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Showing papers in "Carcinogenesis in 1982"


Journal ArticleDOI
TL;DR: The enzymatic 32P-postlabeling method appears applicable to the ultrasensitive detection of a large number of carcinogen--DNA adducts of diverse structure without requiring radioactive carcinogens or specific antibodies.
Abstract: A newly developed enzymatic /sup 32/P-postlabeling method was applied to the analysis of DNA's containing non-radioactive arylamine, arylamide, and polycyclic aromatic hydrocarbon adducts. DNA reacted in vitro with N-hydroxy-2-amino-fluorene, N-acetoxy-2-acetylaminofluorene, and 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, respectively, as well as DNA preparations from the liver of rats treated with N-hydroxy-2-acetylaminofluorene and benzo(a)pyrene, respectively, were enzymatically digested to deoxyribonucleoside 3'-monophosphates, which were then converted to (5'-/sup 32/P)deoxyribonucleoside 3',5'-bisphosphates by T4 polynucleotide kinase-catalyzed (/sup 32/P)phosphate transfer from (gamma-/sup 32/P)ATP. The /sup 32/P-labeled nucleotides were resolved by anion-exchange t.l.c. on polyethyleneimine-cellulose and detected by autoradiography. Aromatic adduct nucleotides were found to be retained at the origin in aqueous electrolyte solutions, but to migrate as distinct spots in solvents containing 7-8.5 M urea. Advantage was taken of this observation to remove /sup 32/P-labeled normal DNA nucleotides from adduct nucleotides. This purification enabled the detection of a single adduct in 10(7)-10(8) normal nucleotides. The method appears applicable to the ultrasensitive detection of a large number of carcinogen--DNA adducts of diverse structure without requiring radioactive carcinogens or specific antibodies.

670 citations


Journal ArticleDOI
TL;DR: S-Adenosylmethionine was found to methylate DNA non-enzymatically to produce the same putative promutagenic and procarcinogenic lesions formed by carcinogenic chemical methylating agents, and may indicate the mechanism whereby methylated guanine is formed in the liver DNA of rats with chemically induced liver damage.
Abstract: S-Adenosylmethionine was found to methylate DNA non-enzymatically to produce the same putative promutagenic and procarcinogenic lesions formed by carcinogenic chemical methylating agents. The formation of 7-methylguanine was confirmed by u.v. spectrophotometry, the formation of O6-methylguanine and 3-methyladenine was suggested by the cochromatography of radioactivity with standard bases. It is possible that this reaction may explain the presence of constitutive cellular enzymes specifically for the repair of methylated DNA, and may indicate the mechanism whereby methylated guanine is formed in the liver DNA of rats with chemically induced liver damage.

172 citations


Journal ArticleDOI
TL;DR: Since 1998, she and her colleagues at CCCEH have tracked the health of more than 700 NYC pregnant women and their children and studied the combustion pollutants polycyclic aromatic hydrocarbons, pesticides, secondhand smoke, and chemicals in plastics and flame retardants.
Abstract: Frederica Perera, DrPH, PhD, is a Professor of Environmental Health Sciences and serves as the Director of the Columbia Center for Children’s Environmental Health (CCCEH). Dr. Perera is internationally recognized for pioneering the field of molecular epidemiology, beginning with studies of cancer and then applying molecular techniques within studies of pregnant women and their children. Since 1998, she and her colleagues at CCCEH have tracked the health of more than 700 NYC pregnant women and their children. Exposures being studied include the combustion pollutants polycyclic aromatic hydrocarbons (PAH), pesticides, secondhand smoke, and chemicals in plastics and flame retardants. Outcomes include asthma, neurobehavioral development, cancer, and obesity.

