Elevation of the intracellular Zn2+level by 2-n-octyl-4-isothiazolin-3-one in rat thymocytes: an involvement of a temperature-sensitive Zn2+pathway

Fukunaga, Eri; Oyama, Tomohiro M.; Oyama, Yasuo

doi:10.1039/c4tx00060a

Cited by 5 publications

(8 citation statements)

References 25 publications

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“…We previously reported that OIT increased intracellular Zn 2+ levels through the activation of a temperaturesensitive Zn 2+ pathway (Zn 2+ influx) in rat thymocytes (Fukunaga et al, 2015). Three μM OIT significantly increased the intensity of FluoZin-3 fluorescence (Fig.…”

Section: Oit-induced Changes In Intracellular Zn 2+ Levelsmentioning

confidence: 70%

“…High concentrations of OIT have been detected in some household products (Nakashima et al, 2000;Aalto-Korte et al, 2007;Kawakami et al, 2014). In our previous study (Fukunaga et al, 2015), we found that OIT increased membrane Zn 2+ permeability through the activation of the temperature-sensitive Zn 2+ pathway, which resulted in increased intracellular Zn 2+ levels in rat thymic lymphocytes. However, the Zn 2+ -dependent insults that were induced by OIT were not elucidated.…”

Section: Introductionmentioning

confidence: 69%

“…Our previous study (Fukunaga et al, 2015) suggested that the simultaneous application of OIT and ZnCl 2 induces oxidative stress. Thus, we examined the cellular changes with annexin V-FITC and propidium iodide after simultaneous treatment with OIT and ZnCl 2 for 60 min.…”

Section: Annexin V-fitc and Propidium Iodide Assessments Of The Oit-induced Cellular Changesmentioning

confidence: 96%

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Zn2+-dependent increase in cells with phosphatidylserine-exposed membranes after treatment with submicromolar concentrations of 2-n-octyl-4-isothiazolin-3-one in rat thymocytes

Fukunaga

Honda

Hashimoto

et al. 2015

Fundam. Toxicol. Sci.

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Some household products have high levels of the antimicrobial 2-n-octyl-4-isothiazolin-3-one (OIT). Although the diverse effects of OIT are of concern, information regarding its cellular actions is limited. In a previous study, we found that OIT increased intracellular Zn 2+ levels in rat thymocytes. However, because Ca 2+ is considered the essential cation that causes cell injury and death, we examined whether Ca 2+ and Zn 2+ were involved in OIT-induced cytotoxicity and proposed the mechanisms underlying these results. The effects of OIT on the membrane and cellular parameters of rat thymocytes were examined with a flow cytometer and appropriate fluorescent probes. OIT (0.3-3 μM) increased intracellular Zn 2+ levels but not intracellular Ca 2+ levels. Therefore, the involvement of Zn 2+ was studied further. The simultaneous application of 0.3 μM OIT and 3 μM ZnCl 2 significantly increased cells with phosphatidylserine-exposed membranes without changing the dead cells. In contrast, applications of 0.3 μM OIT or 3 μM ZnCl 2 alone had no effects. The combination of OIT (0.1-1 μM) and ZnCl 2 (1-3 μM) significantly decreased the cellular non-protein thiol contents. These changes that were induced by their combination were completely suppressed by adding an intracellular Zn 2+ chelator. These results suggested that submicromolar concentrations of OIT induced Zn 2+ -dependent cytotoxicity in the presence of micromolar concentrations of external Zn 2+ . Because the threshold of OIT levels that affected cellular parameters in the presence of micromolar concentrations of Zn 2+ are much lower than the OIT contents in some household products, the adverse effects of OIT are of great concern.

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Section: Oit-induced Changes In Intracellular Zn 2+ Levelsmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 69%

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Zn2+-dependent increase in cells with phosphatidylserine-exposed membranes after treatment with submicromolar concentrations of 2-n-octyl-4-isothiazolin-3-one in rat thymocytes

Fukunaga

Honda

Hashimoto

et al. 2015

Fundam. Toxicol. Sci.

