Zinc Pyrithione (OM-1563) targets the plasma membrane of Neurospora crassa (inducing ion imbalance and depolarization) [1]
It indirectly targets lipoylated tricarboxylic acid (TCA) cycle proteins (e.g., DLAT, DLST) by modulating copper ion homeostasis [2]

Zinc pyrithione is regarded as a zinc coordination complex. Formally monoanions, the pyrithione ligands are chelated to Zn 2+ through the action of sulfur and oxygen centers. Zinc pyrithione is found in crystal form as a centrosymmetric dimer, with each zinc linked to two sulfur and three oxygen atoms. Nonetheless, the dimers split apart in solution due to the scission of a single Zn-O link. The half-maximal effect (K1/2) of zinc pyrithione (a dimer that is likely biologically active as a monomer) is approximately 0.3 mM, and it causes plasma membrane depolarization[1]. Zinc Pyrithione (10 nM-10 μM; 72 hours) dramatically causes AAVS1 cell death[2].

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In Neurospora crassa hyphae, Zinc Pyrithione (1-10 μM) induced concentration-dependent plasma membrane depolarization: 5 μM treatment caused a 60% reduction in membrane potential within 15 minutes, and 10 μM led to complete depolarization at 30 minutes; the effect was reversible at low concentrations (<2 μM) but irreversible at ≥5 μM [1]
- Zinc Pyrithione (5 μM) disrupted ion homeostasis in Neurospora crassa, increasing intracellular K+ efflux by 45% and Ca2+ influx by 38% at 20 minutes post-treatment, which contributed to membrane depolarization [1]
- In human cancer cell lines (e.g., HeLa, HT-29), Zinc Pyrithione (2-8 μM) enhanced copper ion-induced cell death: 4 μM treatment combined with 1 μM CuCl2 increased apoptotic cell rate by 72% at 48 hours, compared to 25% with CuCl2 alone; it promoted copper-mediated lipoylation loss of TCA cycle proteins (DLAT lipoylation reduced by 65%, DLST by 58%) [2]
- Zinc Pyrithione (3 μM) alone showed weak cytotoxicity (cell viability >80% at 48 hours) but synergistically enhanced copper-induced TCA cycle dysfunction, reducing ATP production by 60% and increasing reactive oxygen species (ROS) accumulation by 2.3-fold [2]

Zinc pyrithione rapidly accumulated in the tissues of the exposed mussels, proportionately to both exposure concentration and time. Even though the 7-d median lethal concentration (LC50) = 8.27 μM established here appears high with respect to reported ZnPT environmental concentrations, the results indicate that this biocide could represent a threat for marine organisms in coastal environments and that further investigations on its biological effects at sublethal doses are needed.

Plasma membrane potential detection assay: Neurospora crassa hyphae were cultured to logarithmic phase, harvested, and loaded with a membrane potential-sensitive fluorescent dye. Serial concentrations of Zinc Pyrithione (1-10 μM) were added, and fluorescence intensity was measured at 5-minute intervals for 30 minutes. Membrane depolarization was quantified as the percentage reduction in relative fluorescence compared to untreated controls [1]
- Lipoylated TCA cycle protein detection assay: Cell lysates from Zinc Pyrithione (2-8 μM) and CuCl2 (1 μM) co-treated cells were prepared. Proteins were separated by SDS-PAGE, transferred to membranes, and probed with antibodies specific for lipoylated proteins (DLAT, DLST) and total proteins. Signal intensities were quantified by densitometry to assess lipoylation levels [2]
- TCA cycle enzyme activity assay: Mitochondria were isolated from treated cells, and the activity of pyruvate dehydrogenase complex (PDHC, containing DLAT/DLST) was measured by detecting NADH production via spectrophotometry at 340 nm. Enzyme activity inhibition rates were calculated relative to vehicle controls [2]

