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Diuron metabolites and urothelial cytotoxicity: In vivo, in vitro and molecular approaches

dc.contributor.authorDa Rocha, Mitscheli S. [UNESP]
dc.contributor.authorArnold, Lora L.
dc.contributor.authorDodmane, Puttappa R.
dc.contributor.authorPennington, Karen L.
dc.contributor.authorQiu, Fang
dc.contributor.authorCamargo, João Lauro Viana de [UNESP]
dc.contributor.authorCohen, Samuel Monroe [UNESP]
dc.contributor.institutionUniv Nebraska Med Ctr
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.date.accessioned2014-12-03T13:10:35Z
dc.date.available2014-12-03T13:10:35Z
dc.date.issued2013-12-15
dc.description.abstractDiuron is carcinogenic to the rat urinary bladder at high dietary levels. The proposed mode of action (MOA) for diuron is urothelial cytotoxicity and necrosis followed by regenerative urothelial hyperplasia. Diuron-induced urothelial cytotoxicity is not due to urinary solids. Diuron is extensively metabolized, and in rats, N-(3,4-dichlorophenyl)urea (DCPU) and 4,5-dichloro-2-hydroxyphenyl urea (2-OH-DCPU) were the predominant urinary metabolites; lesser metabolites included N-(3,4-dichlorophenyl)-3-methylurea (DCPMU) and trace levels of 3,4-dichloroaniline (DCA). In humans, DCPMU and DCPU have been found in the urine after a case of product abuse. To aid in elucidating the MOA of diuron and to evaluate the metabolites that are responsible for the diuron toxicity in the bladder epithelium, we investigated the urinary concentrations of metabolites in male Wistar rats treated with 2500 ppm of diuron, the urothelial cytotoxicity in vitro of the metabolites and their gene expression profiles. DCPU was found in rat urine at concentrations substantially greater than the in vitro IC50 and induced more gene expression alterations than the other metabolites tested. 2-OH-DCPU was present in urine at a concentration approximately half of the in vitro IC50, whereas DCPMU and DCA were present in urine at concentrations well below the IC50. For the diuron-induced MOA for the rat bladder, we suggest that DCPU is the primary metabolite responsible for the urothelial cytotoxicity with some contribution also by 2-OH-DCPU. This study supports a MOA for diuron-induced bladder effects in rats consisting of metabolism to DCPU (and 2-OH-DCPU to a lesser extent), concentration and excretion in urine, urothelial cytotoxicity, and regenerative proliferation. (C) 2013 Elsevier Ireland Ltd. All rights reserved.en
dc.description.affiliationUniv Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA
dc.description.affiliationSao Paulo State Univ, UNESP, Ctr Evaluat Environm Impact Human Hlth TOXICAM, Dept Pathol,Botucatu Med Sch, Botucatu, SP, Brazil
dc.description.affiliationUnespSao Paulo State Univ, UNESP, Ctr Evaluat Environm Impact Human Hlth TOXICAM, Dept Pathol,Botucatu Med Sch, Botucatu, SP, Brazil
dc.description.sponsorshipNCRR
dc.description.sponsorshipNational Institute for General Medical Science (NIGMS)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipIdNCRR5P20RR016469
dc.description.sponsorshipIdNCRRRR018788-08
dc.description.sponsorshipIdNational Institute for General Medical Science (NIGMS)8P20GM103427
dc.description.sponsorshipIdNational Institute for General Medical Science (NIGMS)GM103471-09
dc.format.extent238-246
dc.identifierhttp://dx.doi.org/10.1016/j.tox.2013.10.005
dc.identifier.citationToxicology. Clare: Elsevier Ireland Ltd, v. 314, n. 2-3, p. 238-246, 2013.
dc.identifier.doi10.1016/j.tox.2013.10.005
dc.identifier.issn0300-483X
dc.identifier.urihttp://hdl.handle.net/11449/112294
dc.identifier.wosWOS:000329008400006
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofToxicology
dc.relation.ispartofjcr3.265
dc.rights.accessRightsAcesso restrito
dc.sourceWeb of Science
dc.subjectBladderen
dc.subjectDiuronen
dc.subjectMetabolitesen
dc.subjectCytotoxicityen
dc.subjectRaten
dc.subjectIn vitroen
dc.titleDiuron metabolites and urothelial cytotoxicity: In vivo, in vitro and molecular approachesen
dc.typeArtigo
dcterms.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dcterms.rightsHolderElsevier B.V.
dspace.entity.typePublication
unesp.author.orcid0000-0001-9953-3226[3]
unesp.author.orcid0000-0003-0477-2887[3]
unesp.campusUniversidade Estadual Paulista (UNESP), Faculdade de Medicina, Botucatupt
unesp.departmentPatologia - FMBpt

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