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Griffiths AJF, Miller JH, Suzuki DT, et al. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000.

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An Introduction to Genetic Analysis. 7th edition.

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Relation between mutagens and carcinogens

Mutagenicity and carcinogenicity are clearly correlated. One study showed that 157 of 175 known carcinogens (approximately 90 percent) are also mutagens. The somatic mutation theory of cancer holds that these agents cause cancer by inducing the mutation of somatic cells. Thus, understanding mutagenesis is of great relevance to our society.

Induced mutations and human cancer

Understanding the specificity of mutagens in bacteria has led to the direct implication of certain environmental mutagens in the causation of human cancers. Ultraviolet light and aflatoxin B1 have long been suspected of causing skin cancer and liver cancer, respectively. Now, DNA sequence analysis of mutations in a human cancer gene has provided direct evidence of their involvement. The gene in question is termed p53 and is one of a number of tumor-suppressor genes—genes that encode proteins that suppress tumor formation. (We will learn more about these genes in Chapter 23.) A sizable proportion of human cancer patients have mutated tumor-suppressor genes.

Liver cancer is prevalent in southern Africa and East Asia, and a high exposure to AFB1 in these regions has been correlated with the high incidence of liver cancer. When p53 mutations in cancer patients were analyzed, G → T transversions, the signature of AFB1-induced mutations, were found in liver cancer patients from South Africa and East Asia but not in patients from these regions with lung, colon, or breast cancer. On the other hand, p53 mutations in liver cancer patients from areas of low AFB1 exposure did not result from G → T transversions. These findings, together with the results from the mutagenic specificity studies of AFB1 (see Figure 16-13), allow us to conclude that AFB1-induced mutations are a prime cause of liver cancer in South Africa and East Asia.

Sequencing p53 mutations has also strengthened the link between UV and human skin cancers. The majority of invasive human squamous cell carcinomas analyzed so far have p53 mutations, all of them mutations at dipyrimidine sites, most of which are C → T substitutions when the C is the 3′ pyrimidine of a TC dimer. This is the profile of UV-induced mutations. In addition, several tumors have p53 mutations resulting from a CC → TT double base change, which is found most frequently among UV-induced mutations.

The modern environment exposes everyone to a wide variety of chemicals in drugs, cosmetics, food preservatives, pesticides, compounds used in industry, pollutants, and so forth. Many of these compounds have been shown to be carcinogenic and mutagenic. Examples include the food preservative AF-2, the food fumigant ethylene dibromide, the antischistosome drug hycanthone, several hair-dye additives, and the industrial compound vinyl chloride; all are potent, and some have subsequently been subjected to government control. However, hundreds of new chemicals and products appear on the market each week. How can such vast numbers of new agents be tested for carcinogenicity before much of the population has been exposed to them?

Ames test

Many test systems have been devised to screen for carcinogenicity. These tests are time consuming, typically requiring laborious research with small mammals. More rapid tests do exist that make use of microbes (such as fungi or bacteria) and test for mutagenicity rather than carcinogenicity. The most widely used test was developed in the 1970s by Bruce Ames, who worked with Salmonella typhimurium. This Ames test uses two auxotrophic histidine mutations, which revert by different molecular mechanisms (Figure 16-22). Further properties were genetically engineered into these strains to make them suitable for mutagen detection. First, they carry a mutation that inactivates the excision-repair system (described later). Second, they carry a mutation that eliminates the protective lipopolysaccharide coating of wild-type Salmonella to facilitate the entry of many different chemicals into the cell.

Figure 16-22. Ames test results showing the mutagenicity of aflatoxin B1, which is also a potent carcinogen.

Figure 16-22

Ames test results showing the mutagenicity of aflatoxin B1, which is also a potent carcinogen. TA100, TA1538, and TA1535 are strains of Salmonella bearing different his auxotrophic mutations. The TA100 strain is highly sensitive to reversion through base-pair (more...)

Bacteria are evolutionarily a long way removed from humans. Can the results of a test on bacteria have any real significance in detecting chemicals that are dangerous for humans? First, we have seen that the genetic and chemical nature of DNA is identical in all organisms, so a compound acting as a mutagen in one organism is likely to have some mutagenic effects in other organisms. Second, Ames devised a way to simulate the human metabolism in the bacterial system. In mammals, much of the important processing of ingested chemicals takes place in the liver, where externally derived compounds normally are detoxified or broken down. In some cases, the action of liver enzymes can create a toxic or mutagenic compound from a substance that was not originally dangerous (Figure 16-23). Ames incorporated mammalian liver enzymes in his bacterial test system, using rat livers for this purpose. Figure 16-24 outlines the procedure used in the Ames test.

Figure 16-23. The metabolic conversion of benzo(a)pyrene (BP) into a mutagen (and a carcinogen).

Figure 16-23

The metabolic conversion of benzo(a)pyrene (BP) into a mutagen (and a carcinogen). Benzo(a)pyrene goes through several steps (a) as it is made more water soluble prior to excretion. One of the intermediates in this process, a diol epoxide (3), is capable (more...)

Figure 16-24. Summary of the procedure used for the Ames test.

Figure 16-24

Summary of the procedure used for the Ames test. First, rat liver enzymes are mobilized by injecting the animals with Arochlor. (Enzymes from the liver are used because they carry out the metabolic processes of detoxifying and toxifying body chemicals.) The (more...)

Chemicals detected by this test can be regarded not only as potential carcinogens (sources of somatic mutations), but also as possible causes of mutations in germinal cells. Because the test system is so simple and inexpensive, many laboratories throughout the world now routinely test large numbers of potentially hazardous compounds for mutagenicity and potential carcinogenicity.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2000, W. H. Freeman and Company.
Bookshelf ID: NBK21788


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