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Genotoxicity
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==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 = 1315β22 | 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 GβT [[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 = 183β96 | date = April 2010 | pmid = 20112250 | pmc = 6376482 | doi = 10.1002/jat.1504 }}</ref> The most common mutation within the genes are G:C β 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 = 7β8 | pages = 509β26 | date = October 2010 | pmid = 21170807 | pmc = 5894094 | doi = 10.1080/10937404.2010.509013 | bibcode = 2010JTEHB..13..509M }}</ref>
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