Article: Ionic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethane
| Title | Ionic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethane | ||||||
|---|---|---|---|---|---|---|---|
| Authors | Zhou, Y1 Wu, HJ1 Zhang, YH1 Sun, HY1 Wong, TM1 Li, GR1 | ||||||
| Keywords | Arrhythmogenic effect Cardiac toxicity Multiple ion channel blockade Trichloromethane Ventricular fibrillation | ||||||
| Issue Date | 2011 | ||||||
| Publisher | Elsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/toxicol | ||||||
| Citation | Toxicology, 2011, v. 290 n. 2-3, p. 296-305 [How to Cite?] DOI: http://dx.doi.org/10.1016/j.tox.2011.10.009 | ||||||
| Abstract | Trichloromethane (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. | ||||||
| ISSN | 0300-483X 2011 Impact Factor: 3.681 2011 SCImago Journal Rankings: 0.227 | ||||||
| DOI | http://dx.doi.org/10.1016/j.tox.2011.10.009 | ||||||
| ISI Accession Number ID | WOS:000298534700092
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. | ||||||
| References | References in Scopus |
| dc.contributor.author | Zhou, Y | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | Wu, HJ | ||||||
| dc.contributor.author | Zhang, YH | ||||||
| dc.contributor.author | Sun, HY | ||||||
| dc.contributor.author | Wong, TM | ||||||
| dc.contributor.author | Li, GR | ||||||
| dc.date.accessioned | 2011-11-24T10:04:11Z | ||||||
| dc.date.available | 2011-11-24T10:04:11Z | ||||||
| dc.date.issued | 2011 | ||||||
| dc.description.abstract | Trichloromethane (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.nature | Link_to_subscribed_fulltext | ||||||
| dc.identifier.citation | Toxicology, 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.citeulike | 9932027 | ||||||
| dc.identifier.doi | http://dx.doi.org/10.1016/j.tox.2011.10.009 | ||||||
| dc.identifier.epage | 305 | ||||||
| dc.identifier.hkuros | 197773 | ||||||
| dc.identifier.isi | WOS:000298534700092
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.issn | 0300-483X 2011 Impact Factor: 3.681 2011 SCImago Journal Rankings: 0.227 | ||||||
| dc.identifier.issue | 2-3 | ||||||
| dc.identifier.pmid | 22024336 | ||||||
| dc.identifier.scopus | eid_2-s2.0-84858619354 | ||||||
| dc.identifier.spage | 296 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/143373 | ||||||
| dc.identifier.volume | 290 | ||||||
| dc.language | eng | ||||||
| dc.publisher | Elsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/toxicol | ||||||
| dc.publisher.place | Ireland | ||||||
| dc.relation.ispartof | Toxicology | ||||||
| dc.relation.references | References in Scopus | ||||||
| dc.subject.mesh | Bradycardia - chemically induced | ||||||
| dc.subject.mesh | Chloroform - administration and dosage - toxicity | ||||||
| dc.subject.mesh | Ion Channels - antagonists and inhibitors | ||||||
| dc.subject.mesh | Solvents - administration and dosage - toxicity | ||||||
| dc.subject.mesh | Ventricular Fibrillation - chemically induced | ||||||
| dc.subject | Arrhythmogenic effect | ||||||
| dc.subject | Cardiac toxicity | ||||||
| dc.subject | Multiple ion channel blockade | ||||||
| dc.subject | Trichloromethane | ||||||
| dc.subject | Ventricular fibrillation | ||||||
| dc.title | Ionic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethane | ||||||
| dc.type | Article |
Author Affiliations
- The University of Hong Kong Li Ka Shing Faculty of Medicine