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C N Martin

Publications and source records attributed to C N Martin.

34 records · Page 2Linked to original sources
PubMed1983

Nitration of carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons results in products able to induce transformation of Syrian hamster cells.

Five nitrated polycyclic aromatic hydrocarbons, synthesized from benzo[a]pyrene, fluoranthene, pyrene, and chrysene induced dose-dependent transformation of Syrian hamster embryo cells. Benzo[a]pyrene, a known carcinogen, induced transformation while the other parental compounds, which are non-carcinogens, were not effective. The transforming potential of the nitro derivatives varied from compound to compound; on a molar basis, 1,8-dinitropyrene was the most effective nitrated hydrocarbon followed in order by 3-nitrofluoranthene, 1-nitropyrene, 6-nitrochrysene, and 6-nitrobenzo[a]pyrene. The ability to obtain dose-dependent transformation frequencies indicates that hamster cell transformation represents a responsive model for elucidating the mechanism of action of nitrated carcinogens. Because of their ubiquitous distribution and their ability to induce morphological transformation in mammalian cells, nitrated polycyclic aromatic hydrocarbons must be considered as potential carcinogens.

Animals↗
PubMed1983

Binding of benzidine, N-acetylbenzidine, N, N'-diacetylbenzidine and Direct Blue 6 to rat liver DNA.

Studies were performed to assess covalent binding of [3H]benzidine, [14C]N-acetylbenzidine, [14C]N, N'-diacetylbenzidine, and the benzidine-derived azo dye Direct Blue 6 to rat hepatic DNA. Following IP injection into male Sprague-Dawley rats, benzidine and N-acetylbenzidine bound to liver DNA to yield the same adduct: N-(deoxyguanosin-8-yl)-N'-acetylbenzidine. The isomeric N-(deoxyguanosin-8-yl)-N-acetylbenzidine and the deacetylated adduct N-(deoxyguanosin-8-yl) benzidine were also synthesized, but neither of these adducts was detected in vivo. Injection of N,N'-diacetylbenzidine resulted in only barely detectable binding which was insufficient for adduct analysis. [3H]Direct Blue 6 was administered to male Wistar rats either by IP injection or by gavage. In both instances, Direct Blue 6 bound covalently to liver DNA; however, binding occurred at a much higher level in the IP injected animals. With IP injected animals, high pressure liquid chromatographic analysis indicated that approximately 70% of the radioactivity was associated with N-(deoxyguanosin-8-yl) benzidine.

Animals↗
PubMed1982

Macromolecular binding of [3H]6-nitrobenzo[a]pyrene in male rats.

Generally labelled [3H]6-nitrobenzo[a]pyrene (6NBP) when administered to male rats by i.p. injection was widely distributed throughout the body. After a single injection of 4.2 mg/kg the highest concentration was found in the liver (5% at 2 h) followed by the spleen greater than kidney greater than lung. Maximal covalent binding to macromolecules occurred between 8 and 24 h depending upon the organ; the order of binding/mg macromolecule was RNA greater than DNA greater than protein for all organs studied. In the liver maximal binding was found 8 h after 6NBP administration at which time there were 45 +/- 7 pmol 6NBP/mg bound to DNA and 114 +/- 40 pmol/mg to RNA following a dose of 4.2 mg/kg. These levels fall to 14 +/- 4 and 12 +/- 6 pmol/mg, respectively, after 168 h, the longest time point so far studied. At a lower dose of 1.4 mg/kg the values for DNA at 8 h were 14 +/- 2 pmol/mg and at 168 h 3 +/- 2 pmol/mg while for RNA the corresponding values were 29 +/- 8 and 15 +/- 3 pmol/mg. After gastric intubation at a dose of 4.2 mg/kg there was no difference in liver macromolecular binding at 24 h between conventional and germ-free animals. Enzymic digestion of liver DNA from [3H]6NBP injected animals and reversed-phase h.p.l.c. of the digests showed two peaks of radioactivity. The percentage of total radioactivity in each peak varied from preparation to preparation suggesting that one peak may be a degradation product of the other although experimental variability cannot be ruled out. The implications of these findings in relation to the potential carcinogenicity of 6NBP are discussed.

