Editing Genotoxicity

{{Short description|Concept in toxicology}}
'''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 [[mutagen]]icity, 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.<ref name="genotoxicity.carcinogenicity">{{cite web |url=http://www.basf.com/group/corporate/alternatives/en/microsites/alternatives/methods-in-use/genotocity |archive-url=https://archive.today/20130628173220/http://www.basf.com/group/corporate/alternatives/en/microsites/alternatives/methods-in-use/genotocity |url-status=dead |archive-date=2013-06-28 |title=Genotoxicity and Carcinogenicity |last=Kolle |first=Susanne | name-list-style = vanc |date=2012-06-01 |publisher=BASF The Chemical Company |access-date=2013-03-16 }}</ref> 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|assay]] 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.<ref name="genotoxicity">{{cite web |url=http://alttox.org/ttrc/existing-alternatives/genotoxicity.html |title=Genotoxicity: Validated Non-animal Alternatives |date=2011-06-20 |publisher=AltTox.org |access-date=2013-03-16}}</ref> 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.

==Mechanism==
[[File:Transitions_and_transversions.svg|thumb|right|300px|Definition of [[Transition (genetics)|transitions]] and [[transversion]]s. They are a common mutation caused by genotoxic compounds.]]

Genotoxic substances induce damage to the genetic material in the cells through interactions with the DNA sequence and structure.  For example, the transition metal [[chromium]] interacts with DNA in its high-valent oxidation state, incurring DNA lesions which lead to [[carcinogenesis]].  The metastable oxidation state Cr(V) is achieved through reductive activation.  Researchers performed an experiment to study the interaction between DNA with the carcinogenic chromium by using a Cr(V)-Salen complex at the specific oxidation state.<ref name=Sugden>{{cite journal | vauthors = Sugden KD, Campo CK, Martin BD | title = Direct oxidation of guanine and 7,8-dihydro-8-oxoguanine in DNA by a high-valent chromium complex: a possible mechanism for chromate genotoxicity | journal = Chemical Research in Toxicology | volume = 14 | issue = 9 | pages = 1315–22 | date = September 2001 | pmid = 11559048 | doi = 10.1021/tx010088+ }}</ref>  The interaction was specific to the [[guanine]] nucleotide in the genetic sequence.  In order to narrow the interaction between the Cr(V)-Salen complex with the guanine base, the researchers modified the bases to 8-oxo-G so to have site specific oxidation.  The reaction between the two molecules caused DNA lesions; the two lesions observed at the modified base site were guanidinohydantoin and spiroiminodihydantoin.  To further analyze the site of lesion, it was observed that polymerase stopped at the site and [[adenine]] was inappropriately incorporated into the DNA sequence opposite of the 8-oxo-G base.  Therefore, these lesions predominately contain G→T [[transversions]].  High-valent chromium is seen to act as a carcinogen as researchers found that "the mechanism of damage and base oxidation products for the interaction between high-valent chromium and DNA...  are relevant to ''in vivo'' formation of DNA damage leading to cancer in chromate-exposed human populations".<ref name="Sugden"/>  Consequently, it shows how high-valent chromium can act as a carcinogen with 8-oxo-G forming [[xenobiotics]].<ref name="Sugden"/>

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''."<ref name=Chen>{{cite journal | vauthors = Chen T, Mei N, Fu PP | title = Genotoxicity of pyrrolizidine alkaloids | journal = Journal of Applied Toxicology | volume = 30 | issue = 3 | pages = 183–96 | date = April 2010 | pmid = 20112250 | pmc = 6376482 | doi = 10.1002/jat.1504 }}</ref>  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.<ref name="Chen"/>  [[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|endothelial cells]] 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,".<ref name=Mei>{{cite journal | vauthors = Mei N, Guo L, Fu PP, Fuscoe JC, Luan Y, Chen T | title = Metabolism, genotoxicity, and carcinogenicity of comfrey | journal = Journal of Toxicology and Environmental Health Part B: Critical Reviews | volume = 13 | issue = 7–8 | pages = 509–26 | date = October 2010 | pmid = 21170807 | pmc = 5894094 | doi = 10.1080/10937404.2010.509013 | bibcode = 2010JTEHB..13..509M }}</ref>

