing carcinogens, procarcinogens, and noncarcinogens.

4-Nitroquinoline-1-oxide↗

PubMed1978