Animals↗
PubMed1982

The release of 4,4'-diaminobiphenyls from azodyes in the rat.

Six azodyes derived from benzidine, o-tolidine or o-dianisidine were separately administered orally by gavage to rats. Urine was collected over a 24 h period. Following dichloromethane extraction, urines were analysed by h.p.l.c. for the presence of the respective parent amine and its N-acetylated and N,N'-diacetylated derivatives. After alkaline hydrolysis, urines were analysed for the amines resulting from the cleavage of N-conjugates. All six dyes, direct black 38, direct brown 95, direct blue 6, Congo red, trypan blue and Chicago sky blue were found to be reduced, N-acetylated and N-conjugated. However, no N,N'-diacetylated metabolites were detected. After administration of the same dyes via injection into the hepatic portal vein, bile was collected over a 3 h period by cannulation of the bile duct. Urine was withdrawn from the bladder by syringe at the end of the three hours. Both body fluids were analysed for reduction products which were found only in the case of direct black 38, direct brown 95 and direct blue 6. Of the six dyes examined only the three direct dyes were mutagenic to S. typhimurium strains TA98 and TA1538 in the absence of flavin mononucleotide. The same three dyes were also substrates for rat liver microsomal azoreductase enzymes whereas Congo red, trypan blue and Chicago sky blue were shown to be inactive in a previous publication. The possible relationship between these results and the potent carcinogenicity exhibited by direct black 38, direct blue 6 and direct brown 95 is discussed.

Aminobiphenyl Compounds↗
PubMed1982

Covalent binding of benzidine and N-acetylbenzidine to DNA at the C-8 atom of deoxyguanosine in vivo and in vitro.

Benzidine, a human urinary bladder carcinogen, induces hepatic tumors in mice and rats. In this study, [3H]benzidine was administered in drinking water to mice for 1 week, and the covalent binding of the carcinogen to hepatic DNA was then determined. A single carcinogen:DNA adduct was detected which decreased in concentration by approximately 50% at 1 day after treatment and then remained at a nearly constant level for at least 7 days. Injection of radiolabeled benzidine or N-acetyl-benzidine into rats also resulted in a single carcinogen:DNA adduct that was chromatographically identical to that obtained in mouse liver. While administration of benzidine and N-acetylbenzidine resulted in high levels of the adduct in rat hepatic DNA, injection of N,N'-[ring-14C]diacetylbenzidine did not give detectable binding (less than 0.3 residue/mg DNA). The same carcinogen:DNA adduct found in rat and mouse liver was prepared synthetically by: (a) hydrolysis of calf thymus DNA reacted with N-hydroxy-N'-acetylbenzidine at pH 5; and (b) reaction of N-acetoxy-N,N'-diacetylbenzidine with deoxyguanosine and subsequent selective deacetylation of the product with methanolic ammonia. The in vitro and in vivo products were found to have identical high-pressure liquid chromatography retention times and to exhibit similar pH-dependent solvent partitioning characteristics. Mass and nuclear magnetic resonance spectral data on the synthetic products established the structure of the hepatic adduct as N-(deoxyguanosin-8-yl)-N'-acetylbenzidine. The structural isomer, N-(deoxyguanosin-8-yl)-N-acetylbenzidine, was synthesized by treatment of N-(deoxyguanosin-8-yl)-N,N'-diacetylbenzidine (the intermediate in b) with carboxylesterase and was shown to be chromatographically distinct from the in vivo adduct. Similarly, the nonacetylated derivative, N-(deoxyguanosin-8-yl) benzidine, was synthesized by carboxylesterase treatment of N-(deoxyguanosin-8-yl)-N'-acetylbenzidine and was shown not to occur in rat and mouse liver DNA. These data indicate that the metabolic activation of benzidine to an ultimate carcinogen in rats and mice does not involve N-hydroxybenzidine or sulfotransferase-catalyzed activation of N-hydroxy-N,N'-diacetylbenzidine. The remaining pathways for metabolic conversion of benzidine to an ultimate carcinogenic species are discussed in relation to liver and urinary bladder carcinogenesis.