==Test techniques==

The purpose of genotoxicity testing is to determine if a substrate will influence genetic material or may cause cancer.  They can be performed in bacterial, yeast, and mammalian cells.<ref name="genotoxicity" />  With the knowledge from the tests, one can control early development of vulnerable organisms to genotoxic substances.<ref name="genotoxicity.carcinogenicity" />

===Bacterial Reverse Mutation Assay===
{{See also|Ames test}}
The Bacterial Reverse Mutation Assay, also known as the [[ames test|Ames Assay]], is used in laboratories to test for gene mutation.  The technique uses many different bacterial strains in order to compare the different changes in the genetic material.  The result of the test detects the majority of genotoxic [[carcinogens]] and genetic changes; the types of mutations detected are [[frameshift mutation|frame shifts]] and base substitutions.<ref name="genotoxicity.testing">{{cite web|url=http://www.pharmatek.com/pdf/PTEKU/Apr172008.pdf |title=Genotoxicity Testing for Pharmaceuticals Current and Emerging Practices |last=Furman |first=Grace | name-list-style = vanc |date=2008-04-17 |publisher=Paracelsus, Inc. |access-date=2013-03-16 |url-status=dead |archive-url=https://web.archive.org/web/20140116114751/http://www.pharmatek.com/pdf/PTEKU/Apr172008.pdf |archive-date=2014-01-16 }}</ref>

[[File:Ames test.svg|500px|right|thumb|Ames test procedure to test for gene mutations present in the various bacterial strains]]

==''in vitro'' toxicology testing==
The purpose of ''[[in vitro]]'' testing is to determine whether a substrate, product, or environmental factor induces genetic damage.  One technique entails cytogenetic assays using different mammalian cells.<ref name="genotoxicity.testing" />  The types of [[chromosome abnormality|aberrations]] detected in cells affected by a genotoxic substance are chromatid and chromosome gaps, chromosome breaks, chromatid deletions, fragmentation, translocation, complex rearrangements, and many more. The [[clastogen]]ic or [[aneugen]]ic effects from the genotoxic damage will cause an increase in frequency of structural or numerical aberrations of the genetic material.<ref name="genotoxicity.testing" />  This is similar to the [[micronucleus test]] and chromosome aberration assay, which detect structural and numerical chromosomal aberrations in mammalian cells.<ref name="genotoxicity.carcinogenicity" />

In a specific mammalian tissue, one can perform a mouse [[lymphoma]] TK+/- assay to test for changes in the genetic material.<ref name="genotoxicity.testing" />  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|chromosomes']] 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).<ref name="genotoxicity.testing" />

The [[SOS chromotest|SOS/umu assay test]] 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.<ref name="invitro.genotoxicitytesting">{{cite web |url=http://www.nib.si/eng/index.php/storitve-in-oprema/testi-genotoksinosti-in-vitro.html |title=In Vitro Genotoxicity Testing |last=Končar |first=Helena | name-list-style = vanc |year=2011 |publisher=National Institute of Biology |access-date=2013-03-16 |url-status=dead |archive-url=https://web.archive.org/web/20130307220932/http://www.nib.si/eng/index.php/storitve-in-oprema/testi-genotoksinosti-in-vitro.html |archive-date=2013-03-07 }}</ref>

[[File:Genotoxic Damage.png|500px|right|thumb|Overview of the use of the SOS response for genotoxicity testing]]

===''in vivo'' testing===
The purpose for ''[[in vivo]]'' testing is to determine the potential of DNA damage that can affect chromosomal structure or disturb the [[mitotic spindle|mitotic apparatus]] that changes chromosome number; the factors that could influence the genotoxicity are ADME and DNA repair.  It can also detect genotoxic agents missed in ''in vitro'' tests.  The positive result of induced chromosomal damage is an increase in frequency of micronucelated PCEs.<ref name="genotoxicity.testing" />  A [[micronucleus]] is a small structure separate from the nucleus containing nuclear DNA arisen from DNA fragments or whole chromosomes that were not incorporated in the daughter cell during mitosis.  Causes for this structure are mitotic loss of acentric chromosomal fragments (clastogenicity), mechanical problems from chromosomal breakage and exchange, mitotic loss of chromosomes (aneugenicity), and apoptosis.  The micronucleus test ''in vivo'' is similar to the ''in vitro'' one because it tests for structural and numerical chromosomal aberrations in mammalian cells, especially in rats' blood cells.<ref name="genotoxicity.testing" />