158 citations


Journal ArticleDOI
TL;DR: Changes in enzyme pattern are supportive of a developmental sequence leading from glycogen storage foci through mixed cell foci and neoplastic nodules to hepatocellular carcinomas.
Abstract: The livers from a total of 51 Sprague-Dawley rats treated with different doses of N-nitrosomorpholine (80-120 mg/l in the drinking water) for up to 14 weeks together with the livers of 28 control animals were histochemically investigated at the cessation of carcinogenic insult and at varying periods thereafter for their glycogen content, basophilia and activities of various enzymes of carbohydrate metabolism: glycogen synthetase, glycogen phosphorylase, glucose-6-phosphatase, glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate dehydrogenase The enzymatic patterns of normal tissue, preneoplastic and neoplastic lesions were characterized and compared with reference to the morphologically defined stages of tumor development in the liver The early appearing glycogen storing areas, localized in the peripheral and intermediate lobular regions, did not show significant changes in the histochemically demonstrable activities of the enzymes tested After cessation of the carcinogen treatment the more pronounced glycogen storage foci which developed within the aforementioned regions of the liver acinus usually showed a reduction in the activities of phosphorylase and glucose-6-phosphatase while the activity of glucose-6-phosphate dehydrogenase, a key enzyme for the pentose phosphate pathway, was increased The mixed cell foci, neoplastic nodules and tumors which emerged at later stages were characterized by a progressive shift away from glycogen metabolism towards glycolysis and the pentose phosphate pathway, as indicated by an increase in glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate dehydrogenase activities These changes in enzyme pattern are supportive of a developmental sequence leading from glycogen storage foci through mixed cell foci and neoplastic nodules to hepatocellular carcinomas

154 citations


Journal ArticleDOI
TL;DR: The results support the hypothesis that at least some of the products of arachidonic acid transformation are essential for tumor promotion.
Abstract: 12-O-Tetradecanoylphorbol-13-acetate promotion of skin tumors in mice can be inhibited by topical application of either the phospholipase A2 inhibitor dibromoacetophenone or the cyclooxygenase-lipoxygenase inhibitors 5,8,11,14-eicosatetrayonic acid or 1-phenyl-3-pyrazolidinone. The phospholipase A2 inhibitors in particular appear to be among the most potent inhibitors of skin tumor promotion known. These results support the hypothesis that at least some of the products of arachidonic acid transformation are essential for tumor promotion.

147 citations


Journal ArticleDOI
TL;DR: Quercetin was not carcinogenic when given at the concentrations of 4% and 1%; even with the administration of 1% croton oil after 1% quercetIn, there was no increase in tumor incidence.
Abstract: Quercetin and its glycoside, rutin were tested for carcinogenicity in non-inbred golden hamsters of both sexes. In Experiment I, 10% quercetin, 10% rutin, or control diet was given to animals for 735 days. In this experiment, tumors appeared mainly in the forestomach, but the incidence was not statistically different among the three groups. Quercetin and rutin were not carcinogenic under these conditions. In Experiment II, Group 1 was given 4% quercetin diet for 709 days. Group 2 was given 1% quercetin diet for 351 days and then the basal diet for 350 days. Group 3 was given 1% quercetin diet and then 1% croton oil diet and Group 4 was given the basal diet followed by 1% croton oil diet, for the same periods as Group 2. Group 5 was given the basal diet for 701 days. In Experiment II, papillomas of the forestomach appeared in Groups 1, 2, and 5, and papillomatosis in Group 3 and 4. There were no statistical differences among experimental groups and respective controls. Thus, quercetin was not carcinogenic when given at the concentrations of 4% and 1%; even with the administration of 1% croton oil after 1% quercetin, there was no increase in tumor incidence.

141 citations


Journal ArticleDOI
TL;DR: Treatment of rats with 10 or 15% ethanol in drinking water for 3 days causes a 4- to 5-fold enhancement in microsomal N-nitrosodimethylamine demethylase (NDMAd) activity and a 40-60% increase in gross P-450 content.
Abstract: The effects of ethanol on the metabolism of nitrosamines by rat liver microsomes have been studied. Treatment of rats with 10 or 15% ethanol in drinking water for 3 days causes a 4- to 5-fold enhancement in microsomal N-nitrosodimethylamine demethylase (NDMAd) activity and a 40-60% increase in gross P-450 content. The enhancement is mainly due to the induction of a low Km form (Km = 0.07 mM) of NDMAd. The treatment induces protein species with molecular weights between 50000 and 52000, some of which are believed to be P-450 isozymes with high affinity to NDMA. In addition to NDMA, treatment with ethanol also enhances the metabolism of N-nitroso-N-methylethylamine, N-nitrosomethylaniline, and N-nitroso-N-methylbenzylamine. When added to the incubation mixture, ethanol and its homologs inhibit the demethylation of these nitrosamines by microsomes. Ethanol is a competitive inhibitor of the low Km NDMAd with a Ki of 0.31 mM and is less effective in inhibiting the metabolism of more lipophilic nitrosamines.

