As soon as zinc enters the blood, its origin is no longer important. But up to this point, picolinate and gluconate behave differently: they release zinc differently in the intestine, and their "partner" molecules have their own biological fate. The editors analyzed the mechanism of action of both forms and compared their side effects.
Functions of zinc in the body
The body of an adult contains only about 2–3 g of zinc, mainly in muscles and bones. However, this trace element is a structural or catalytic component of a huge number of proteins. Zinc "fingers" stabilize proteins that bind to DNA and regulate gene transcription, and zinc in the active center of enzymes — from carbonic anhydrase to alcohol dehydrogenase — ensures their work.
Zinc is critical for immunity: its deficiency impairs T-lymphocyte maturation and neutrophil function. It is also needed for wound healing, taste and smell perception, spermatogenesis and testosterone synthesis. That is why zinc deficiency manifests itself in such a variety of ways - from frequent infections to a decrease in libido.
There is no special "depot" of zinc in the body, which could be quickly mobilized. Homeostasis is maintained mainly by the regulation of absorption in the intestine and excretion with pancreatic and intestinal secretions. If intake decreases, absorption increases, and vice versa.
These functions are the same for zinc from any source. Therefore, by comparing picolinate and gluconate, we are effectively comparing two "delivery systems" of the same ion to the intestinal epithelium.
How zinc is absorbed
Zinc is absorbed mainly in the small intestine. The main transporter on the apical membrane of enterocytes is the ZIP4 protein (encoded by the SLC39A4 gene). Mutations in this gene cause the hereditary disease acrodermatitis enteropathica, illustrating the key role of ZIP4 in zinc absorption.
Inside the enterocyte, zinc binds to metallothionein, a protein that acts as a buffer. Further, zinc enters the blood via the ZnT1 transporter on the basolateral membrane and is carried in the plasma mainly by albumin. With a high intake of zinc, the synthesis of metallothionein increases, and part of the zinc "gets stuck" in the enterocytes, which are subsequently sloughed off - this is a natural defense against excess.
For absorption, zinc must be released in soluble form. Gluconate dissolves well and dissociates, releasing zinc ions. A stable isotope study by Wegmüller et al (2014) showed a fractional absorption of zinc from gluconate of about 60% in healthy adults when taken on an empty stomach.
Picolinic acid forms a stable chelate complex with zinc. It has been hypothesized that endogenous picolinic acid from the pancreas aids zinc absorption, and that taking ready-made picolinate facilitates this process. However, later work has questioned the key role of picolinic acid in zinc absorption, and the mechanism of its possible benefit has not been proven.
The fate of "partner" molecules
Gluconic acid is an oxidized form of glucose widely used in the food industry. After dissociation of the salt, it is metabolized or excreted without a noticeable pharmacological effect. In the quantities contained in zinc supplements, it is biologically neutral.
Picolinic acid is a tryptophan metabolite formed by the kynurenine pathway. It has its own biological activity: it chelates metals, in experiments it affects the function of macrophages. The amounts of picolinic acid in common zinc supplements are small, and no clinically significant effects from it have been described in humans.
It is important to distinguish: picolinic acid as a chelator can affect not only zinc, but also the assimilation of other bivalent metals — iron, copper, chromium. That is why picolinate is also used for chromium. There are no reliable data on whether this has clinical significance when taking zinc picolinate.
| aspect | Zinc Picolinate | Zinc gluconate |
|---|---|---|
| Release of zinc | Stable chelate, slower dissociation | Easy dissociation in water |
| Biology of the anion | Tryptophan metabolite, metal chelator | Glucose derivative, practically neutral |
| Data with isotopic methods | There is none | Yes (assimilation ~60%) |
| Application in lollipops | Not researched | It has been studied for colds |
Side effects
The most common acute side effect of any zinc supplement is nausea, sometimes with vomiting and abdominal pain, especially when taken on an empty stomach. Free zinc ions irritate the gastric mucosa. This effect depends on the dose and more on the elemental zinc content than on the form.