===Comet assay===
{{See also|Comet assay}}
[[Comet assay]]s are one of the most common tests for genotoxicity. The technique involves lysing cells using detergents and salts. The DNA released from the lysed cell is electrophoresed in an agarose gel under [[neutral pH]] conditions. Cells containing DNA with an increased number of double-strand breaks will migrate more quickly to the anode. This technique is advantageous in that it detects low levels of DNA damage, requires only a very small number of cells, is cheaper than many techniques, is easy to execute, and quickly displays results. However, it does not identify the mechanism underlying the genotoxic effect or the exact chemical or chemical component causing the breaks.<ref name="Tice">{{cite journal | vauthors = Tice RR, Agurell E, Anderson D, Burlinson B, Hartmann A, Kobayashi H, Miyamae Y, Rojas E, Ryu JC, Sasaki YF | display-authors = 6 | title = Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing | journal = Environmental and Molecular Mutagenesis | volume = 35 | issue = 3 | pages = 206–21 | year = 2000 | pmid = 10737956 | doi = 10.1002/(SICI)1098-2280(2000)35:3<206::AID-EM8>3.0.CO;2-J | url = http://cometassayindia.org/COMET%20ASSAY%20GUIDELINES.pdf | doi-access = free | bibcode = 2000EnvMM..35..206T }}</ref>

==Cancer==
Genotoxic effects such as deletions, breaks and/or rearrangements can lead to cancer if the damage does not immediately lead to cell death. Regions sensitive to breakage, called [[fragile sites]], may result from genotoxic agents (such as pesticides). Some chemicals have the ability to induce fragile sites in regions of the chromosome where [[oncogenes]] are present, which could lead to carcinogenic effects. In keeping with this finding, occupational exposure to some mixtures of pesticides are positively correlated with increased genotoxic damage in the exposed individuals. DNA damage is not uniform in its severity across populations because Individuals vary in their ability to activate or detoxify genotoxic substances, which leads to variability in the incidence of cancer among individuals. The difference in ability to detoxify certain compounds is due to individuals' inherited [[polymorphism (biology)|polymorphisms]] of genes involved in the metabolism of the chemical. Differences may also be attributed to individual variation in efficiency of DNA repair mechanisms.<ref name=Bolognesi>{{cite journal|author=Bolognesi, Claudia|date=June 2003|title= Genotoxicity of pesticides: A review of human biomonitoring studies|journal=Mutation Research|doi=10.1016/S1383-5742(03)00015-2|volume=543|issue=3|pages=251–272|pmid=12787816|bibcode=2003MRRMR.543..251B }}</ref>

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.<ref name=Liu>{{cite journal | vauthors = Liu SX, Athar M, Lippai I, Waldren C, Hei TK | title = Induction of oxyradicals by arsenic: implication for mechanism of genotoxicity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 4 | pages = 1643–8 | date = February 2001 | pmid = 11172004 | pmc = 29310 | doi = 10.1073/pnas.98.4.1643 | bibcode = 2001PNAS...98.1643L | doi-access = free }}</ref>  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 [[white blood cell|inflammatory cells]].<ref name=Schins>{{cite journal | vauthors = Schins RP | title = Mechanisms of genotoxicity of particles and fibers | journal = Inhalation Toxicology | volume = 14 | issue = 1 | pages = 57–78 | date = January 2002 | pmid = 12122560 | doi = 10.1080/089583701753338631 | bibcode = 2002InhTx..14...57S | s2cid = 24802577 }}</ref>

===Genotoxins implicated in the four most common cancers worldwide===
Major genotoxic agents responsible for the four most common cancers worldwide (lung, breast, colon and stomach) have been identified.
 
