A mixture of chloromethylisothiazolinone and methylisothiazolinone impairs rat vascular smooth muscle by depleting thiol
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MOLECULAR TOXICOLOGY
A mixture of chloromethylisothiazolinone and methylisothiazolinone impairs rat vascular smooth muscle by depleting thiols and thereby elevating cytosolic Zn2+ and generating reactive oxygen species Van Quan Do1 · Yoon‑Seok Seo1 · Jung‑Min Park1 · Jieun Yu2 · Men Thi Hoai Duong1 · Junichi Nakai3 · Sang‑Kyum Kim2 · Hee‑Chul Ahn1 · Moo‑Yeol Lee1 Received: 13 June 2020 / Accepted: 8 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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 Z n2+ 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. Keywords Chloromethylisothiazolinone (CMIT) · Methylisothiazolinone (MIT) · Vascular toxicity · Cytotoxicity · Humidifier disinfectant
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02930-z) contains supplementary material, which is available to authorized users. * Moo‑Yeol Lee [email protected] 1
College of Pharmacy, Integrated Research Institute for Drug Development, and BK21 FOUR team, Dongguk University, 32 Dongguk‑ro, Ilsandong‑gu, Goyang‑si, Gyeonggi‑do 10326, Republic of Korea
2
College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
3
Graduate School of Dentistry, Tohoku University, Miyagi 980‑8575, Japan
5-Chloro-2-methyli
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