129 citations


Journal ArticleDOI
TL;DR: It is proposed that mutagenicity in V79 cells, which correlates closely with reported carcinogenicity data in mice, is a consequence of reaction with DNA at the amino-group of guanine and that the difference found between the (+) and (-) stereoisomers results from differences in the spatial orientation of the benzo[a]pyrene residue at this site.
Abstract: Monolayer cultures of V79 cells were treated with tritium labelled (+) and (-) stereoisomers of anti-benzo[a]pyrene diolepoxide. Cell survival and induction of 8-azaguanine resistant mutants by the two stereoisomers were related to the extent of reaction with cellular DNA and to the nature of the reaction products. At equal extents of DNA reaction both isomers were equally cytotoxic but the (+) anti-isomer was considerably more mutagenic. This difference of mutagenicity could not be related to any particular product of DNA reaction or to differential excision repair by the V79 cells. It is proposed that mutagenicity in V79 cells, which correlates closely with reported carcinogenicity data in mice, is a consequence of reaction with DNA at the amino-group of guanine and that the difference found between the (+) and (-) stereoisomers results from differences in the spatial orientation of the benzo[a]pyrene residue at this site.

103 citations


Journal ArticleDOI
TL;DR: Results indicate that GGT is not a phenotypic marker in Wy-14,643 induced hepatic carcinogenesis, and whether the neoplastic alterations induced in liver by other peroxisome proliferators are similarly GGT negative remains to be determined.
Abstract: Administration of Wy-14,643, a hypolipidemic agent which induces peroxisome proliferation, at a concentration of 0.1% (w/w) in the diet, leads to the development of altered foci, neoplastic nodules and hepatocellular carcinomas (HCC) in the liver of rats between 21 and 70 weeks. These various lesions in liver were analyzed histochemically for gamma-glutamyl transpeptidase (GGT) activity. The presence of lipofuscin, a putative indicator of lipid peroxidation was evaluated by autofluorescence. All the altered foci, neoplastic nodules and HCC were consistently negative for GGT, and had small amounts of lipofuscin contrasted to large deposits of this pigment in the surrounding normal liver. These results indicate that GGT is not a phenotypic marker in Wy-14,643 induced hepatic carcinogenesis. Whether the neoplastic alterations induced in liver by other peroxisome proliferators are similarly GGT negative remains to be determined.

88 citations


Journal ArticleDOI
TL;DR: The effect of various metal compounds on the DNA of Chinese hamster ovary cells was studied and nickel and other metals which cause cellular transformation have a very selective and specific effect upon DNA.
Abstract: The effect of various metal compounds on the DNA of Chinese hamster ovary (CHO) cells was studied. Both NiCl2 and crystalline NiS caused DNA strand breaks in cultured CHO cells, whereas amorphous NiS did not. Strand breaks were quantitated by determining the number of average molecular weight of DNA following treatment with the metal compounds. Exposure of cells to crystalline NiS, CoS, CdS, AgS, CuS and Ni3S2 at 10 micrograms/ml for 24 h also induced DNA strand breaks. Similar exposure to activated charcoal, which was also actively phagocytosed, failed to cause any effect on the DNA of CHO cells. In the case of NiCl2 and NiS the effect was shown to be both time and dose dependent. Other soluble metal compounds such as HgCl2, CaCrO4, and CdCl2 also decreased the molecular weight of DNA while MnCl2, ZnCl2 and FeCl2 caused no significantly detectable change in DNA molecular weight. These effects, which occur at low metal concentrations suggest that nickel and other metals which cause cellular transformation have a very selective and specific effect upon DNA.