[[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).<ref name = Ferlay2008>{{cite journal |vauthors=Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM |title=Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 |journal=Int J Cancer |volume=127 |issue=12 |pages=2893–2917 |date=December 2010 |pmid=21351269 |doi=10.1002/ijc.25516 }}</ref> [[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.<ref>{{cite journal |vauthors=Cunningham FH, Fiebelkorn S, Johnson M, Meredith C |title=A novel application of the Margin of Exposure approach: segregation of tobacco smoke toxicants |journal=Food Chem Toxicol |volume=49 |issue=11 |pages=2921–33 |date=November 2011 |pmid=21802474 |doi=10.1016/j.fct.2011.07.019 }}</ref> 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,<ref>{{cite journal |vauthors=Liu D, Cheng Y, Tang Z, Mei X, Cao X, Liu J |title=Toxicity mechanism of acrolein on DNA damage and apoptosis in BEAS-2B cells: Insights from cell biology and molecular docking analyses |journal=Toxicology |volume=466 |issue= |pages=153083 |date=January 2022 |pmid=34958888 |doi=10.1016/j.tox.2021.153083 |bibcode=2022Toxgy.46653083L }}</ref> formaldehyde,<ref>{{cite journal |vauthors=Mulderrig L, Garaycoechea JI, Tuong ZK, Millington CL, Dingler FA, Ferdinand JR, Gaul L, Tadross JA, Arends MJ, O'Rahilly S, Crossan GP, Clatworthy MR, Patel KJ |title=Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response |journal=Nature |volume=600 |issue=7887 |pages=158–163 |date=December 2021 |pmid=34819667 |doi=10.1038/s41586-021-04133-7 |bibcode=2021Natur.600..158M |hdl=20.500.11820/5c198932-e822-43cb-a2cf-56369f454de9 |hdl-access=free }}</ref> and acrylonitrile.<ref>{{cite journal |vauthors=Pu X, Kamendulis LM, Klaunig JE |title=Acrylonitrile-induced oxidative stress and oxidative DNA damage in male Sprague-Dawley rats |journal=Toxicol Sci |volume=111 |issue=1 |pages=64–71 |date=September 2009 |pmid=19546159 |pmc=2726299 |doi=10.1093/toxsci/kfp133 }}</ref>
 
[[Breast cancer]] is the second most frequent cancer worldwide on a yearly basis [(1.38 million cases, 10.9% of all cancer cases), and ranks 5th as cause of death (458,000, 6.1% of all cancer deaths)].<ref name = Ferlay2008/> Breast cancer risk is associated with persistently high blood levels of [[estrogen]].<ref>{{cite journal |vauthors=Yager JD, Davidson NE |title=Estrogen carcinogenesis in breast cancer |journal=N Engl J Med |volume=354 |issue=3 |pages=270–82 |date=January 2006 |pmid=16421368 |doi=10.1056/NEJMra050776 }}</ref>  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.<ref>{{cite journal |vauthors=Ansell PJ, Espinosa-Nicholas C, Curran EM, Judy BM, Philips BJ, Hannink M, Lubahn DB |title=In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens |journal=Endocrinology |volume=145 |issue=1 |pages=311–7 |date=January 2004 |pmid=14551226 |doi=10.1210/en.2003-0817 }}</ref><ref>{{cite journal |vauthors=Belous AR, Hachey DL, Dawling S, Roodi N, Parl FF |title=Cytochrome P450 1B1-mediated estrogen metabolism results in estrogen-deoxyribonucleoside adduct formation |journal=Cancer Res |volume=67 |issue=2 |pages=812–7 |date=January 2007 |pmid=17234793 |doi=10.1158/0008-5472.CAN-06-2133 }}</ref><ref>{{cite journal |vauthors=Bolton JL, Thatcher GR |title=Potential mechanisms of estrogen quinone carcinogenesis |journal=Chem Res Toxicol |volume=21 |issue=1 |pages=93–101 |date=January 2008 |pmid=18052105 |pmc=2556295 |doi=10.1021/tx700191p }}</ref> The principal human estrogen, [[estradiol]], can be metabolized to [[quinone]] derivatives that form [[DNA adduct]]s.<ref>{{cite journal |vauthors=Yue W, Santen RJ, Wang JP, Li Y, Verderame MF, Bocchinfuso WP, Korach KS, Devanesan P, Todorovic R, Rogan EG, Cavalieri EL |title=Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis |journal=J Steroid Biochem Mol Biol |volume=86 |issue=3–5 |pages=477–86 |date=September 2003 |pmid=14623547 |doi=10.1016/s0960-0760(03)00377-7 }}</ref>  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 million cases (9.7% of all cancer cases), 608,000 deaths (8.0% of all cancer deaths)].<ref name = Ferlay2008/> In the United States, tobacco smoke may be responsible for up to 20% of colorectal cancers.<ref>{{cite journal |vauthors=Giovannucci E, Martínez ME |title=Tobacco, colorectal cancer, and adenomas: a review of the evidence |journal=J Natl Cancer Inst |volume=88 |issue=23 |pages=1717–30 |date=December 1996 |pmid=8944002 |doi=10.1093/jnci/88.23.1717 }}</ref> In addition, [[bile acid]]s are implicated by substantial evidence as an important genotoxic factor in colon cancer.<ref name = Bernstein2022>{{cite journal |vauthors=Bernstein H, Bernstein C |title=Bile acids as carcinogens in the colon and at other sites in the gastrointestinal system |journal=Exp Biol Med (Maywood) |volume=248 |issue=1 |pages=79–89 |date=January 2023 |pmid=36408538 |pmc=9989147 |doi=10.1177/15353702221131858 }}</ref> In particular, the bile acid [[deoxycholic acid]] acid causes the production of DNA-damaging reactive oxygen species in human and rodent colon epithelial cells.<ref name = Bernstein2022/>
 
