A mixture of chloromethylisothiazolinone and methylisothiazolinone impairs rat vascular smooth muscle by depleting thiols and thereby elevating cytosolic Zn2+ and generating reactive oxygen species
| Autor: | Yoon Seok Seo, Sang Kyum Kim, Jung-Min Park, Van Quan Do, Moo Yeol Lee, Men Thi Hoai Duong, Hee Chul Ahn, Jieun Yu, Junichi Nakai |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Reactive oxygen species Vascular smooth muscle Superoxide Health Toxicology and Mutagenesis General Medicine 010501 environmental sciences Pharmacology Toxicology 01 natural sciences 03 medical and health sciences Cytolysis chemistry.chemical_compound Cytosol 030104 developmental biology chemistry medicine medicine.symptom Phenylephrine Vasoconstriction 0105 earth and related environmental sciences medicine.drug Myograph |
| Zdroj: | Archives of Toxicology. 95:541-556 |
| ISSN: | 1432-0738 0340-5761 |
| Popis: | Chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) are biocidal preservatives and the active ingredients in Kathon CG, which contains ca. 1.5% mixture of CMIT and MIT at a ratio of 3:1 (CMIT/MIT). CMIT/MIT was misused as humidifier disinfectant products, which caused serious health problems in Korea. Here, the vascular effects of CMIT/MIT were investigated to evaluate claims of putative cardiovascular toxicity observed in humidifier disinfectant users. CMIT/MIT did not affect the basal tension of the rat thoracic aorta up to 2.5 μg/mL in myograph experiments. Instead, pretreatment with CMIT/MIT impaired phenylephrine- or 5-hydroxytryptamine-induced vasoconstriction in a range of 0.5–2.5 μg/mL, which was largely irreversible and not recovered by washing out the CMIT/MIT. Similarly, the application of CMIT/MIT to pre-contracted aorta caused a gradual loss of tension. In primary cultured vascular smooth muscle cells (VSMCs), CMIT/MIT caused thiol depletion, which in turn led to cytosolic Zn2+ elevation and reactive oxygen species (ROS) formation. CMIT/MIT-induced shrinkage, detachment, and lysis of VSMCs depending on the concentration and the treatment time. All events induced by CMIT/MIT were prevented by a thiol donor N-acetylcysteine (NAC). Cytolysis could be inhibited by a Zn2+ chelator TPEN and a superoxide scavenger TEMPOL, whereas they did not affect shrinkage and detachment. In accordance with these results, CMIT/MIT-exposed aortas exhibited dissociation and collapse of tissue in histology analysis. Taken together, CMIT/MIT causes functional impairment and tissue damage to blood vessels by depleting thiol and thereby elevating cytosolic Zn2+ and generating ROS. Therefore, exposure to CMIT/MIT in consumer products may be a risk factor for cardiovascular disorders. |
| Databáze: | OpenAIRE |
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