ISSN:0098-4108    

DOI:10.1080/15287397709529523

出版商:Taylor & Francis Group    

年代:1977

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287397709529524

出版商:Taylor & Francis Group    

年代:1977

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287397709529525

出版商:Taylor & Francis Group    

年代:1977

数据来源: Taylor

摘要:

Aflatoxins are associated with acute toxicoses in poultry and livestock and with liver cancer in human populations in Africa and Southeast Asia. Comparative metabolism studies indicate that aflatoxin B1, the most potent of these compounds, requires metabolic activation to the ultimate carcinogen. The mycotoxin (1) is oxidatively demethylated to form the phenolic derivative, (2) is hydroxylated directly at three sites, and (3) undergoes reduction of the carbonyl group in the cyclopentenone ring to a hydroxyl group; these five hydroxy derivatives all appear to be part of detoxication pathways. Considerable evidence is now available to support the hypothesis that activation of aflatoxinB1to the ultimate carcinogen involves epoxidation of the double bond in the terminal furan ring. The epoxide decomposes to form a carbonium ion at C‐2, which attacks nucleophilic sites in DNA, especially on the guanine moiety. Thus, like carcinogenic polycyclic hydrocarbons andN‐nitroso compounds, aflatoxin B1,appears to be activated to an alkylating agent.

ISSN:0098-4108    

DOI:10.1080/15287397709529526

出版商:Taylor & Francis Group    

年代:1977

数据来源: Taylor

摘要:

Separation of the metabolic products of benzo[a]pyrene has been readily accomplished by high‐pressure liquid chromatography. This technique is uniquely suited for compounds labile to air and light and for resolving positional isomers of phenolic or other types of oxygenated metabolites of this carcinogen. This procedure has been utilized to separate and compare benzo[a]pyrene activation and detoxification products between rat, mouse, and hamster hepatic microsomes and mouse and hamster embryo cell cultures. While metabolite profiles exhibited the same types of derivatives, marked quantitative variation was observed. Microsomal preparation produced large amounts of noncarcinogenic phenols, while intact cell metabolism favored diol formation. These results are in agreement with reactivation of metabolic diols as substrates for further activation to a more proximate carcinogenic species of benzo[a]pyrene and caution against extrapolating metabolic results from any single test system to other species or tissues.

ISSN:0098-4108    

DOI:10.1080/15287397709529527

出版商:Taylor & Francis Group    

年代:1977

数据来源: Taylor

摘要:

Evidence supporting the conclusion that 7,8‐dihydroxy‐9,10‐epoxy‐7,8,9,10‐tetra‐hydrobenzo[a]pyrenes are ultimate mutagenic and carcinogenic forms of benzo[a]‐pyrene (BP) is summarized. Quantum mechanical calculations that predict reactivity of diol epoxides derived from BP and other polycyclic aromatic hydrocarbons are described. The calculations predict that diol epoxides in which the oxirane ring forms part of a “bay region” of a tetrahydrobenzo ring should be the most reactive for a given aromatic hydrocarbon. Experiments with dihydrodiols and diol epoxides from benzo[a]anthracene (BA) are described. The ability to metabolically activate BA 3,4‐dihydrodiol to species much more mutagenic than those obtained from other BA dihydrodiols and the much greater mutagenicity of the diastereoisomeric 3,4‐diol‐1,2‐epoxides of 1,2,3,4‐tetrahydro BA relative to other diol epoxides of BA are in accord with predictions of the quantum mechanical calculations.

ISSN:0098-4108    

DOI:10.1080/15287397709529528

出版商:Taylor & Francis Group    

年代:1977

数据来源: Taylor

摘要:

Brief reviews are presented on the occurrence ofN‐nitroso (NNO) compounds, the chemistry and kinetics of NNO compound formation from nitrite and amines or amides, thein vivoformation of these compounds (as detected by tumor induction) on feeding nitrite with amines or amides to rodents, and the carcinogenicity for rats of some new nitrosamides. The possible human hazard caused by exposure to specific readily nitrosated compounds is reviewed. Whether NNO compounds might be causing human cancer of various organs (e.g., pancreatic, nasopharyngeal, and esophageal cancer) is discussed. Some of our results on [3H] thymidine incorporation in the rat esophageal epithelium are presented. Nitrosamines that cause esophageal cancer in rats were found to inhibit [3H] thymidine incorporation, bothin vivoandin vitro,when esophagi were incubated with nitrosamines. With reference to the hypothesis that human gastric cancer is caused by nitrosamides (e.g., nitrosoureas), certain correlations were examined between gastric cancer and environmental exposure to nitrate, nitrite, and nitrosatable amides. In studies from our laboratory, dried, salted fish, which was treated with excess nitrite at pH 1 and then “denitrosated” at pH 0, yielded 16 mg methylurea/kg fish, possibly derived from methylguanidine.

ISSN:0098-4108    

DOI:10.1080/15287397709529529

出版商:Taylor & Francis Group    

年代:1977

数据来源: Taylor

摘要:

The site of alkylation of a nucleic acid, in vitroorin vivo,is greatly dependent on the type of alkylating agent. Most alkylating agents of low mutagenicity or carcinogenicity (such as dimethylsulfate) react primarily with the ring nitrogens. The carcinogenic N‐nitroso compounds have a great affinity for alkylating oxygens and react with all ring oxygens as well as the phosphodiesters and, in the case of RNA, with the 2'‐O of ribose. Ethylating agents, though in absolute terms less reactive than the corresponding methylating agents, show even greater affinity toward oxygens. It appears that the ethyl nitroso compounds that are carcinogenic are also the most reactive with oxygens.

ISSN:0098-4108    

DOI:10.1080/15287397709529530

出版商:Taylor & Francis Group    

年代:1977

数据来源: Taylor

摘要:

An assay system has been developed for measuring the fidelity of DNA synthesisin vitroby using synthetic polynucleotide templates and purified DNA polymerases. Nearest‐neighbor analysis of the synthesized product indicates that noncomplementary nucleotides are incorporated as single base substitutions. The accuracy of DNA synthesis can be decreased by (1) prior alkylation of the template, (2) increasing the relative concentration of incorrect nucleotides, and (3) addition of specific metal salts to the reaction mixture. As an initial evaluation of the utility of this system, the effects of 31 metal salts on the fidelity of DNA synthesis have been determined. The results indicate that potential metal mutagens and/or carcinogens may be detected by measuring alterations in the fidelity of DNA synthesis.

ISSN:0098-4108    

DOI:10.1080/15287397709529531

出版商:Taylor & Francis Group    

年代:1977

数据来源: Taylor

摘要:

An extended summary is presented of current progress in research on the basic mechanism of chemical carcinogenesis conducted in the Division of Biophysics, School of Hygiene and Public Health, at The Johns Hopkins University. The first section concerns the involvement of free radicals in benzo[a]pyrene metabolism and carcinogenesis, the second the relationship between neoplastic transformation and somatic mutation, and the third the changes in DNA sequence organization and gene expression in neoplastic transformation.

ISSN:0098-4108    

DOI:10.1080/15287397709529532

出版商:Taylor & Francis Group    

年代:1977

数据来源: Taylor