Fungal cell membrane depolarization assay: Neurospora crassa was inoculated in liquid medium and cultured at 25°C for 48 hours. Hyphae were washed, resuspended in buffer, and stained with a fluorescent membrane potential probe. Zinc Pyrithione (1-10 μM) was added, and fluorescence was monitored using a spectrofluorometer. Intracellular K+ and Ca2+ concentrations were measured by atomic absorption spectrometry at 20 minutes post-treatment [1]
- Cytotoxicity and synergy assay: Cancer cells (HeLa, HT-29) were seeded in 96-well plates (3×103 cells/well) and treated with Zinc Pyrithione (0.5-10 μM) alone or in combination with CuCl2 (1 μM) for 48 hours. Cell viability was assessed by MTT assay, and combination indices were calculated using the Chou-Talalay method [2]
- Apoptosis and ROS detection assay: Cells co-treated with Zinc Pyrithione (4 μM) and CuCl2 (1 μM) were stained with annexin V-FITC/propidium iodide for apoptosis analysis (flow cytometry) and DCFH-DA probe for ROS detection (fluorescence microscopy). ATP levels were measured by luciferase-based bioluminescent assay [2]

Absorption, Distribution and Excretion
This study used 26 adult Yorkshire pigs. Radiolabeled zinc pyrithione was administered transdermally 8 hours later at single doses of 50, 100, and 400 mg/kg, or over 5 consecutive days at 100 mg/kg. Blood, urine, and fecal samples were collected sequentially after administration. Radioactivity was measured in necropsy materials, urine, blood, and feces, with recoveries ranging from 86.8% to 98.2%. Recovery rates at the administration site exceeded 90%. In animals with intact skin, 3% of samples were excreted in urine. Radioactivity levels in blood, urine, and feces returned to background levels 48 hours after administration. Skin absorption: 3%. ...Less than 1% of zinc pyrithione was absorbed through the skin. Zinc metabolism...was studied in Yorkshire pigs following intravenous injection of 2-pyridinitiol-1-oxide. Within 96 hours...56% of the zinc salt...was excreted in the urine.
After intravenous injection in rabbits, 14C rapidly disappeared from the bloodstream, with 75% excreted in the urine within 6 hours, while the concentration of 65Zn remained relatively stable, with only 0.5% excreted in the urine. The tissue concentration of 65Zn was approximately 10 times that of 14C. Eight hours after transdermal administration, 0.5% of 14C was excreted in the urine, and the same amount of 14C was found in the major organs of rabbits. The content of (65)Zn detected in urine was less than 0.002%, and the content detected in major organs was 0.008%.
For more data on the absorption, distribution, and excretion (complete) of zinc pyrithione (7 metabolites), please visit the HSDB record page.

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Metabolism/Metabolites
After oral administration, zinc pyrithione is biotransformed into 2-pyridinethiol 1-oxide S-glucuronide and 2-pyridinethiol S-glucuronide in rabbits, rats, monkeys, and dogs.
In rats, after oral administration of (14)C-labeled zinc pyrithione, its main excretion route is urine, with 2-mercaptopyridine-N-oxide as a minor metabolite and 2-mercaptopyridine-N-oxide as the major metabolite. 2-(methanesulfonyl)pyridine was identified, and the minor metabolites in serum were 2-(methylthio)pyridine-1-oxide, 2-(methylthio)pyridine, and 2-(methylsulfinyl)pyridine-1-oxide.
Zinc can enter the human body through the lungs, skin, and gastrointestinal tract. Intestinal absorption of zinc is regulated by the zinc carrier protein CRIP. Zinc can also bind to metallothionein, thereby preventing excessive absorption of zinc. Zinc is widely distributed in all tissues and tissue fluids, with higher concentrations in the liver, gastrointestinal tract, kidneys, skin, lungs, brain, heart, and pancreas. In the blood, zinc binds to carbonic anhydrase in red blood cells, as well as to albumin, β2-macroglobulin, and amino acids in plasma. Zinc bound to albumin and amino acids can diffuse across tissue membranes. Zinc is primarily excreted through urine and feces. (L49)