87 citations


Journal ArticleDOI
TL;DR: Results from this study indicate that in vitro anaerobic incubations of rat intestinal microorganisms were able to reduce and cleave the azo bonds of dyes derived from benzidine, 3,3'-dimethylbenzidine and 3, 3'-dimethoxybenzazine to form potentially carcinogenic aromatic amines.
Abstract: The metabolism of a benzidine-based dye, Direct Black 38, a 3,3'-dimethylbenzidine-based dye, Direct Red 2 and a 3,3'-dimethoxybenzidine-based dye, Direct Blue 15 has been studied both in pure cultures of anaerobic bacteria and in bacterial suspensions derived from the intestinal contents of the rat. All of the pure cultures and the rat intestinal bacteria were able to reduce the azo linkages of Direct Black 38, Direct Red 2 and Direct Blue 15 with the subsequent formation of benzidine, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine, respectively. The metabolites of Direct Black 38, Direct Red 2 and Direct Blue 15 were isolated and identified by gas chromatography/mass spectrometry and had similar chromatographic and mass spectral properties with those of authentic standards. Results from this study indicate that in vitro anaerobic incubations of rat intestinal microorganisms were able to reduce and cleave the azo bonds of dyes derived from benzidine, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine to form potentially carcinogenic aromatic amines.

Journal ArticleDOI
TL;DR: No evidence was found to suggest that pronounced focal populations were reversible upon cessation of NNM-treatment under the present experimental conditions, and Morphometric analysis demonstrated that the rare small clear cell foci apparent after 7 weeks treatment with NNM increase in number and size with progression through the sequence to carcinomas without further administration of carcinogen.
Abstract: Different doses of N-nitrosomorpholine (NNM) (80, 120, 160, 200 mg/l drinking water) were administered for various periods of time (1, 4, 7, 14, 20 weeks) to male Sprague-Dawley rats in order to investigate the dose dependence and sequential appearance of preneoplastic and neoplastic lesions in the liver. With all dose levels studied a sequence was established leading from clear cell and acidophilic cell glycogen storage foci through mixed cell foci and neoplastic nodules to hepatocellular carcinomas. The first appearance and frequency of the different lesions investigated proved dependent on dose of carcinogen administered. Morphometric analysis demonstrated that the rare small clear cell foci apparent after 7 weeks treatment with NNM increase in number and size with progression through the sequence to carcinomas without further administration of carcinogen. No evidence was found to suggest that pronounced focal populations were reversible upon cessation of NNM-treatment under the present experimental conditions.


Journal ArticleDOI
TL;DR: Phenobarbital (PB) and barbital (BB) promoted the development of thyroid tumors in rats treated with a sub-effective dose of N-bis(2-hydroxypropyl)nitrosamine (DHPN) for thyroid tumorigenesis.
Abstract: Phenobarbital (PB) and barbital (BB) promoted the development of thyroid tumors in rats treated with a sub-effective dose of N-bis(2-hydroxypropyl)nitrosamine (DHPN) for thyroid tumorigenesis. Rats were given s.c. injections of 70 mg DHPN/100 g body weight once a week for 4 or 6 weeks with or without diet containing 500 p.p.m. PB or BB for the next 12 weeks. The incidences of thyroid tumors at the end of week 20 of the experiment were 66% in rats given DHPN for 4 weeks and then PB, 23% in rats given DHPN for 4 weeks and then BB, 100% in rats given DHPN for 6 weeks and then PB, 45% in rats given DHPN for 6 weeks and then BB, and 23% in rats given DHPN for 6 weeks. Rats given only DHPN for 4 weeks or only PB or BB had no thyroid tumors after 20 weeks.

Journal ArticleDOI
TL;DR: All-trans-4-hydroxyphenyl retinamide was among the most active and least toxic of the retinoids tested, and appears to be the compound of choice for further study.
Abstract: A series of experiments was conducted to determine the efficacy of 15 synthetic retinoic acid amides (retinamides) as inhibitors of chemical carcinogenesis of the urinary bladder in C57BL/6 x DBA/2F1 mice. Eight of the retinamides tested had significant protective activity when administered at nontoxic levels in the diet. Minor structural alterations, such as the addition of a methyl or hydroxyl group to the terminal amide moiety had a major influence on the anticarcinogenic activity of the retinamides. Although 13-cis retinamides generally were less toxic on a molar basis than were their all-trans isomers, no consistent pattern of differential anticarcinogenic activity was noted among the six pairs of all-trans and 13-cis isomers tested. All-trans-4-hydroxyphenyl retinamide was among the most active and least toxic of the retinoids tested, and appears to be the compound of choice for further study.