[[Stomach cancer]] is the fourth most common cancer worldwide [990,000 cases (7.8% of all cancer cases), 738,000 deaths (9.7% of all cancer deaths )].<ref name = Ferlay2008/> 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).<ref>{{cite journal |vauthors=Ding SZ, Minohara Y, Fan XJ, Wang J, Reyes VE, Patel J, Dirden-Kramer B, Boldogh I, Ernst PB, Crowe SE |title=Helicobacter pylori infection induces oxidative stress and programmed cell death in human gastric epithelial cells |journal=Infect Immun |volume=75 |issue=8 |pages=4030–9 |date=August 2007 |pmid=17562777 |pmc=1952011 |doi=10.1128/IAI.00172-07 }}</ref><ref>{{cite journal |vauthors=Handa O, Naito Y, Yoshikawa T |title=Redox biology and gastric carcinogenesis: the role of Helicobacter pylori |journal=Redox Rep |volume=16 |issue=1 |pages=1–7 |date=2011 |pmid=21605492 |pmc=6837368 |doi=10.1179/174329211X12968219310756 }}</ref>  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.<ref>{{cite journal |vauthors=Noto JM, Piazuelo MB, Shah SC, Romero-Gallo J, Hart JL, Di C, Carmichael JD, Delgado AG, Halvorson AE, Greevy RA, Wroblewski LE, Sharma A, Newton AB, Allaman MM, Wilson KT, Washington MK, Calcutt MW, Schey KL, Cummings BP, Flynn CR, Zackular JP, Peek RM |title=Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori-induced inflammation-driven gastric carcinogenesis |journal=J Clin Invest |volume=132 |issue=10 |pages= |date=May 2022 |pmid=35316215 |pmc=9106351 |doi=10.1172/JCI147822 }}</ref>

===Genotoxic chemotherapy===
Genotoxic chemotherapy is the treatment of cancer with the use of one or more genotoxic drugs. The treatment is traditionally part of [[Chemotherapy regimen|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|proliferation]] continues. If this damage is severe enough, it will induce cells to undergo [[apoptosis]].<ref name="Genotoxic Drugs">{{cite web |url=http://www.cancerquest.org/genotoxic-chemotherapy-drugs.html |title=Genotoxic Drugs |last=Walsh |first=Declan | name-list-style = vanc |date=2011-11-18 |publisher=[[CancerQuest]] |access-date=2013-03-16 |archive-url=https://web.archive.org/web/20130302063922/http://www.cancerquest.org/genotoxic-chemotherapy-drugs.html |archive-date=2013-03-02 |url-status=dead }}</ref>