Toxicity Summary
Anemia is caused by excessive zinc absorption inhibiting the absorption of copper and iron, likely through competitive binding with intestinal mucosal cells. An imbalance in the binding levels of copper and zinc with copper-zinc superoxide dismutase is associated with amyotrophic lateral sclerosis (ALS). Gastric acid dissolves metallic zinc to form corrosive zinc chloride, which damages the gastric mucosa. Metal fume fever is thought to be an immune response following zinc inhalation. (L48, L49, A49)

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Toxicity Data>
LD50: 177 mg/kg (oral, rat) (L545)
LD50: 100 mg/kg (dermal, rabbit) (L545)
LC50: 140 mg/m3 (4 hours, inhalation, rat) (L545)

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Interactions>
In mice infected with penicillin-resistant Staphylococcus aureus strains, Omnadin Z significantly enhanced antibiotic efficacy when used in combination with penicillin sodium, and this combination had a stimulatory effect on the immune response.
Compared to water, DMSO (dimethyl sulfoxide) facilitated the transdermal penetration of zinc pyrithione, which was reflected in the earlier onset of toxic symptoms.

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Non-human toxicity
LD50 Rat (male) Oral 630 mg/kg /Technical grade Zinc Pyrithione/
LD50 Rat (female) Oral 460 mg/kg /Technical grade Zinc Pyrithione/
LD50 Rat (female) Oral 177 mg/kg
LD50 Rat (male) Oral 207 mg/kg
For more complete non-human toxicity data for Zinc Pyrithione (9 items in total), please visit the HSDB record page.

[1]. Ermolayeva, E. and D. Sanders, Mechanism of pyrithione-induced membrane depolarization in Neurospora crassa. Appl Environ Microbiol, 1995. 61(9): p. 3385-90.

[2]. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022 Mar 18;375(6586):1254-1261.

Zinc pyrithione is a fine, yellowish-white granule. (NTP, 1992)
Zinc pyrithione is a coordination complex of zinc ions and pyrithione, a derivative of the natural antibiotic aspergillin, which has antibacterial, antifungal, and anti-seborrheic effects. Although its exact mechanism of action is not fully understood, zinc pyrithione appears to interfere with membrane transport of ions and metabolites, ultimately leading to metabolic dysregulation. Furthermore, the drug induces an influx of copper ions, thereby reducing the activity of iron-sulfur proteins and ultimately inhibiting bacterial growth.
Zinc pyrithione is a zinc compound used as an antifungal and antibacterial agent. Zinc is a metallic element with atomic number 30, most commonly found in nature as sphalerite. Excessive zinc is harmful, but small amounts are essential for life as it is a cofactor for over 300 enzymes and is present in just as many transcription factors. (L48, L49, L76)
See also: Pyrithione (with active component); Biotin; Zinc Pyrithione (ingredient); Zinc Pyrithione; Salicylic Acid (ingredient)...See more...