Journal ArticleDOI
TL;DR: It is confirmed that teleocidin is as potent as TPA in in vivo two-stage carcinogenesis in mouse skin, and two structurally unrelated classes, indole alkaloid and phorbol ester, showed tumor promoting activity in almost the same range.
Abstract: Teleocidin, isolated from Streptomyces mediocidicus ISP 5021, is an indole alkaloid. The teleocidin used was composed of teleocidin A, teleocidin B and their isomers. A hydrogenated derivative of teleocidin B, dihydroteleocidin B, was recently reported to have tumor promoting activity in vivo and various biological activities in vitro, with a specific activity comparable to that of 12-O-tetradecanoylphorbol-13-acetate (TPA). This paper describes the potent tumor promoting activity of the parent compound of dihydroteleocidins, teleocidin, on mouse skin in two-stage carcinogenesis. The tumor promoting activity was evaluated by measuring the incidence and yield of tumors, and by histological examination. Groups of mice were given a single application of 100 micrograms of 7,12-dimethylbenz[a]anthracene (DMBA) and then 2.5 micrograms of teleocidin twice weekly or the same dose of DMBA plus 2.5 micrograms of TPA twice weekly. Both groups showed 100% tumor incidence after 24 weeks, and the tumor yields were 4.0 tumors per mouse in the former group and 9.8 per mouse in the latter group in week 30. We confirmed, through this experiment, that teleocidin is as potent as TPA in in vivo two-stage carcinogenesis in mouse skin. These two structurally unrelated classes, indole alkaloid and phorbol ester, showed tumor promoting activity in almost the same range.

Journal ArticleDOI
TL;DR: Monitoring of N-nitrosamino acids excreted in the urine and feces appears to provide a valuable index for endogenous N-Nitrosation.
Abstract: A simple and sensitive method for the quantitative estimation of endogenous N-nitrosation in rats has been developed. This approach is based on the findings that N-nitrosamino acids (e.g., nitrosoproline (NPRO), nitrosohydroxyproline (NHPRO) and nitrososarcosine (NSAR)) when administered orally to rats, are excreted unchanged almost quantitatively (88-96% of the dose) in the urine and feces. After sequential administration of a nitrosatable amino acid and sodium nitrite the nitrosamino acid excreted in the urine and feces was analyzed. The amount of NPRO excreted in the urine of rats was proportional to the dose of proline and to the square of the nitrite dose. Co-administration of ascorbic acid and alpha-tocopherol together with the precursors decreased the urinary NPRO whereas thiocyanate increased the yield. After feeding an amino acid precursor and nitrite, the yield of nitrosamino acids formed in vivo and excreted in the urine increased in the order: NPRO less than NSAR less than NHPRO. The same order was seen when the nitrosation rates of the amino acids in vitro were compared. Thus N-nitrosation in vivo in rats occurs via a similar mechanism as observed in vitro. Monitoring of N-nitrosamino acids excreted in the urine and feces thus appears to provide a valuable index for endogenous N-nitrosation.

Journal ArticleDOI
TL;DR: The organochlorine pesticides chlordane and heptachlor were evaluated for their genotoxicity and epigenetic membrane effects and both markedly inhibited intercellular communication between cultured liver cells, whereas benzo[a]pyrene did not produce this epigenetic effect.
Abstract: The organochlorine pesticides chlordane and heptachlor were evaluated for their genotoxicity and epigenetic membrane effects. Both compounds were non-genotoxic in the ARLHGPRT mutagenesis assay in which the genotoxic carcinogens 7, 12-dimethylbenz[a]anthracene and benzo[a]pyrene induced significant increases in mutant incidence. The pesticides both markedly inhibited intercellular communication between cultured liver cells, a property demonstrated by many tumor promoting agents, whereas benzo[a]pyrene did not produce this epigenetic effect.