In candies with gluconate, according to data from clinical studies, a metallic or unpleasant taste and irritation of the oral mucosa often occur. This effect is not characteristic of picolinate capsules that are swallowed.
The most serious risk of long-term excessive zinc intake is secondary copper deficiency. A high intake of zinc stimulates the synthesis of metallothionein in enterocytes, and metallothionein binds copper even more strongly than zinc. As a result, copper does not enter the blood. Consequences of copper deficiency:
- anemia that does not respond to iron treatment;
- neutropenia and susceptibility to infections;
- myeloneuropathy with impaired sensitivity and gait, which may be partially irreversible;
- lowering the level of HDL cholesterol.
This mechanism is the basis for establishing an upper limit of 40 mg of elemental zinc per day for adults (Institute of Medicine, 2001). Described cases of severe myeloneuropathy are most often associated with long-term intake of very high doses of zinc or with the use of creams for dental prostheses with zinc.
A separate risk associated with gluconate is loss of smell when administered intranasally. The FDA in 2009 warned of cases of anosmia after using zinc nasal gels. This risk is specific to nasal application, not ingestion.
Interactions with drugs and nutrients
Zinc forms complexes with tetracyclines and fluoroquinolones, reducing the absorption of these antibiotics. It also reduces the absorption of penicillamine, which is used in Wilson's disease. In such cases, the receptions should be staggered in time, and the exact interval should be specified in the instructions or with the doctor.
Some drugs, on the contrary, reduce the level of zinc: thiazide diuretics increase its excretion in the urine, and ACE inhibitors, according to some data, can also affect the balance of zinc. People who take such drugs for a long time are sometimes advised to monitor their zinc levels.
Among nutrients, the main "competitor" of zinc is iron in the form of supplements: when taken simultaneously on an empty stomach, high doses of iron can reduce the absorption of zinc. Calcium and phytates from plant foods also reduce absorption. These interactions apply to both forms of zinc.
Finally, high doses of zinc are known to be used medically to treat Wilson's disease precisely because of its ability to block copper absorption. This clearly shows how powerful the influence of zinc can be on the metabolism of other metals, and why independent long-term intake of large doses is dangerous.
Editorial conclusion
The mechanism of action of zinc from picolinate and gluconate is the same: the ions are absorbed through ZIP4, buffered by metallothionein and further perform their functions in hundreds of proteins. The differences are limited to how easily the compound gives up zinc and which "partner" molecule is released.
Side effects — nausea, copper deficiency with long-term excess, interactions with antibiotics — are determined by zinc itself and its dose, not the form. Gluconate-specific risks are associated with lozenges (taste) and intranasal use (anosmia).
For safe intake, it is important to calculate the total elemental zinc from all supplements and not exceed 40 mg per day without a doctor's prescription.
We described the practical choice between the forms in the article "Zinc Picolinate or Zinc Gluconate: What's the Difference". We also recommend our materials on copper and anemia and zinc and testosterone.
References
- Wegmüller R, Tay F, Zeder C, BrniÄ M, Hurrell RF. Zinc absorption by young adults from supplemental zinc citrate is comparable with that from zinc gluconate and higher than from zinc oxide. J Nutr. 2014;144(2):132â136.
- Barrie SA, Wright JV, Pizzorno JE, et al. Comparative absorption of zinc picolinate, zinc citrate and zinc gluconate in humans. Agents Actions. 1987;21(1â2):223â228.
- Hemilä H. Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage. JRSM Open. 2017;8(5):2054270417694291.
- Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press; 2001.
- Prasad AS. Discovery of human zinc deficiency: its impact on human health and disease. Adv Nutr. 2013;4(2):176â190.
- U.S. Food and Drug Administration. Warnings on three Zicam intranasal zinc products. 2009.