Animals↗
PubMed1981

Rat liver microsomal azoreductase activity on four azo dyes derived from benzidine, 3,3'-dimethylbenzidine or 3,3'-dimethoxybenzidine.

The ability of rat liver microsomes from phenobarbitone pretreated animals to reduce the azo groups of amaranth, sunset yellow, congo red, trypan blue, chloramine sky blue FF and direct black 38 was measured spectrophotometrically in vitro. The dyes amaranth and sunset yellow acted as positive controls. Of the dyes derived from benzidine or its congeners, only direct black 38 was reduced to an appreciable extent; the rate of reduction was 10% of that for amaranth. The dyes were tested for mutagenicity in the Salmonella/microsome assay, the only active compound being direct black 38. Mutagenicity of this dye may be due in part to the mutagen 1,2,4-triaminobenzene. Mutagenic activity and azo-reduction of direct black 38 was independent of the presence of oxygen. The results presented suggest that mammalian liver may play only a minor or negligible role in the azo-reduction of dyes derived from benzidine or its congeners.

Animals↗
PubMed1981

Nitrated polycyclic aromatic hydrocarbons: potent bacterial mutagens and stimulators of DNA repair synthesis in cultured human cells.

Ten polycyclic aromatic hydrocarbons (PAHs), viz. anthracene pyrene, chrysene, perylene, fluoranthene, benzo[a]pyrene, benzo[a]pyrene, benz[a]anthracene, benzo[ghi]perylene, benzo[k]fluoranthene, have been nitrated using concentrated nitric acid and the crude nitrated mixture examined for biological activity. All the nitro PAHs examined were mutagenic to Salmonella typhimurium in the absence of a rat liver preparation. Addition of Aroclor-1254 induced liver had little effect on mutagenicity. Mutagenic potency differed for the various nitrated mixtures with nitrated pyrene and nitrated fluoranthene the most potent and nitrated anthracene the least potent. Both frame-shift and base-substitution mutations were induced by the nitrated PAHs. The nitrated PAHs were also able to induce DNA repair synthesis in cultured HeLa cells in the absence of liver, indicating that these cells have the necessary enzymes to activate nitro PAHs. Potency again varied from compound to compound with nitrated pyrene appearing to be the most active. Isolation of individual components from the crude nitrated mixtures has not been carried out in this study. In view of the possible wide-spread distribution of nitrated PAHs in the environment further work is required to assess the carcinogenic potency of these compounds which possibly pose a risk to man.

Animals↗
PubMed1980

The use of isolated rat hepatocytes to measure unscheduled DNA synthesis as a screen for chemical carcinogens.

Isolated rat hepatocytes are being used in a variety of ways to answer fundamental questions concerning the metabolism of chemical compounds. These cells retain a high capacity to metabolise xenobiotics when treated shortly after isolation, as either suspensions or after attachment. The advantage of intact cells over rat liver enzyme preparations such as post-mitochondrial supernatant in assessing the likely in vivo metabolic fate of xenobiotics are numerous. When unscheduled DNA synthesis (UDS) induced in these cells is used as an endpoint to detect electrophile generation by carcinogens, again important questions concerning the extent and route of activation can be answered. However, the detection of UDS in these cells has been suggested as a possible screen for the detection of chemical carcinogens. It is the very advantage of the system in approaching the true in vivo situation that may work against its usefulness as such a screen by reducing its sensitivity.

