Genotoxic Substances

Genotoxic Agents

A genotoxic agent is a chemical or another agent that damages cellular DNA, resulting in mutations or cancer. Toxic to the genome! Genotoxic substances are known to be potentially mutagenic or carcinogenic when inhaled, ingested or penetrate the skin. A mutagen is an agent that is responsible ro inducing a change to the genetic material of an organism. That agent might be physical, chamical or biological. As many mutations may ultimately result into cancer (or be part of the multistep process of carcinogenesis), mutagens are typically also carcinogens.

Genotoxicity "Facts"

• Not all carcinogens are of genotoxic nature
• Genotoxic carcinogens are mutagens
• Epigenetic carcinogens do not damage DNA, but cause damage to DNA repair enzymes rendering the genome unstable (genomic instability). In such a case the last chance to save cells are NK cells

The Ames Test

This is a very rapid test for mutagens. It utilizes bacteria of the species Salmonella Typhimurium that have a mutation in the histidine operon and cannot synthesize histidine.

Compounds are tested to determine whether they can induce reversion of this mutation. The test can be carried out very simply by plating out His- (negative) mutants on an agar plate that contains only a trace of histidine. A crystal, or a filter disc containing a solution of the compound to be tested, is placed on the surface of the agar. The bacteria grow only for a short time until histidine is depleted. After that point the only bacteria that are capable of continued growth colony formation are those, which have undergone reversion and are capable of synthesizing their own histidine, histidine prototrophs (His+).

If the test compound is not mutagenic a few revertant colonies will be found randomly scattered along the agar plate. If it is mutagenic then the number of colonies will be clustered around the point were the compound was placed on the plate. Note that the can be constructed in a more quantitative manner to give a dose response curve for any compound under test.

Chemical Carcinogens

1. Direct Acting Agents

a. Alkylating Agents

Alkylated DNA either does not coil or uncoil properly, or cannot be processed by information-decoding enzymes. This results in cytotoxicity with the effects of inhibition the growth of the cell, initiation of programmed cell death or apoptosis. However, mutations are also triggered, including carcinogenic mutations, explaining the higher incidence of cancer after exposure. Examples include: β-propiolactone, Dimethyl sulfate, Diepoxybutane, Anticander drugs (cyclophosphamide, chlorambucil, nitrosoureas and others)

b. Acylating Agents

Examples include: 1-actyl-imidazole, Dimethylcarbamyl chloride

2. Indirect Acting Agents/Procarcinogens

a. Polycyclic Aromatic Hydrocarbons

Found in cigarette smoke, exhaust fumes. Examples include:Benz(a)anthracene [Group 2], Benz(a)pyrene (imp according to Bencko; 1st chemical carcinogen to be discovered) [Group 1], Dibenz(a,h)anthracene [Group 2], 3-methylchloanthrene, 7,12-Dimethylbenz(a)anthracene.

b. Aromatic amines, Amides, Azo Dyes

Aromatic amines form covalent bonds with DNA and prevent replication. Examples include: 2-Naphthylamine (β-naphthylamine) [Group 1]

3. Natural Plant and Microbial Products

• Aflatoxin B1 [Group 1]
• Griseofulvin
• Cycasin
• Betel nuts

Note: Protection from genotoxic substances may be conferred by antioxidant vitamins e.g. through reduction after oxidization by free radicals (vitamin A, C and E)

Effects on health: Somatic Mutation → cancer Developemental defects → during pregnancy → teratogenesis Germline mutation (e.g. genitals exposed to radiation – stochastic effects with long latency) → hereditary disorder

Links

Bibliography

• BENCKO CHARLES UNIVERSITY, PRAGUE 2004, 270 P, V, et al. Hygiene and epidemiology. Selected Chapters. 2nd edition. Prague. 2008. ISBN 9788024607931.