Journal ArticleDOI
TL;DR: In the rat hepatocyte GSH and GSH-transferases may be important in protecting DNA from electrophilic attack by reactive BP-7,8-diol and 9-OH-BP species.
Abstract: The binding to DNA of reactive metabolites of trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (BP-7,8-diol) was studied following the incubation of tritiated benzo[a]pyrene (BP) and BP-7,8-diol with nuclei from livers of 3-methylcholanthrene-treated rats. Binding was inhibited to a small extent by glutathione (GSH) alone and to a much greater extent by GSH and cytosol or purified GSH-transferases B and E. In this respect GSH-transferases A and C were also active, but less so. Inhibition of binding of BP-7,8-diol metabolites to DNA mediated by GSH-transferases was associated with the formation of GSH conjugates. The extent of inhibition of binding was similar in incubations of nuclei alone, nuclei and rat liver microsomes, and calf thymus DNA and rat liver microsomes. This indicates that reactive metabolites of BP-7,8-diol, formed either by nuclei or microsomes, are readily accessible to soluble GSH-transferases. GSH and cytosol were also active in inhibiting DNA-binding of reactive metabolites from 9-hydroxybenzo[a]pyrene (9-OH-BP). Thus, in the rat hepatocyte GSH and GSH-transferases may be important in protecting DNA from electrophilic attack by reactive BP-7,8-diol and 9-OH-BP species.

Journal ArticleDOI
TL;DR: Results are consistent with the carcinogenicity studies and indicate that tgDNT is a potent genotoxic agent, with 2, 6-DNT contributing the major portion of the effect.
Abstract: The purpose of this study was to examine the induction of unscheduled DNA synthesis (UDS) by the potent hepatocarcinogen technical grade dinitrotoluene (tgDNT; 76% 2, 4-DNT, 19% 2, 6-DNT) using the in vivo-in vitro hepatocyte DNA repair assay, Male Fischer-344 rats were treated by gavage and hepatocytes were isolated by liver perfusion and cultured with [3H] thymidine. UDS was measured by quantitative autoradiography as net grains/nucleus (NG); greater than or equal to 5 NG was considered positive. Controls consistently had -3 to -6 NG. A dose-related increase in UDS was observed 12 h after treatment, with 200 mg/kg tgDNT producing 26 NG. AZ 50-fold increase in the number of cells in S-phase was observed at 48 h after treatment. This increase in S-phase cells could be suppressed in the presence of 10-20 mM hydroxyurea (HU), while the same levels of HU did not affect the level of UDS at 12 h after treatment, 2,4-DNT produced only a weak response, in contrast to 2,6-DNT which was a potent inducer of UDS. Treatment of female rats with tgDNT yielded only modest increases in UDS and DNA replication relative to males. These results are consistent with the carcinogenicity studies and indicate that tgDNT is a potent genotoxic agent, with 2,6-DNT contributing the major portion of the effect.

Journal ArticleDOI
TL;DR: Evidence is presented that strains totally lacking in the nitroreductase which recognizes niridazole and related substances are not mutagenized by this group of chemicals and yet they are fully responsive to the mutagenic action of dinitropyrenes.
Abstract: Previous studies on the mutagenicity of nitroheterocyclics and nitrated polycyclic aromatic hydrocarbons had indicted the probable existence in Salmonella typhimurium of a multiplicity of nitroreductase activities of varying specificities which are required for the expression of the mutagenicity of nitro-containing chemicals. In the present study evidence is presented that these activities reside in different gene products: (a) strains totally lacking in the nitroreductase which recognizes niridazole and related substances are not mutagenized by this group of chemicals and yet they are fully responsive to the mutagenic action of dinitropyrenes; (b) double mutants which have lost both types of specificities can be constructed. Finally, the presence of a third type of nitroreductase with a specificity for 4-nitroquinoline-1-oxide is implied by the finding that the nitroreductase-deficient strains described herein retain full sensitivity to the mutagenic action of this chemical.