Animals↗
PubMed1979

Mutagenicity of methyl-, ethyl-, propyl- and butylnitrosourea towards Escherichia coli WP2 strains with varying DNA repair capabilities.

Methyl- (MNUA), ethyl- (ENUA), propyl- (PNUA) and butylnitrosourea (BNUA) have been tested for toxicity and mutation in a liquid suspension assay towards Escherichia coli WP2 and some of its repair deficient derivatives. A comparison of survival rates after nitrosourea exposure between WP2 and WP2 uvrA showed no difference between the two strains but a consistent difference in potency between the various nitrosoureas studied. Toxicity increased in the order MNUA less than PNUA less than ENUA less than BNUA. ENUA and PNUA induced a greater number of trp+ revertants in both strains than did MNUA and BNUA, particularly at low survival rates. None of these differences in biological potency could be accounted for by differences in rates of hydrolysis. ENUA, PNUA and BNUA were non-mutagenic towards WP2 lexA, WP2 recA and WP2 uvrA lexA, whereas MNUA did induce mutations. Ethyl methanesulphonate (EMS) was able to mutate WP2 lexA. These results are discussed in the light of current theories regarding the mechanism of action of these compounds.

DNA Repair↗
PubMed1979

Comparison of aflatoxin B1 and aflatoxin G1 binding to cellular macromolecules in vitro, in vivo and after peracid oxidation; characterisation of the major nucleic acid adducts.

A comparison between [14C]aflatoxin B1 (AFB1) and [14C]aflatoxin G1 (AFG1) binding to rat liver and kidney cellular macromolecules has shown AFG1-DNA and-ribosomal RNA binding to be lower in both organs. For both mycotoxins more was bound to nucleic acids than to protein. Two hours after intraperitoneal injection (60 microgram/100 g) of [14C] AFB1, 40 ng, 151 ng/mg. Loss of radioactivity bound to liver DNA for both [14C]AFB1 and protein respectively and for [14C]AFG1 the respective figures were 10, 7 and 1 ng/mg. Loss of liver bound radioactivity to DNA for both [14C]AFG1 and [14C]AFG1 appeared to be biphasic indicating that an enzymic DNA repair process may be operating. In vitro binding studies also showed less AFG1 was bound to exogenous DNA after microsomal activation than AFB1. This difference was not a result of differences in the chemical reactivity of the "ultimate" electrophilic species, the respective expoxides, since chemical activation studies using 3-chloroperbenzoic acid showed similar amounts of AFG1 and AFB1 to be converted to the epoxides and to bind to DNA. Studies on the distribution coefficients of the two mycotoxins showed AFB1 to be more lipophilic than AFG1 and this may be an important factor in determining the weaker carcinogenicity of the latter compound. Characterisation of the major AFG1-DNA adduct formed in vitro, in vivo and after peracid oxidation showed it to have the structure trans-9,10-dihydro-9-(7-guanyl)-10-hydroxy-aflatoxin G1. This adduct is similar to that obtained from AFB1 by activation in vivo, in vitro and after peracid oxidation.

Aflatoxins↗
PubMed1978

Testing of known carcinogens and noncarcinogens for their ability to induce unscheduled DNA synthesis in HeLa cells.