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“…The chemical structure of noctyl-4-isothiazolin-3-one (OIT), an antimicrobial agent, is similar to that of DCOIT. OIT-induced increases in FluoZin-3 fluorescence are completely abolished by TPEN (Fukunaga et al, 2015). Therefore, DCOIT may increase the intensity of FluoZin-3 fluorescence in a Zn 2+ -independent manner.…”

Section: Possible Mechanism For Synergistic Action By H 2 O 2 and Dcoitmentioning

confidence: 92%

Zn2+-dependence of the synergistic increase in rat thymocyte cell lethality caused by simultaneous application of 4,5-dichloro-2-octyl-4-isothiazolin-3-one (DCOIT) and H2O2

et al. 2015

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“…It is to be mentioned that Zn 2+ enters rat thymic lymphocytes through a temperature-sensitive pathway. The application of ZnCl 2 significantly increases the (Zn 2+ )i and this phenomenon is completely suppressed in cold condition (Takahashi et al, 2012;Fukunaga et al, 2015). The thymus gland is very active in the pre-adolescent and neonatal periods.…”

Section: Introductionmentioning

confidence: 96%

Azoxystrobin at sub-cytotoxic concentrations disrupts intracellular zinc homeostasis: A flow cytometric analysis with rat thymic lymphocytes and fluorescent probes

Shoji

Asada

Matsumoto

et al. 2020

Fundam. Toxicol. Sci.

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Azoxystrobin is a broad-spectrum fungicide having a wide usage. However, the toxic effect of azoxystrobin in humans is not reported. In Japan, azoxystrobin was detected at a five-fold higher concentration than the normal upper limit (2.5 mg/kg) in a shipment of an Australian barley used in different food products. Thus, there is a chance of azoxystrobin exposure through food to humans, and hence it is imperative to study the toxic effects of this compound. In this study, the toxic effect of azoxystrobin was evaluated to predict its adverse effects on human. Azoxystrobin at 3-30 µM (approximately 1.2-12.1 mg/L) raised the intracellular Zn 2+ concentration of rat thymic lymphocytes. This increase was due to an influx of extracellular Zn 2+ and a release of intracellular Zn 2+. Azoxystrobin partially inhibited the temperature-dependent Zn 2+ influx, thus jeopardizing the cellular Zn 2+ homeostasis. Because Zn 2+ is an important intracellular messenger in lymphocytes, this altered Zn 2+ homeostasis might lead to adverse effects if the blood concentration of azoxystrobin reaches 3 µM or more in humans. However, by extrapolating the azoxystrobin pharmacokinetics data of rats to human, it can be predicted that such high blood concentration may be unlikely in humans.

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Elevation of the intracellular Zn²⁺level by 2-n-octyl-4-isothiazolin-3-one in rat thymocytes: an involvement of a temperature-sensitive Zn²⁺pathway

Abstract: High amounts of 2-n-octyl-4-isothiazolin-3-one (OIT), an antimicrobial, are found in wet polyvinyl alcohol towels with cooling properties.

Cited by 5 publications

References 25 publications

Zn<sup>2+</sup>-dependent increase in cells with phosphatidylserine-exposed membranes after treatment with submicromolar concentrations of 2-<i>n</i>-octyl-4-isothiazolin-3-one in rat thymocytes

Zn<sup>2+</sup>-dependent increase in cells with phosphatidylserine-exposed membranes after treatment with submicromolar concentrations of 2-<i>n</i>-octyl-4-isothiazolin-3-one in rat thymocytes

Zn2+-dependence of the synergistic increase in rat thymocyte cell lethality caused by simultaneous application of 4,5-dichloro-2-octyl-4-isothiazolin-3-one (DCOIT) and H2O2

Azoxystrobin at sub-cytotoxic concentrations disrupts intracellular zinc homeostasis: A flow cytometric analysis with rat thymic lymphocytes and fluorescent probes

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