Core Concepts
In this article, we will explore what vitamin A is, how it was discovered, where it is found, its purpose, and its impacts on day-to-day life.
What is a vitamin?
To begin our discussion, let’s first broadly discuss what a vitamin is. Vitamins are groups of organic compounds that, in small quantities, are essential for life. They serve to facilitate metabolic function, cell growth, tissue repair, and more! Vitamins can act as catalysts in the body, pushing forward critical processes. For example, vitamin K2 can bind and activate the receptor responsible for bone tissue, which can treat osteoporosis. Now, let’s discuss the intricacies of vitamin A!
What is vitamin A?
Vitamin A is the name of a fat-soluble vitamin that’s essential for proper metabolic function. Encompassing a diverse group of chemically related compounds, it has many forms. Within these compounds, “vitamin A” can refer to retinols, retinyl esters, ß-carotene, and some provitamin carotenoids.
The Discovery of Vitamin A
We can split the discovery of vitamin A into two portions: characterization and structural identification. During the characterization period, researchers worked with vitamin A over approximately 130 years!
The Journey to Characterization
In 1816, François Magendie, considered a pioneer in experimental physiology, conducted nutritional deprivation experiments on dogs. During these experiments, he observed that restricting sugar and water in the dogs’ diet led to the development of corneal ulcers and a higher mortality rate.
Later on, Nikolai Lunin, at the time a doctoral candidate in chemistry at the University of Dorpat in Estonia, found that an unknown substance in milk is essential for nutrition. He experimented with the diet of mice, isolating out known nutrients in milk, like proteins, fats, carbohydrates, salts, and water. Lunin noted that, even with all of these nutrients, mice were still not able to live. This indicated, therefore, that some other unknown substance with crucial nutrients must be present within the milk.
Medical school graduate Wilhelm Stepp sought to take up Lunin’s findings and dig deeper. He eventually proved that Lunin’s unknown substance was fat-soluble! Once again, using mice, Stepp had three separate diets introducing each designed to be “adequate for survival.” He found that all three mice not only survived — they thrived! As a secondary test, he took the food source, milk bread, and extracted it with alcohol. Then, he fed the extracted diet to nine other mice. All of the mice died within three weeks of receiving this new diet. From this study, Stepp concluded that the unknown substance must be fat-soluble, or even the fat itself.
The following year Sir Frederick Gowland Hopkins confirmed these findings, and also determined that the amount of this unknown substance is present in “astonishingly small amounts.” His work eventually led to a Nobel Prize in Physiology in 1929, as well as the renaming of this unknown substance as fat-soluble A, eventually shortened to vitamin A, as we know it today. This wasn’t the end of this vitamin’s journey, though. The secondary step in discovering vitamin A was the determination of its structure.
The Structure of Vitamin A
By this point, scientists knew what vitamin A was, but not what it looked like. Not until 1932, when the structure of vitamin A was described by Professor Paul Karrer, a skilled Swiss organic chemist. Karrer, who worked with plant pigments, found particularly interesting the yellow carotenoid, related to the pigment in carrots. As he worked on elucidating the structures of these carotenoids, Karrer ran into ß-carotene (beta-carotene), which is strong red-orange pigment.
Around this time, significant research was being put into the vitamins, and specifically the relationship between them and carotenoids. This is because some carotenoids are provitamins of vitamins, making them crucial to the production of vitamins. Professor Karrer, through his past work on saffron, knew that carotene typically contains numerous conjugated double bonds within their molecule. He also acknowledged the relationship that had already been confirmed between vitamin A and carotene, as past studies showed that carotene can replace vitamin A in animals, transforming it into vitamin A.
Utilizing these relationships and the previously elucidated structure of ß-carotene, Karrer was able to use chemical degradation and analysis to identify key components. He then synthesized a saturated version of vitamin A and compared it to the degraded product. From there, he was able to posit the structure of vitamin A, officially confirmed in 1950.