====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.<ref name="Genotoxic Drugs"/>

Another risk of treatment is that, in addition to being genotoxic, many of the drugs are also [[mutagenic]] and [[Cytotoxicity|cytotoxic]]. 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|carcinogens]] themselves, raising the risk of secondary cancers, such as [[leukemia]].<ref name="Genotoxic Drugs"/>

====Different treatments====
This table depicts different genotoxic-based cancer treatments along with examples.<ref name="Genotoxic Drugs"/>

{| class="wikitable"
|-
! Treatment !! Mechanism !! Examples
|-
| [[Alkylating agent]]s || interfere with DNA replication and transcription by modifying DNA bases. || [[Busulfan]], [[Carmustine]], [[Mechlorethamine]]
|-
| [[Intercalating agent]]s || interfere with DNA replication and transcription by wedging themselves into the spaces in between DNA's nucleotides || [[Daunorubicin]], [[Doxorubicin]], [[Epirubicin]]
|-
| [[Enzyme inhibitor]]s || inhibit enzymes that are crucial to DNA replication || [[Decitabine]], [[Etoposide]], [[Irinotecan]]
|}

===Kidney===

Genotoxic [[DNA damage (naturally occurring)|DNA damage]] in the [[kidney]] has been implicated in both acute and [[chronic kidney disease|chronic kidney injury]], as well as in [[renal cell carcinoma]].<ref name = Garaycoechea2023>{{cite journal |vauthors=Garaycoechea JI, Quinlan C, Luijsterburg MS |title=Pathological consequences of DNA damage in the kidney |journal=Nat Rev Nephrol |volume=19 |issue=4 |pages=229–243 |date=April 2023 |pmid=36702905 |doi=10.1038/s41581-022-00671-z }}</ref>   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.<ref name = Garaycoechea2023/>

== See also ==
* [[Cancer]]
* [[Carcinogen]]
* [[Carcinogenesis]]
* [[Carcinogenicity]]
* [[Dysgenics]]
* [[Mutagen]]
* [[Mutagenesis]]

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Jha AN, Cheung VV, Foulkes ME, Hill SJ, Depledge MH | title = Detection of genotoxins in the marine environment: adoption and evaluation of an integrated approach using the embryo-larval stages of the marine mussel, Mytilus edulis | journal = Mutation Research | volume = 464 | issue = 2 | pages = 213–28 | date = January 2000 | pmid = 10648908 | doi = 10.1016/s1383-5718(99)00188-6 | bibcode = 2000MRGTE.464..213J }}
* {{cite book | vauthors = Sigel A, Sigel H, Sigel RK | editor-first1 = Astrid | editor-first2 = Helmut | editor-first3 = Roland K O. | editor-last1 = Sigel | editor-last2 = Sigel | editor-last3 = Sigel| title = Metal ions in toxicology: effects, interactions, interdependencies | volume = 8 | pages = vii-viii | year = 2011 | pmid = 21473373 | doi = 10.1039/9781849732512 | isbn = 978-1-84973-094-5 | series = Metal Ions in Life Sciences }}
* {{cite book |editor1=Sigel R, Sigel |editor2=Sigel H | title = Metal Ions in Toxicology: Effects, Interactions, Interdependencies (Metal Ions in Life Sciences) | publisher = Royal Society of Chemistry | location = Cambridge, Eng | year = 2011 | pages = 319–373| isbn = 978-1-84973-091-4 | chapter =13. Genotoxicity of metal ions: chemical insights |vauthors=Bal W, Protas AM, Kasprzak KS | doi = 10.1039/9781849732116-00319 | volume = 8 }}
* {{cite journal | vauthors = Smith MT | title = The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia | journal = Environmental Health Perspectives | volume = 104 | pages = 1219–25 | date = December 1996 | issue = Suppl 6 | pmid = 9118896 | pmc = 1469721 | doi = 10.1289/ehp.961041219 }}
{{refend}}

{{Genotoxicity}}

[[Category:Mutation]]
[[Category:Carcinogenesis]]