Journal ArticleDOI
TL;DR: Samples of opium pipe scrapings, but not of crude opium, collected in an area with a high incidence of oesophageal cancer in north-east Iran, were shown to contain pro-mutagens, producing mostly frameshift mutations in Salmonella typhimurium strains TA1538 and TA98 after metabolic activation.
Abstract: Samples of opium pipe scrapings (opium dross, called sukhteh locally), but not of crude opium, collected in an area with a high incidence of oesophageal cancer in north-east Iran, were shown to contain pro-mutagens, producing mostly frameshift mutations in Salmonella typhimurium strains TA1538 and TA98 after metabolic activation. Pyrolysis of opium and of its major alkaloid, morphine, yielded smoke condensates with mutagenic activities 10 and 100 times higher, respectively, than that of the sukhteh samples tested. Heterocyclic aromatic hydrocarbons and primary aromatic amines present at different concentrations in these three pyrolysates are considered to be the major active principles. Opium addiction has been implicated as a risk factor in bladder cancer in humans and the ingestion of opium pyrolysates, in conjunction with dietary deficiencies, may be related to the high incidence of oesophageal cancer in north-east Iran, although causality has not been established.

Journal ArticleDOI
TL;DR: Vitamin E deficiency may increase the risk of neoplastic development, especially when coupled with a high polyunsaturated fat intake; however, a high vitamin E supplementation does not seem to have any prophylactic effect on tumorigenesis by itself.
Abstract: Using the dimethylbenz[a]anthracene-induced mammary tumor model, the present study demonstrated that a low vitamin E intake (7.5 mg/kg of diet) had minimal effect on carcinoma development in rats fed a 5% stripped corn oil diet, but resulted in a marked enhancement in tumor incidence and yield in those rats fed a 25% stripped corn oil ration. Control animals in this experiment received an adequate supply of vitamin E (30 mg/kg as DL-alpha-tocopheryl acetate). Thus, the effect of vitamin E deficiency on mammary carcinogenesis was accentuated in rats maintained on a high polyunsaturated fat diet, an observation similar to that of selenium deficiency which was reported by the author in a previous publication. In view of the biochemical interaction between vitamin E and selenium as endogenous antioxidants, another experiment was conducted to determine whether supranutritional supplementation of vitamin E (1000 mg/kg) was able to block the enhancement in mammary tumorigenesis due to selenium deprivation. Results of this experiment indicated that vitamin E excess failed to overcome the augmented tumor yield in selenium-deficient rats, nor did it provide any protection in rats that received an adequate supply of selenium. In summary, vitamin E deficiency may increase the risk of neoplastic development, especially when coupled with a high polyunsaturated fat intake; however, a high vitamin E supplementation does not seem to have any prophylactic effect on tumorigenesis by itself.

Journal ArticleDOI
TL;DR: Nitropyrenes, which are highly mutagenic in the Salmonella assay, were shown also to be potent mutagens on Chinese hamster lung cells without metabolic activation when resistance to diphtheria toxin was used as a selective marker.
Abstract: Nitropyrenes, which are highly mutagenic in the Salmonella assay, were shown also to be potent mutagens on Chinese hamster lung cells without metabolic activation when resistance to diphtheria toxin was used as a selective marker. Among nitropyrenes tested, 1,8- and 1,6-dinitropyrenes were the most mutagenic, and 1,3-dinitro- and 1,3,6-trinitropyrenes were less active, but showed still much higher mutagenic activity than methyl methanesulfonate or N-methyl-N-nitrosourea. 1-Nitropyrene and 1,3,6,8-tetranitropyrene did not induce diphtheria toxin-resistant mutants at concentrations of up to 20 micrograms/ml.

Journal ArticleDOI
TL;DR: The present data support the view that CrO3, like other soluble hexavalent chromium compounds, is genetically active in vivo.
Abstract: Chromosomal aberrations in cultured lymphocytes obtained from workers occupationally exposed to chromic acid (CrO3) were detected. Four separate groups of workers were examined, two of which were engaged in plating factories employing nickel in addition to chromium, and two coming from plating factories where only chromium was used. In the latter groups the frequency of sister chromatid exchanges (SCEs) were also detected in the cultured lymphocytes. A statistically significant increase of chromosomal aberrations, mostly of the chromosome-type, was found in two of the exposed groups of workers compared to the level observed in control donors. The frequency of SCEs in the exposed groups was higher than in controls, particularly in the factor which employed the younger workers. Besides the negative correlation with the age of workers, a positive correlation between the frequency of SCEs and the level of urinary chromium was found and such a correlation was strongly enchanced by smoking. The present data support the view that CrO3, like other soluble hexavalent chromium compounds, is genetically active in vivo.


