The Mutagenicity of Chemical Carcinogens: Correlations, Problems, and Interpretations

Miller, Elizabeth C.; Miller, James A.

doi:10.1007/978-1-4615-8966-2_3

Cited by 148 publications

(50 citation statements)

References 129 publications

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“…Table 1 shows that ratliver homogenates can activate 18 different aromatic type carcinogens to mutagens. The compounds were chosen for testing because they were known to be carcinogenic in humans or in animals (7,15). Control values are presented both for the number of revertant colonies on plates with compound and no S-9 Mix, and for the number of colonies on plates [8][9] fraction and carcinogen concentration on mutagenesis of TA1538.…”

Section: Resultsmentioning

confidence: 99%

“…With this test we have also shown that the active forms of a large number of known carcinogens are mutagens (1)(2)(3)(4)(5). The active forms of carcinogens such as aflatoxin, polycyclic hydrocarbons, dimethylnitrosamine, and various aromatic amines are formed by mammalian metabolism, in particular by the TPNH-dependent microsomal enzymes of liver (6)(7)(8)(9)(10)(11). The principal limitation of any bacterial system for detecting carcinogens as mutagens is that bacteria do not duplicate mammalian metabolism in activating carcinogens.…”

mentioning

confidence: 97%

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Carcinogens are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection

Ames

Durston

Yamasaki

et al. 1973

Proc. Natl. Acad. Sci. U.S.A.

1,747

581

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ABSTRACT18 Carcinogens, including aflatoxin Bi, benzo(a)pyrene, acetylaminofluorene, benzidine, and dimethylamino-trans-stilbene, are shown to be activated by liver homogenates to form potent frameshift mutagens. We believe that these carcinogens have in common a ring system sufficiently planar for a stacking interaction with DNA base pairs and a part of the molecule capable of being metabolized to a reactive group: these structural features are discussed in terms of the theory of frameshift mutagenesis. We propose that these carcinogens, and many others that are mutagens, cause cancer by somatic mutation. A simple, inexpensive, and extremely sensitive test for detection of carcinogens as mutagens is described. It consists of the use of a rat or human liver homogenate for carcinogen activation (thus supplying mammalian metabolism) and a set of Salmonella histidine mutants for mutagen detection. The homogenate, bacteria, and a TPNHgenerating system are all incubated together on a petri plate. With the most active compounds, as little as a few nanograms can be detected.We have previously described the use of a set of mutants of Salmonella typhimurium for detecting and classifying chemical mutagens with great simplicity and sensitivity (1, 2). With this test we have also shown that the active forms of a large number of known carcinogens are mutagens (1-5). The active forms of carcinogens such as aflatoxin, polycyclic hydrocarbons, dimethylnitrosamine, and various aromatic amines are formed by mammalian metabolism, in particular by the TPNH-dependent microsomal enzymes of liver (6-11). The principal limitation of any bacterial system for detecting carcinogens as mutagens is that bacteria do not duplicate mammalian metabolism in activating carcinogens. Mammalian-liver homogenates have been used by Garner et al., (6) to activate aflatoxin B1 to a compound lethal to our bacterial tester strain lacking excision repair, by Malling (12) to activate dimethylnitrosamine to a compound that reverts one of our bacterial tester strains, and by Slater et al. (13) to activate dimethylnitrosamine to a compound lethal for bacteria lacking polymerase I. In this study we have extended this work and shown that carcinogens can be detected as mutagens simply and with great sensitivity by incubation of the carcinogen, a rat or human liver homogenate, and our bacterial tester strain together on a petri plate. MATERIALS AND METHODSCompounds. Glucose-6-phosphate, TPN, TPNH, and 2-naphthylamine were obtained from Sigma. Benzo(a)pyrene, 2-acetylaminofluorene, and benzidine were from Aldrich. DiAbbreviation: Me2SO, dimethylsulfoxide. methylsulfoxide (Me2SO), spectrophotometric grade, was obtained from Schwarz/Mann, sodium phenobarbital from Mallinckrodt, aflatoxin B1 from Calbiochem, and 3-methylcholanthrene from Eastman; 7,12-dimethylbenz(a)anthracene was a gift of P. L. Grover. Schuchardt (Munich) was the source for the other carcinogens.Bacterial Strains used are mutants of S. typhimurium LT-2 and have been discussed in detail (2).Sourc...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 97%

Carcinogens are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection

Ames

Durston

Yamasaki

et al. 1973

Proc. Natl. Acad. Sci. U.S.A.