The ability of 51 compounds, of known carcinogenic potential, to induce "unscheduled DNA synthesis" in HeLa cells has been tested in the presence or absence of a rat liver mixed-function oxidase preparation. Chemicals tested included those giving erroneous results in bacterial mutagenicity assays as well as representative compounds from various classes of chemical carcinogens including nitrosamines, polycyclic aromatic hydrocarbons, aromatic amines, and mycotoxins. Of the compounds assayed, all noncarcinogens failed to induce DNA repair; of 38 compounds of demonstrated carcinogenicity, 34 were active; safrole, N-propyl-N-nitrosourea, aflatoxin B2 and N-butyl-N-nitrosourea were, however, inactive. Six compounds for which carcinogenicity data are incomplete were active, namely, 4-nitro-o-phenylenediamine, 2-nitro-p-phenylenediamine, formaldehyde, 2,2'-dichlorobenzidine, 3,3',5,5'-tetrafluorobenzidine, and 3,3',5,5'-tetrachlorobenzidine. Three carcinogens that are weakly active or inactive in bacterial mutagenicity assays, i.e., urethan, N-dimethyl-p-aminoazobenzene, and diethylstilbestrol were active in our assay. The bacterial mutagens sodium azide and 9-aminoacridine were both inactive. The use of this assay in a tier scheme for the short-term testing of potential chemical carcinogens is discussed.

Biotransformation↗
PubMed1977

Measurement of 'unscheduled' DNA synthesis in HeLa cells by liquid scintillation counting after carcinogen treatment.

HeLa cells, conditioned in an arginine-deficient medium to reduce DNA S-phase synthesis, were treated with one of four ultimate carcinogens (MNNG, BrMBA, N-acetoxy AAF and EMS) and one precarcinogen, AFB1. All treated cells preferentially incorporated [3H] thymidine as a result of DNA repair monitored by liquid scintillation counting of the extracted DNA. The cells showed some capacity to activate AFB1, but repair synthesis was much increased if a rat liver mixed function oxidase preparation was also present. At equimolar concentrations the various carcinogens stimulated different amounts of DNA repair; this variation was not proportional to the carcinogenic potency of the chemicals tested. Reasons for this are discussed as is the use of this technique as a screen for chemical carcinogens.

Acetoxyacetylaminofluorene↗
PubMed1975

Molecular mechanisms in alkylation mutagenesis. Induced reversion of bacteriophage T4rII AP72 by ethyl methanesulphonate in relation to extent and mode of ethylation of purines in bacteriophage deoxyribonucleic acid.

Survival and reversion to T4r+ of bacteriophage T4rII AP72 after treatment with ethyl methanesulphonate at 37 degrees or 45 degrees C were studied in relation to the extent and mode of alkylation of purines in DNA of ethylated bacteriophage. A single-burst technique was used for reversion assay. Survival was lower at 45 degrees C than at 37 degrees C at a given extent of ethylation of bacteriophage DNA, confirming that events subsequent to ethylation, probably depurinations, are the main cause of decreased survival. Reversion was positively correlated (approximately linearly except at low extents at 37 degrees C) with ethylation of bacteriophage DNA, showing that ethylation itself causes mutation. Following the concept that reversion results from G-C leads to A-T transition at a single site (Krieg, 1963a,b) and the suggestion that O6-alkylation of guanine generates the miscoding base (Loveless, 1969), it was calculated that about one-third of induced O6-ethylguanines at this site would miscode to induce mutation.

Alkylation↗
PubMedDate not supplied

Correlation of DNA adduct levels in human lung with cigarette smoking.

Lung cancer is the most common cancer in men in the United Kingdom and the second most common in women, accounting for between 25 and 40% of all cancer deaths. Cigarette smoking is widely accepted as the major cause of lung cancer and linear relationships have been established between the number of cigarettes smoked and lung cancer risk. Although approximately 50 carcinogenic chemicals have been identified in cigarette smoke, a causal link between specific compounds and lung cancer has yet to be made. Studies on cigarette smokers' urine, blood and placenta have provided indications of carcinogen exposure, and although the presence of covalently-bound adducts in human DNA provides evidence of exposure to carcinogens, there have been no reports of systematic studies on the levels of DNA adducts in human lung. We report here, using the 32P-post-labelling technique, that cigarette smokers have higher adduct levels than non-smokers, that there is a linear relationship between adduct levels and daily or lifetime cigarette consumption, and that people who have given up smoking for at least five years have adduct levels similar to those of non-smokers.

Aged↗