Journal ArticleDOI
TL;DR: X-ray photoelectron spectroscopy analysis of amorphous and crystalline NiS particles revealed that the outermost surface (1-4 nm) of the two particles had striking differences in Ni/S ratios and in their sulfur oxidation states.
Abstract: Crystalline nickel sulfide (alpha NiS) and cobalt sulfide (CoS2) particles can cause greater cell transformation and cellular toxicity than the respective amorphous metal sulfide particles. Cultured mammalian cells phagocytose the crystalline metal sulfide particles more readily than the amorphous ones. In the case of the nickel sulfides, the crystalline metal sulfide particles had negatively charged surfaces (Zeta potential: -27.012 mV) in contrast to the amorphous particles, which were positively charge (Zeta potential: +9.174 mV). X-ray photoelectron spectroscopy analysis of amorphous and crystalline NiS particles revealed that the outermost surface (1-4 nm) of the two particles had striking differences in Ni/S ratios and in their sulfur oxidation states. Rendering particles' surfaces more negative by reduction with lithium aluminum hydride enhanced their phagocytosis, and in the case of amorphous NiS chemical reduction resulted in an incidence of morphological transformation of Syrian hamster embryo cells comparable to that observed with untreated crystalline alpha NiS.

Journal ArticleDOI
TL;DR: The relative potencies observed with this in vitro system qualitatively correlated with the in vivo carcinogenic activity seen in trout, indicating that this assay is of value in predicting the carcinogenic potential of mycotoxins in this species.
Abstract: A modification of the Ames assay using rainbow trout (Salmo gairdneri) liver postmitochondrial fraction (PMF) was developed to investigate the relative mutagenic potential of a series of aflatoxins (AFs). Preliminary experiments revealed that the 20000 x g (S20) liver fraction contained a higher metabolic activity than either the S9 or S30 fractions, and that 5 mg of S20 protein/plate gave the highest mutagenic response. A 9-24 h preincubation period at 25 degrees C was also required. The results from comparative mutagenicity experiments showed the following relative potencies: AFB1 greater than AFL greater than AFG1 greater than AFM1 greater than AFB2 greater than AFP1 greater than AFQ1. The relative potencies observed with this in vitro system qualitatively correlated with the in vivo carcinogenic activity seen in trout, indicating that this assay is of value in predicting the carcinogenic potential of mycotoxins in this species.


Journal ArticleDOI
TL;DR: Data indicate that ethyl carbamate may be metabolically activated by dehydrogenation to vinyl carbamate and subsequent epoxidation of the latter compound as previously proposed.
Abstract: Injection of a single dose of[ethyl-1,2(-3)H]or[ethyl-1(-14C]- ethyl carbamate into 12-day old male[C57BL/6 x C3H/He]F1 mice or of[ethyl-1,2(-3H]ethyl carbamate into adult male A/Jax mice resulted in the formation of labeled 1,N6-ethenoadenosine and 3,N4-ethenocytidine adducts in the hepatic RNA. These adducts were characterized by comigration on h.p.l.c. of 3H or 14C in enzymatic hydrolysates of the RNA with synthetic standards. Both the ethenoadenosine and ethenocytidine were further characterized by their conversion to acetylated products that comigrated with acetylated synthetic standards. The ethenoadenosine was also converted by anhydrous trifluoroacetic acid to a product that comigrated with synthetic 1,N6-ethenoadenine. The levels of adducts in the hepatic RNA 12 h after a single injection of 0.5-0.6 mg of ethyl carbamate/g body weight were 6-10 and 2-3 pmol/mg RNA of ethenoadenosine and ethenocytidine, respectively. No labeled ethenoadenosine or ethenocytidine could be detected in the hepatic RNA of mice given[1-14C]ethanol, an enzymatic hydrolysis product of ethyl carbamate. These data indicate that ethyl carbamate may be metabolically activated by dehydrogenation to vinyl carbamate and subsequent epoxidation of the latter compound as previously proposed. Vinyl carbamate epoxide may form etheno derivatives in a manner analogous to that demonstrated for chloroethylene oxide, an electrophilic metabolite of vinyl chloride. Vinyl carbamate has been shown to have the same spectrum of tumor induction as ethyl carbamate but to be much more active than the latter carcinogen.