Guide: zinc & the
Vitamin A metabolism

Chapter 1: Vitamin A — a fat-soluble vitamin

Vitamin A belongs, together with vitamins D, E and K, to the fat-soluble vitamins. Unlike water-soluble vitamins, the body can store vitamin A — predominantly in the liver, where it is deposited as retinyl esters. This storage capacity means on the one hand that short-term fluctuations in intake can be evened out, but on the other hand also that an excessive intake can lead to accumulation.

1.1 Forms of vitamin A

The term vitamin A covers a group of structurally related compounds. The biologically most relevant forms are:

1. Retinol: The alcohol form, which is transported in the blood and present in the liver as the storage form (after esterification). Retinol serves as the starting substance for the active metabolites.
2. Retinal (retinaldehyde): The aldehyde form, which arises from retinol by enzymatic oxidation. Retinal is a component of the visual pigment rhodopsin and is thereby involved in vision.
3. Retinoic acid: The acid form, which can no longer be converted back into retinol or retinal. Retinoic acid acts as a ligand of nuclear receptors (RAR, RXR) and regulates gene expression in numerous cell types.
4. Beta-carotene: A provitamin that occurs in plant foods and that can be cleaved into retinal in the body by the enzyme beta-carotene 15,15’-dioxygenase.

1.2 The metabolic pathway in overview

Vitamin A metabolism begins with uptake in the small intestine. Preformed retinol from animal sources is absorbed directly, while beta-carotene is first cleaved enzymatically. In the enterocytes the retinol molecules are esterified and packed into chylomicrons, which reach the bloodstream via the lymph. The liver takes up the chylomicron remnants and stores the vitamin A in the Ito cells (hepatic stellate cells).

When needed, retinol is released from the liver, coupled to retinol-binding protein (RBP) and transported through the blood to the target tissues. There it is converted into the active forms retinal or retinoic acid.

Chapter 2: Zinc in vitamin A metabolism

2.1 Retinol-binding protein and zinc

Retinol-binding protein (RBP) is a transport protein synthesised in the liver and responsible for mobilising vitamin A from the hepatic stores. Gene expression of RBP is controlled by transcription factors that contain zinc as a structural component — so-called zinc finger proteins.

Without an adequate supply of zinc, the synthesis of RBP can be impaired. As a result, vitamin A can indeed be stored in the liver but not released efficiently into the bloodstream. This relationship has been documented in several studies and forms part of the scientific basis for the authorised EU claim.

2.2 Alcohol dehydrogenase — a zinc enzyme

The conversion of retinol to retinal is catalysed by retinol dehydrogenase, which belongs to the family of alcohol dehydrogenases (ADH). This enzyme contains zinc ions in its active site that are required for the oxidation step. In detail, zinc coordinates the binding of the substrate retinol and enables the hydride transfer to the coenzyme NAD⁺.

Without functioning zinc-containing alcohol dehydrogenase, the conversion of retinol into retinal is limited, which can affect downstream processes — the formation of the visual pigment rhodopsin, for instance.

2.3 Further zinc-dependent steps

Alongside the two main mechanisms (RBP synthesis and ADH activity) there are further points in vitamin A metabolism at which zinc is involved:

• Gene regulation by retinoic acid: The nuclear receptors RAR and RXR, to which retinoic acid binds, contain zinc finger structures that are required for DNA binding.
• Beta-carotene cleavage: There are indications that the enzymatic cleavage of beta-carotene into retinal can likewise be modulated by zinc status.
• Hepatic storage: The esterification of retinol in the liver by lecithin retinol acyltransferase (LRAT) can be indirectly influenced by zinc status.

Chapter 3: Zinc and vitamin A sources in the diet

3.1 Zinc sources and daily requirement

Under EU Regulation 1169/2011 the reference value for daily zinc intake is 10 mg. Zinc occurs in both animal and plant foods, with bioavailability from animal sources generally being higher.

3.2 Vitamin A sources and reference values

Under EU rules the daily reference value for vitamin A is 800 µg retinol equivalent (RE). Here 1 µg RE = 1 µg retinol = 6 µg beta-carotene.

3.3 Bioavailability and interactions

The uptake of zinc in the small intestine is influenced by various dietary components. Phytic acid, which occurs in grains, nuts and legumes, can bind zinc and reduce absorption. Methods such as fermentation, sprouting and soaking reduce the phytic acid content and can increase the bioavailability of zinc.

As a fat-soluble vitamin, vitamin A is best absorbed in combination with dietary fats. Even small amounts of fat (5–10 g per meal) can markedly favour the absorption of beta-carotene and retinol.

Chapter 4: Molecular foundations in detail

4.1 Zinc finger proteins and gene expression

Zinc finger proteins are one of the largest transcription factor families in the human genome. Each zinc finger consists of a loop of about 30 amino acids held in a particular three-dimensional conformation by a zinc ion. The coordinating amino acids are typically cysteine and histidine in various combinations (C2H2, C4, C6).

In the context of vitamin A metabolism, the nuclear receptors RAR (Retinoic Acid Receptor) and RXR (Retinoid X Receptor) are of particular importance. Both receptors contain zinc finger domains in their DNA-binding region. When retinoic acid binds to these receptors, they dimerise and bind to specific DNA sequences (Retinoic Acid Response Elements, RAREs) in order to activate or inhibit the transcription of downstream genes.

4.2 Retinol transport in the blood

Retinol is transported in the blood bound to two proteins: retinol-binding protein (RBP4) and transthyretin (TTR). The RBP4–TTR complex protects retinol from premature breakdown and filtration by the kidneys. The synthesis of RBP4 in the liver is a zinc-dependent process, since the transcription factors that influence the RBP4 gene have zinc finger structures.

At the target cells, retinol is taken up from the RBP4 complex by the receptor STRA6 (Stimulated by Retinoic Acid 6). Intracellularly it is then processed further by the corresponding dehydrogenases.

Chapter 5: Frequently asked questions

Why is zinc linked with vitamin A metabolism?

As a cofactor, zinc takes part in several enzymatic and regulatory processes required for normal vitamin A metabolism. These include the synthesis of retinol-binding protein, the activity of alcohol dehydrogenase and the function of the nuclear retinoid receptors. EFSA has examined these relationships scientifically and assessed them as the basis for the authorised claim.

Does the EU claim mean that zinc can replace vitamin A?

No. The claim describes zinc’s contribution to the normal course of vitamin A metabolism — not a substitute for vitamin A itself. Both nutrients have to be supplied in sufficient amounts for the physiological processes to run properly.

In which foods do zinc and vitamin A occur together?

Some foods supply both zinc and preformed vitamin A in appreciable amounts. These include in particular liver, egg yolk and certain dairy products. On a purely plant-based diet, zinc and provitamin A (beta-carotene) are taken in from different sources — pumpkin seeds (zinc) and carrots (beta-carotene), for example.

What does “normal” vitamin A metabolism mean?

The term “normal” in the EU claim refers to the physiologically proper course of vitamin A metabolism given an adequate supply of zinc. No therapeutic effect and no increase beyond the physiological measure is described.

Does the authorised claim apply to all groups of people?

The health claim pursuant to Regulation (EU) No 432/2012 refers to the general adult population. For pregnant and breastfeeding women, children and people with specific conditions, different recommendations may apply. Individual advice from qualified medical professionals is recommended.