Determination of endogenous and exogenously derived N7-(2-hydroxyethyl)guanine adducts in ethylene oxide-treated rats.

2.50
Hdl Handle:
http://hdl.handle.net/10146/25472
Title:
Determination of endogenous and exogenously derived N7-(2-hydroxyethyl)guanine adducts in ethylene oxide-treated rats.
Authors:
Marsden, Debbie A.; Jones, Donald J.L.; Lamb, John H.; Tompkins, Elaine M.; Farmer, Peter B.; Brown, Karen
Abstract:
Ethylene oxide (EO) is one of the most widely used intermediates in the chemical industry. It is also formed endogenously as a result of cytochrome P450-mediated metabolism of ethylene, which is ubiquitous in the environment. Additionally, ethylene is generated in vivo during normal physiological processes such as methionine oxidation and lipid peroxidation; therefore, humans are continually exposed to EO. EO is classed by the IARC as carcinogenic to humans and reacts with DNA, primarily forming N7-(2-hydroxyethyl)guanine adducts (N7-HEG), which can be used as biomarkers of exposure and potential cancer risk. To assess the risks to humans associated with occupational exposure to low EO concentrations, it is necessary to establish the relative contribution of DNA damage arising from endogenous and exogenously derived EO. Using a newly developed highly sensitive LC-MS/MS assay with selected reaction monitoring that offers a limit of detection of 0.1 fmol of N7-HEG on column, we have established background levels of N7-HEG (1.1-3.5 adducts/10(8) nucleotides) in tissues of rats. Following intraperitoneal administration of a single dose or three daily doses of EO (0.01-1.0 mg/kg), N7-HEG adducts generally increased with dose, except at the lowest concentration where total N7-HEG levels were no different to that detected in control animals, indicating that any increase was negligible as compared to the endogenous damage already present. In the 3 day study, the kinetics of adduct removal were also investigated and in comparing N7-HEG formation in the two studies, DNA damage did not appear to accumulate with repeated administration.
Citation:
Chem. Res. Toxicol. 2007, 20 (2):290-299
Journal:
Chemical Research in Toxicology
Issue Date:
Feb-2007
URI:
http://hdl.handle.net/10146/25472
DOI:
10.1021/tx600264t
PubMed ID:
17263564
Additional Links:
http://pubs.acs.org/cgi-bin/abstract.cgi/crtoec/2007/20/i02/abs/tx600264t.html
Type:
Article
Language:
en
ISSN:
0893-228X
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorMarsden, Debbie A.-
dc.contributor.authorJones, Donald J.L.-
dc.contributor.authorLamb, John H.-
dc.contributor.authorTompkins, Elaine M.-
dc.contributor.authorFarmer, Peter B.-
dc.contributor.authorBrown, Karen-
dc.date.accessioned2008-05-12T08:47:20Z-
dc.date.available2008-05-12T08:47:20Z-
dc.date.issued2007-02-
dc.identifier.citationChem. Res. Toxicol. 2007, 20 (2):290-299en
dc.identifier.issn0893-228X-
dc.identifier.pmid17263564-
dc.identifier.doi10.1021/tx600264t-
dc.identifier.urihttp://hdl.handle.net/10146/25472-
dc.description.abstractEthylene oxide (EO) is one of the most widely used intermediates in the chemical industry. It is also formed endogenously as a result of cytochrome P450-mediated metabolism of ethylene, which is ubiquitous in the environment. Additionally, ethylene is generated in vivo during normal physiological processes such as methionine oxidation and lipid peroxidation; therefore, humans are continually exposed to EO. EO is classed by the IARC as carcinogenic to humans and reacts with DNA, primarily forming N7-(2-hydroxyethyl)guanine adducts (N7-HEG), which can be used as biomarkers of exposure and potential cancer risk. To assess the risks to humans associated with occupational exposure to low EO concentrations, it is necessary to establish the relative contribution of DNA damage arising from endogenous and exogenously derived EO. Using a newly developed highly sensitive LC-MS/MS assay with selected reaction monitoring that offers a limit of detection of 0.1 fmol of N7-HEG on column, we have established background levels of N7-HEG (1.1-3.5 adducts/10(8) nucleotides) in tissues of rats. Following intraperitoneal administration of a single dose or three daily doses of EO (0.01-1.0 mg/kg), N7-HEG adducts generally increased with dose, except at the lowest concentration where total N7-HEG levels were no different to that detected in control animals, indicating that any increase was negligible as compared to the endogenous damage already present. In the 3 day study, the kinetics of adduct removal were also investigated and in comparing N7-HEG formation in the two studies, DNA damage did not appear to accumulate with repeated administration.en
dc.language.isoenen
dc.relation.urlhttp://pubs.acs.org/cgi-bin/abstract.cgi/crtoec/2007/20/i02/abs/tx600264t.htmlen
dc.subject.meshAnimals-
dc.subject.meshChromatography, Liquid-
dc.subject.meshDNA Adducts-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshEthylene Oxide-
dc.subject.meshGuanine-
dc.subject.meshInjections, Intraperitoneal-
dc.subject.meshMale-
dc.subject.meshMolecular Structure-
dc.subject.meshRats-
dc.subject.meshRats, Inbred F344-
dc.subject.meshSensitivity and Specificity-
dc.subject.meshTandem Mass Spectrometry-
dc.subject.meshTime Factors-
dc.subject.meshTissue Distribution-
dc.titleDetermination of endogenous and exogenously derived N7-(2-hydroxyethyl)guanine adducts in ethylene oxide-treated rats.en
dc.typeArticleen
dc.identifier.journalChemical Research in Toxicologyen
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