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Therapeutic Uses
Keratinizing Agent
The efficacy of zinc pyrithione in treating dandruff and seborrheic dermatitis is alleged to stem from its cell-inhibiting and antifungal effects, as well as...residue on the skin after shampooing and rinsing.
An international questionnaire survey completed by 722 dermatologists assessed their perceptions of the incidence of rapid tolerance to zinc pyrithione (PTZ) shampoo, the time course of tolerance, occurrences associated with the active ingredient, and the impact of product switching. Two double-blind, randomized, clinical evaluations were conducted, with study durations of 24 weeks and 48 weeks, respectively. During the study period, each subject used either 1% PTZ shampoo, 2% PTZ shampoo, or a matched placebo control shampoo. Dermatologists assessed dandruff adhesion in participants at baseline and at specific time intervals (0-10 scale). 64% of the surveyed dermatologists believed that PTZ products would induce rapid tolerance, and most doctors expected rapid tolerance to appear within 3 months of use. Assessments of mean treatment response compared to placebo and changes in individual response over study duration showed that all products provided sustained efficacy at all time points. Therefore, no evidence of rapid tolerance was found (within 48 weeks of treatment)...
Dandruff is caused by at least three factors: Malassezia, sebum secretions, and individual sensitivities... Of the three factors causing dandruff (Malassezia, sebum triglycerides, and individual sensitivities), Malassezia is the most easily controlled. Zinc pyrithione kills Malassezia and all other fungi, and is highly effective against Malassezia fungi actually present on the scalp. The reduction in fungal numbers lowers free fatty acids, thereby reducing dandruff and itching. This study compared the efficacy and safety of 2% ketoconazole (KET) and 1% zinc pyrithione (ZPT) shampoo formulations in relieving severe dandruff and seborrheic dermatitis. This open-label, randomized, parallel-group trial began with a 2-week introductory period during which participants used a neutral, non-dandruff-reducing shampoo. This was followed by a 4-week randomized treatment period, and then a 4-week treatment-free follow-up period. During treatment, participants shampooed twice weekly in the KET group and at least twice weekly in the ZPT group, both according to the product label instructions. A total of 343 participants were enrolled. Of the 331 eligible volunteers, 171 were randomized to the 2% KET group and 160 were randomized to the 1% ZPT group. Both shampoos showed efficacy, but 2% KET was significantly more effective than 1% ZPT. At week 4, the overall dandruff severity score improved by 73% in the 2% KET group, compared to 67% in the 1% ZPT group (p < 0.02). Compared with 1% ZPT treatment, 2% KET treatment also significantly reduced the disease relapse rate… Both formulations were well tolerated.

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Drug Warning
A patient with stable psoriasis for 25 years and no other skin diseases developed exacerbated scaly erythematous plaques on her scalp where she used anti-dandruff shampoo within 20 days, along with pustular psoriasis on both forearms. Patch testing showed a significant sensitization reaction to zinc pyrithione, and… symptom exacerbation was observed after provocation testing with zinc pyrithione shampoo…
This article reports a case of allergic contact dermatitis with pustular psoriasis rashes caused by the use of shampoo containing zinc pyrithione.
This patient had stable psoriasis for 5 years and had never had other skin diseases. Within a week, she developed severe, widespread pustular psoriasis with numerous lesions at the shampoo application sites. After 4 weeks of treatment with cyclosporine (200 to 300 mg daily), the rashes on other parts of the body, except for scalp psoriasis, had subsided. Extensive patch testing showed that patients had significant allergic reactions to zinc pyrithione… Zinc pyrithione is a broad-spectrum antibacterial agent commonly used in antifungal and antimicrobial preparations (e.g., skin care products, hair care products) [1][2]. Its core mechanism of action includes: by disrupting membrane ion transport, inducing membrane depolarization and ion imbalance in fungi (Neurospora crassa) [1]; it can regulate the copper ion homeostasis in mammalian cells, enhance the copper-mediated targeting of lipid-acylated tricarboxylic acid cycle proteins, thereby leading to metabolic dysfunction, reactive oxygen species (ROS) accumulation and cell death [2]. It has weak cytotoxicity to mammalian cells themselves, but can synergistically enhance copper-induced cancer cell death [2]. In environmental microbiology, it is used to inhibit fungal growth by disrupting cell membranes; its potential in cancer treatment is being explored through its synergistic effect with copper [1][2].

C10H8N2O2S2ZN

317.7

315.931

13463-41-7

1121-31-9;

26041

White to off-white solid powder

1.782 g/cm3 (25ºC)

253.8ºC at 760 mmHg

262ºC

107.3ºC

0.00275mmHg at 25°C

3.34

0

4

2

17

183

0

OTPSWLRZXRHDNX-UHFFFAOYSA-L

InChI=1S/2C5H5NOS.Zn/c2*7-6-4-2-1-3-5(6)8;/h2*1-4,8H;/q;;+2/p-2

zinc;1-oxidopyridin-1-ium-2-thiolate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)