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Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with , all mutagens are genotoxic, but some genotoxic substances are not mutagenic. The alteration can have direct or indirect effects on the DNA: the induction of mutations, mistimed event activation, and direct DNA damage leading to mutations. The permanent, heritable changes can affect either somatic cells of the organism or germ cells to be passed on to future generations. Cells prevent expression of the genotoxic mutation by either DNA repair or apoptosis; however, the damage may not always be fixed leading to mutagenesis.
To bioassay for genotoxic molecules, researchers assay for DNA damage in cells exposed to the toxic substrates. This DNA damage can be in the form of single- and double-strand breaks, loss of excision repair, cross-linking, alkali-labile sites, point mutations, and structural and numerical chromosomal aberrations. The compromised integrity of the genetic material has been known to cause cancer. As a consequence, many sophisticated techniques including Ames Assay, in vitro and in vivo Toxicology Tests, and Comet Assay have been developed to assess the chemicals' potential to cause DNA damage that may lead to cancer.
Another example of a genotoxic substance causing DNA damage are pyrrolizidine alkaloids (PAs). These substances are found mainly in plant species and are poisonous to animals, including humans; about half of them have been identified as genotoxic and many as tumorigenic. The researchers concluded from testing that when metabolically activated, "PAs produce DNA adducts, DNA cross-linking, DNA breaks, sister chromatid exchange, micronuclei, chromosomal aberrations, gene mutations, and chromosome mutations in vivo and in vitro." The most common mutation within the genes are G:C → T:A tranversions and tandem base substitution. The pyrrolizidine alkaloids are mutagenic in vivo and in vitro and, therefore, responsible for the carcinogenesis prominently in the liver. Comfrey is an example of a plant species that contains fourteen different PAs. The active metabolites interact with DNA to cause DNA damage, mutation induction, and cancer development in liver endothelium and hepatocytes. The researchers discovered in the end that the "comfrey is mutagenic in liver, and PA contained in comfrey appear to be responsible for comfrey-induced toxicity and tumor induction,".
In a specific mammalian tissue, one can perform a mouse lymphoma TK+/- assay to test for changes in the genetic material. Gene mutations are commonly point mutations, altering only one base within the genetic sequence to alter the ensuing transcript and amino acid sequence; these point mutations include base substitutions, deletions, frame-shifts, and rearrangements. Also, chromosome integrity may be altered through chromosome loss and clastogenic lesions causing multiple gene and multilocus deletions. The specific type of damage is determined by the size of the colonies, distinguishing between genetic mutations (mutagens) and chromosomal aberrations (clastogens).
The SOS chromotest evaluates the ability of a substance to induce DNA damage; it is based on the alterations in the induction of the SOS response due to DNA damage. The benefits of this technique are that it is a fast and simple method and convenient for numerous substances. These techniques are performed on water and wastewater in the environment.
The metabolism of some chemicals results in the production of reactive oxygen species (ROS), which is a possible mechanism of genotoxicity. This is seen in the metabolism of arsenic, which produces hydroxyl radicals, which are known to cause genotoxic effects. Similarly, ROS have been implicated in genotoxicity caused by particles and fibers. Genotoxicity of nonfibrous and fibrous particles is characterized by high production of ROS from inflammatory cells.
Lung cancer is the most frequent cancer in the world, both in terms of yearly cases (1.61 million cases; 12.7% of all cancer cases) and deaths (1.38 million deaths; 18.2% of all cancer deaths). Tobacco smoke is the main cause of lung cancer. Risk estimates for lung cancer indicate that tobacco smoke is responsible for 90% of lung cancers in the United States. Tobacco smoke contains more than 5,300 identified chemicals. The most significant carcinogens in tobacco smoke have been determined by a "Margin of Exposure" approach. By this approach, the tumorigenic compounds in tobacco smoke were, in order of importance, acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, cadmium, acetaldehyde, ethylene oxide, and isoprene. In general, these compounds are genotoxic and cause DNA damage. As examples, DNA damaging effects have been reported for acrolein, formaldehyde, and acrylonitrile.
Breast cancer is the second most frequent cancer worldwide on a yearly basis (1.38. Breast cancer risk is associated with persistently high blood levels of estrogen. Estrogen likely contributes to breast carcinogenesis by the following three processes; (1) metabolic conversion of estrogen to genotoxic, mutagenic carcinogens, (2) stimulation of growth of tissues, and (3) repression of phase II detoxification enzymes that metabolize genotoxic reactive oxygen species, thus resulting in increased oxidative DNA damage. The principal human estrogen, estradiol, can be metabolized to quinone derivatives that form . These derivatives can cause the removal of bases from the phosphodiester backbone of DNA (e.g. depurination). This removal may be followed by inaccurate repair or replication of the apurinic site leading to mutation and eventually cancer.
Colorectal cancer is the third most frequent cancer worldwide 1.23. In the United States, tobacco smoke may be responsible for up to 20% of colorectal cancers. In addition, are implicated by substantial evidence as an important genotoxic factor in colon cancer. In particular, the bile acid deoxycholic acid causes the production of DNA-damaging reactive oxygen species in human and rodent colon epithelial cells.
Stomach cancer is the fourth most common cancer worldwide 990,000. Infection by Helicobacter pylori is the main causative factor in stomach cancer. Chronic inflammation due to H. pylori, if untreated, is often long-standing. H. pylori infection of gastric epithelial cells causes increased production of genotoxic reactive oxygen species (ROS). ROS cause oxidative damage to DNA that includes the major base alteration 8-Oxo-2'-deoxyguanosine. In a recent retrospective study it was found that use of a bile acid sequestrant was associated with a significant reduction in gastric cancer risk, suggesting that bile acids may be a contributory factor in stomach cancer.
Another risk of treatment is that, in addition to being genotoxic, many of the drugs are also mutagenic and Cytotoxicity. So the effects of these drugs are not limited to just DNA damage. In addition, some of these drugs that are meant to treat cancers are also Carcinogenic themselves, raising the risk of secondary cancers, such as leukemia.
Genotoxic chemotherapy
Genotoxic chemotherapy is the treatment of cancer with the use of one or more genotoxic drugs. The treatment is traditionally part of standardized regime. By utilizing the destructive properties of genotoxins treatments aims to induce DNA damage into cancer cells. Any damage done to a cancer is passed on to descendent cancer cells as cell growth continues. If this damage is severe enough, it will induce cells to undergo apoptosis.
Risks
A drawback of treatment is that many genotoxic drugs are effective on cancerous cells and normal cells alike. Selectivity of a particular drug's action is based on the sensitivity of the cells themselves. So, while rapidly dividing cancer cells are particularly sensitive to many drug treatments, often normal functioning cells are affected.
Different treatments
This table depicts different genotoxic-based cancer treatments along with examples.
Busulfan, Carmustine, Mechlorethamine Daunorubicin, Doxorubicin, Epirubicin Decitabine, Etoposide, Irinotecan
Kidney
Genotoxic DNA damage in the kidney has been implicated in both acute and chronic kidney injury, as well as in renal cell carcinoma. Studies of humans with genetic deficiencies in DNA repair pathways have revealed that their kidneys are particularly vulnerable to DNA damages such as DNA crosslinks, DNA breaks and transcription-blocking damage.
See also
Further reading
(2025). 9781849730945 ISBN 9781849730945
(2025). 9781849730914, Royal Society of Chemistry. ISBN 9781849730914
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