1,747

581

View full text Add to dashboard Cite

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“…There is now a greater understanding of some of the mechanisms involved in chemical carcinogenesis from metabolic and structure-activity correlation studies (Clayson, 1962;Brookes, 1971;Hueper and Conway, 1964;WHO/IARC, 1974;Miller, 1970;Miller and Miller, 1971a, b, 1972, 1974Dinman, 1974;Arcos and Argus, 1974) but in no case is there unequivocal knowledge of the molecular target critical to the induction of cancer (Miller, 1970).…”

Section: Tionmentioning

confidence: 99%

An evaluation of 6 short-term tests for detecting organic chemical carcinogens

Purchase¹,

Longstaff²,

Ashby³

et al. 1978

Br J Cancer

383

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Summary.-A number of tests have been described which are thought to be capable of identifying carcinogens without using the actual induction of cancer as an endpoint. This study compares the performance of 6 such tests on a selection of 120 organic chemicals. The tests studies were: (1) mutation of Salmonella typhimurium; (2) cell transformation; (3) degranulation of endoplasmic reticulum; (4) sebaceous gland suppression; (5) tetrazolium reduction and (6) subcutaneous implant. A further 4 tests were examined briefly, but were not included in the complete evaluation.The chemicals were classified into carcinogens (58) and non-carcinogens (62) on the basis of published experimental data, and into 1 of 4 broad chemical classes.There was considerable variation between tests in their ability to predict carcinogenicity, with the cell-transformation test and the bacterial-mutation test being the most accurate (94% and 93% accurate respectively). These 2 tests were considered to be of general use in screening, since they were clearly more accurate than the others. Statistical consideration of various combinations of these tests showed that the use of cell transformation and bacterial mutation together, provide an advantage over the use of either test alone. The inclusion of the other 4 tests in a screening battery predictably resulted in a great increase in overall inaccuracy and loss of discrimination, even though the detection of carcinogens is improved. All the tests were shown to generate both false positive and false negative results, a situation which may be controlled by the use, where possible, of appropriate chemical-class controls, to identify the test which is optimal for the class of chemical under test. Structural

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“…In addition, cells that are cygling slowly in the mammary gland of the parous rats, could have enough time to repair any damage inflicted by the carcinogen before it is fixed in the genome (61)(62)(63)(64). It has been demonstrated in tissue culture that cells in the early or mid-GI phase were capable of repairing sublethal radiation-induced damage (65), whereas the damage becomes fixed in S phase (45,66) (Fig. 9).…”

mentioning

confidence: 99%

Basis of Cellular Autonomy in the Subsceptibility to Carcinogenesis

Russo

1983

Toxicol Pathol

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This paper summarizes our contributions in the basic understanding of the different susceptibility of the mammary gland to carcinogenesis according to age and parity history. Mammary carcinomas induced by the administration of 7,12-dimethylbenz-(DMBA) to young virgin rats arise from undifferentiated terminal ductal structures called terminal end buds (TEBs). TEBs, that normally differentiate into alveolar buds (ABs) and lobules, under the influence of DMBA develop intraductal proliferations which progress to carcinoma. The high susceptibility of the young virgin rat TEBs to neoplastic transformation is due to its large proliferative compartment, with cells cycling every 10 'hours, and to a higher 'H-DMBA uptake. Progressive differentiation of TEBs into ABs and lobules or their regression to terminal ducts (TDs) i s seen with aging. Complete differentiation of the gland is attained through pregnancy and lactation or through exogenous administration of chorionic gonadotrophin. The greater differentiation of the gland is manifested as permanent structural changes, consisting in the disappearance of TEBs and in a diminution of the number of TDs due to their differentiation into ABs and lobules. This greater differentiation results in a diminished or total refractoriness of the gland to the carcinogen because ABs and lobules have a lower proliferative compartment, and a longer cell cycle than TEBs and TDs. Cells of parous rats have both in vivo and in v i m lower DMBA-DNA binding capacity, lower DNA synthesis and greater ability to repair DMBA-damaged DNA than cells of young virgin rats. The more efficient DNA repair capacity of the parous rat mammary gland is demonstrated by the induction of unscheduled DNA synthesis and a removal of DMBA-DNA adducts.

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The Mutagenicity of Chemical Carcinogens: Correlations, Problems, and Interpretations

Cited by 148 publications

References 129 publications

Carcinogens are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection

Carcinogens are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection

An evaluation of 6 short-term tests for detecting organic chemical carcinogens

Basis of Cellular Autonomy in the Subsceptibility to Carcinogenesis

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