Mutagen

Mutagen

A mutagen is any substance or agent that can cause a mutation, or change in the sequence or structure of DNA. Mutagens are classified on the basis of their physical nature and the types of damage they do. A mutagen is not the same as a carcinogen. Carcinogens are agents that cause cancer. While many mutagens are carcinogens as well, many others are not. The Ames test is a widely used test to screen chemicals used in foods or medications for mutagenic potential.

Chemical Mutagens

There are many hundreds of known chemical mutagens. Some resemble the bases found in normal DNA; others alter the structures of existing bases; others insert themselves in the helix between bases; while others work indirectly, creating reactive compounds that directly damage the DNA structure.

"Base analogs" are molecules whose chemical structure is similar to one of the four DNA bases (adenine, thymine, cytosine, and guanine). Because of this similarity, they can be incorporated into the helix during DNA replication. A key feature of mutagenic base analogs is that they form base pairs with more than one other base. This can cause mutations during the next round of replication, when the replication machinery tries to pair a new base with the incorporated mutagen. For instance, 5-bromo-deoxyuridine (5BU) exists in two different forms. One mimics thymine and therefore pairs with adenine during replication, while the other mimics cytosine and therefore pairs with guanine. In its thymine-mimicking form, 5BU can be incorporated across from an adenine. If it then converts to its cytosine-like form, during the next round of replication, it will cause a gua-nine to enter the opposite strand, rather than the correct adenine.

"Base-altering mutagens" cause chemical changes in bases that are part of the DNA. For example, nitrite preservatives in food convert to the mutagen nitrous acid. Nitrous acid causes deamination, or loss of an-NH₂ group, of cytosine. When this occurs, cytosine becomes uracil, a base that is not normally incorporated in DNA but that is very similar to thymine. Unless repaired, this uracil will cause an adenine to enter the opposite strand instead of a guanine. Many base-altering mutagens are complex organic molecules. These are formed in large quantities in smoke, making up the "tar" of cigarette smoke, for example. They act as alkylating agents, combining with DNA to form bulky groups that interrupt replication.

"Intercalating agents" are flat molecules that insert themselves between adjacent bases in the double helix, distorting the shape at the point of insertion. Where this occurs, DNA polymerase may add an additional base opposite the intercalating agent. If this occurs in a gene, it induces a frameshift mutation (that is, it alters the reading of the gene transcript, changing which amino acids are added to the encoded protein). Ethidium bromide is one such agent, widely used in DNA research because its dark color allows DNA to be easily visualized. This is useful in gel electrophoresis, for instance, to find the DNA bands that have been separated in a gel.

Other damaging agents include chemicals that create "free radicals" inside a cell. Free radicals are compounds in which an atom, usually an oxygen, has an unbonded electron. Free radicals are highly reactive and can cause several types of damage to DNA.

Light and Radiation

Radiation refers to two different phenomena: light and high-energy particles. Visible light represents a small slice of the electromagnetic spectrum, which includes long-wavelength (low-energy) radio waves and short-wave-length (high-energy) ultraviolet waves, plus X rays and gamma rays. These high-energy forms can directly disrupt DNA by breaking its chemical bonds. In severe cases, this can break apart chromosomes, causing chromosome aberrations. More often, they create mutagenic free radicals in the cell. X rays were first used by Hermann Muller to induce mutations in fruit flies. They continue to be used to create mutations in model organisms to study genes and their effects.

Ultraviolet light is less energetic than X rays but causes mutations nonetheless. The higher-energy form, UV-B, is more toxic than UV-A, because of its potential to cause cross-linking between adjacent thymine or cytosine bases, creating a so-called pyrimidine dimer (cytosine and thymine are chemically classified as pyrimidines). Pyrimidine dimers interrupt replication. UV-A does not cause dimer formation but can still cause mutations by creating free radicals.

Another meaning of the term "radiation" is high-energy particles released during the breakdown of radioactive elements, such as uranium. These particles are either electrons (called beta particles) or helium nuclei (called alpha particles). Their energy is sufficient to disrupt DNA structure, or to create free radicals.

Repairing the Damage

DNA is constantly being damaged, and it is constantly being repaired as well. It is only when the damage is not repaired that a mutation can lead to cancer or cell death. The DNA repair enzymes can recognize damaged nucleotides and remove and replace them. The human liver contains a large number of enzymes whose role is to detoxify toxic compounds, mutagenic or otherwise, by chemically reacting them. However, in some cases these enzymes (called cytochrome P450s) actually create mutagens during the course of these reactions. Such "bioactivation" may be a significant source of mutagens.

see also Carcinogens; Chromosomal Aberrations; DNA Repair; Muller, Hermann; Mutagenesis; Mutation.

Richard Robinson

Bibliography

Philp, Richard B. Ecosystems and Human Health: Toxicology and Environmental Hazards, 2nd ed. Boca Raton, FL: Lewis Publishers, 2001.

Brusick, David. Principles of Genetic Toxicology, 2nd ed. New York: Plenum Press, 1987.