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Article: Ionic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethane
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TitleIonic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethane
 
AuthorsZhou, Y1 1
Wu, HJ1
Zhang, YH1
Sun, HY1
Wong, TM1
Li, GR1 1
 
KeywordsArrhythmogenic effect
Cardiac toxicity
Multiple ion channel blockade
Trichloromethane
Ventricular fibrillation
 
Issue Date2011
 
PublisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/toxicol
 
CitationToxicology, 2011, v. 290 n. 2-3, p. 296-305 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.tox.2011.10.009
 
AbstractTrichloromethane (chloroform) is widely used for industrial chemical synthesis and also as an organic solvent in laboratories or ingredient of pesticides. Sudden death resulted from cardiac arrhythmias has been reported in clinic with acute trichloromethane intoxication. The present study was designed to investigate ionic mechanisms underlying arrhythmogenic effect (cardiac toxicity) of trichloromethane in isolated rat hearts and ventricular myocytes and HEK 293 cells stably expressing human Nav1.5, HCN2, or hERG channel using conventional electrophysiological approaches. It was found that trichloromethane (5mM) induced bradycardia and atrial-ventricular conduction blockade or ventricular fibrillation, and inhibited cardiac contractile function in isolated rat hearts. It shortened action potential duration (APD) in isolated rat ventricular myocytes, and increased the threshold current for triggering action potential, but had no effect on the inward rectifier K + current I K1. However, trichloromethane significantly inhibited the L-type calcium current I Ca.L and the transient outward potassium current I to in a concentration-dependent manner (IC 50s: 1.01 and 2.4mM, respectively). In HEK 293 cells stably expressing cardiac ion channel genes, trichloromethane reduced hNav1.5, HCN2, and hERG currents with IC 50s of 8.2, 3.3, and 4.0mM, respectively. These results demonstrate for the first time that trichloromethane can induce bradycardia or ventricular fibrillation, and the arrhythmogenic effect of trichloromethane is related to the inhibition of multiple ionic currents including I Ca.L, I to, I Na, HCN2, and hERG channels. © 2011 Elsevier Ireland Ltd.
 
ISSN0300-483X
2012 Impact Factor: 4.017
2012 SCImago Journal Rankings: 1.094
 
DOIhttp://dx.doi.org/10.1016/j.tox.2011.10.009
 
ISI Accession Number IDWOS:000298534700092
Funding AgencyGrant Number
Sun Chieh Yeh Heart Foundation of Hong Kong
University of Hong Kong
Funding Information:

The work was supported in part by a grant from Sun Chieh Yeh Heart Foundation of Hong Kong. Yuan Zhou and Hui-Jun Wu are supported by a postgraduate studentship from the University of Hong Kong. The authors thank Dr. G. Robertson for providing the hERG/pcDNA3, Dr. Carol A. Vandenberg for providing the human Kir2.1/pcDNA3, Dr. J. Makielski for providing the human SCNA5/pcDNA3, and Dr. A. Ludwig for providing the human HCN2/pCDNA3. We thank Mr. Chi-Pui Mok for the excellent technical support.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorZhou, Y
 
dc.contributor.authorWu, HJ
 
dc.contributor.authorZhang, YH
 
dc.contributor.authorSun, HY
 
dc.contributor.authorWong, TM
 
dc.contributor.authorLi, GR
 
dc.date.accessioned2011-11-24T10:04:11Z
 
dc.date.available2011-11-24T10:04:11Z
 
dc.date.issued2011
 
dc.description.abstractTrichloromethane (chloroform) is widely used for industrial chemical synthesis and also as an organic solvent in laboratories or ingredient of pesticides. Sudden death resulted from cardiac arrhythmias has been reported in clinic with acute trichloromethane intoxication. The present study was designed to investigate ionic mechanisms underlying arrhythmogenic effect (cardiac toxicity) of trichloromethane in isolated rat hearts and ventricular myocytes and HEK 293 cells stably expressing human Nav1.5, HCN2, or hERG channel using conventional electrophysiological approaches. It was found that trichloromethane (5mM) induced bradycardia and atrial-ventricular conduction blockade or ventricular fibrillation, and inhibited cardiac contractile function in isolated rat hearts. It shortened action potential duration (APD) in isolated rat ventricular myocytes, and increased the threshold current for triggering action potential, but had no effect on the inward rectifier K + current I K1. However, trichloromethane significantly inhibited the L-type calcium current I Ca.L and the transient outward potassium current I to in a concentration-dependent manner (IC 50s: 1.01 and 2.4mM, respectively). In HEK 293 cells stably expressing cardiac ion channel genes, trichloromethane reduced hNav1.5, HCN2, and hERG currents with IC 50s of 8.2, 3.3, and 4.0mM, respectively. These results demonstrate for the first time that trichloromethane can induce bradycardia or ventricular fibrillation, and the arrhythmogenic effect of trichloromethane is related to the inhibition of multiple ionic currents including I Ca.L, I to, I Na, HCN2, and hERG channels. © 2011 Elsevier Ireland Ltd.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationToxicology, 2011, v. 290 n. 2-3, p. 296-305 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.tox.2011.10.009
 
dc.identifier.citeulike9932027
 
dc.identifier.doihttp://dx.doi.org/10.1016/j.tox.2011.10.009
 
dc.identifier.epage305
 
dc.identifier.hkuros197773
 
dc.identifier.isiWOS:000298534700092
Funding AgencyGrant Number
Sun Chieh Yeh Heart Foundation of Hong Kong
University of Hong Kong
Funding Information:

The work was supported in part by a grant from Sun Chieh Yeh Heart Foundation of Hong Kong. Yuan Zhou and Hui-Jun Wu are supported by a postgraduate studentship from the University of Hong Kong. The authors thank Dr. G. Robertson for providing the hERG/pcDNA3, Dr. Carol A. Vandenberg for providing the human Kir2.1/pcDNA3, Dr. J. Makielski for providing the human SCNA5/pcDNA3, and Dr. A. Ludwig for providing the human HCN2/pCDNA3. We thank Mr. Chi-Pui Mok for the excellent technical support.

 
dc.identifier.issn0300-483X
2012 Impact Factor: 4.017
2012 SCImago Journal Rankings: 1.094
 
dc.identifier.issue2-3
 
dc.identifier.pmid22024336
 
dc.identifier.scopuseid_2-s2.0-84858619354
 
dc.identifier.spage296
 
dc.identifier.urihttp://hdl.handle.net/10722/143373
 
dc.identifier.volume290
 
dc.languageeng
 
dc.publisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/toxicol
 
dc.publisher.placeIreland
 
dc.relation.ispartofToxicology
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshBradycardia - chemically induced
 
dc.subject.meshChloroform - administration and dosage - toxicity
 
dc.subject.meshIon Channels - antagonists and inhibitors
 
dc.subject.meshSolvents - administration and dosage - toxicity
 
dc.subject.meshVentricular Fibrillation - chemically induced
 
dc.subjectArrhythmogenic effect
 
dc.subjectCardiac toxicity
 
dc.subjectMultiple ion channel blockade
 
dc.subjectTrichloromethane
 
dc.subjectVentricular fibrillation
 
dc.titleIonic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethane
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine