Carcinogenic compounds Ames test

Bacterial mutagenicity Carcinogenicity Compound (Ames test) (rats)... 

Ames test analy chem A bioassay that uses a set of histidine auxotrophic mutants of Salmomlla typhimurium for detecting mutagenic and possibly carcinogenic compounds. amz, test ... 

These principles of reverse mutation are utilized in one important method, the Ames test (section 4.4.2), which is used to detect compounds that act as mutagens or carcinogens (most carcinogens are mutagens). 

The Ames test involves the reversion from a his— to his+ phenotype in any one of multiple bacterial strains (usually five strains are tested simultaneously). If the addition of test compound to a his— strain of bacteria allows them to grow on histidine deficient media, the obvious conclusion is compound-induced mutagenesis and a high potential hazard for the compound being carcinogenic. This test can also be conducted in the presence or absence of metabolic activation, in order to provide more information on potential risks (i.e., the parent compound may not be mutagenic, but the primary metabolite may present a safety risk). In practice, a positive Ames test almost always leads to discontinuing work on a compound of interest, and so these data are always collected prior to nomination of a compound for development. 

Am ino-1-methy 1-6-phenyl irnidazo 4,5-b]pyridine (29 PhIP), usually the most abundant product of food-derived mutagens, is formed by heating creatine and phenylalanine at 200 °C200. This compound is modestly mutagenic in the Ames test, but is a potent carcinogen in rats and mice, causing breast and colon cancers. 

DAB was genotoxic in the comet assay inducing DNA damage in the stomach, colon liver, bladder, lung, and bone marrow. It is also mutagenic to Salmonella in the Ames test. Because of its demonstrated carcinogenicity in animals, human exposure to DAB by any route should be avoided. In recent years, this compound has been used only in laboratories as a model of tumorigenic activity in animals. It is not produced commercially in the United States and is of little occupational health importance. 

Even if Ames and his critics accepted carcinogenic ranking based on the TI measure, I believe they still would debate which compounds to test (natural or synthetic), how to extrapolate (linearly or nonlinearly), and whether we ought to worry more about the need to protect the public from carcinogens or fhe need fo allow producfs to be developed and sold in the marketplace. Defenders of currenf animal testing believe in linear extrapolation and the need to protect the public from indusfrial carcinogens. Grifics believe animal tesf... 

N,0-Acyltransferase. The /V-acyl transferase enzyme is believed to be involved in the carcinogenicity of arylamines. These compounds are first V-oxidized, and then, in species capable of their A-acetylation, acetylated to arylhydroxamic acids. The effect of N, O-transacetylation is shown in Figure 7.22. The A/-acyl group of the hydroxamic acid is first removed and is then transferred, either to an amine to yield a stable amide or to the oxygen of the hydroxylamine to yield a reactive N-acyloxyarylaminc. These compounds are highly reactive in the formation of adducts with both proteins and nucleic acids, and N, O -acy I Iransfcrasc, added to the medium in the Ames test, increases the mutagenicity of compounds such as A-hydroxy-2-acetylaminofluorine. 

The initial limit based arbitrarily upon a known carcinogen could be relaxed upon submission of favorable short-term testing data for carcinogenicity and mutagenicity (Ames test, cell transformation, DNA repair, chromosome damage. Drosophila etc.,) The test compound could be compared to a known carcinogen (and mutagen). The new limit for the test substance would be decreased in proportion to its potency as related to the standard (e.g., bis-chloromethyl ether). 

The Ames test is used to screen a wide variety of chemicals for potential carcinogenicity or as potential cancer chemotherapeutic agents. The test enables a large number of compounds to be screened rapidly by examining their ability to induce mutagenesis in several specially constructed bacterial mutants derived from Salmonella typhimurium. 

Ames test. A simple bacterial test for carcinogens, based on the assumption that carcinogens are mutagens. Named after its inventor Bruce Ames. Somewhat less favored than it used to be, because of the idea that compounds causing cells to grow more rapidly will sometimes result in cancer. 

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