Where can vitamin A be found?
Let’s now delve into where vitamin A appears in everyday life! In our food supply, we commonly find vitamin A in the form of retinol and retinyl esters, referred to as preformed vitamin A. For example, this form of vitamin A exists naturally in foods like dairy, fish, poultry, and meat, specifically fattier foods like beef liver, other organ meats, salmon, and cod.
In food sources, vitamin A metabolizes mostly within the small intestine within the gastrointestinal tract. In this process, fat is crucial in facilitating retinoid entry into enterocytes (intestinal cells) from the lumen of the gut. Dietary retinol can move into the enterocyte, but a dietary retinyl ester must first undergo hydrolysis within the lumen to convert it into retinol.
Contrary to preformed vitamin A, vitamin A provitamins convert within the body. Such provitamins are contained in vegetables like carrots, sweet potatoes, mangoes, and cantaloupes, in the form of ß-carotene or other carotenoids. Many dark leafy green vegetables, like broccoli and spinach, also contain carotenoids.
The process of metabolizing provitamin A utilizes the scavenger receptor class B type 1 (SR-BI) for transport into the enterocyte. The provitamin inside the enterocyte, ß-carotene, is cleaved by ß-carotene 15,15′-dioxygenase. Abbreviated as BCO1, this is an enzyme that catalyzes the reaction that transforms ß-carotene into retinal, which binds with the cellular retinol-binding protein. Through cleavage, the retinal is reduced in to retinol, making it indistinguishable from preformed vitamin A! Now, both preformed and provitamin A are free to transport to the liver, where vitamin A is stored.
Synthetic Vitamin A
Vitamin A is also synthesized in industrial and commercial settings. Officially published in 1946, the first industrial synthesis route was published by chemists Jozef Ferdinand Arens and David Adriaan van Dorp. First, starting with a ß-ionone, a modified Reformatsky reaction extends the carbon chain and forms the hydroxy-ester intermediate. Then, this intermediate is dehydrated to form an ester with oxalic acid. After methylation, a ketone forms and undergoes a Grignard reaction, followed by a reduction of the triple bond. Finally, a hydrolysis and reduction result in synthesized retinol! Below is a simplified overview of the Arens–van Dorp synthesis route.
A modified version of this synthesis is still used today, known as the Hoffman–La Roche route. In this route, instead of starting with ß-ionone, we begin with acetone and acetylene. The overall process is very similar to the original, and is one of the most common ways to form vitamin A. Below is a simplified synthesis route to help visualize the process.
What does vitamin A do?
Having discussed how to source vitamin A, let’s talk about what exactly vitamin A’s purpose is. Vitamin A, as mentioned above, is extremely important for human and animal survival! Vitamin A plays a role in regenerating visual pigment, supporting the immune system, and even safe reproduction. It also impacts healthy growth and development, as well as organ functions. Vitamin A serves to maintain and form healthy skeletal structure, soft tissue, mucous membranes, and skin. As we’ll see next, deviating too far above or below the optimal amount of vitamin A intake can cause serious medical issues.
Vitamin A Deficiency and Toxicity
Vitamin A toxicity, or having an excess of vitamin A in one’s system, can result in myriad of issues. Also known as hypervitaminosis A, this condition is most often a result of improper supplement or medicine usage. Hypervitaminosis A is fairly uncommon, but children are more at risk because their smaller body size makes them more vulnerable to high doses of the vitamin.
In acute cases, individuals may experience nausea, vomiting, headache, muscular incoordination, dizziness, blurred vision, and irritability. Chronic cases can result in dry or cracked skin, hair loss, and brittle nails. Additionally hypervitaminosis A can result in fatigue, loss of appetite, and bone and joint pain. At this level, we may also see harmful effects on organs, along with serious bone-related issues.
Contrarily, vitamin A deficiency can also have negative impacts on one’s health. Again, vitamin A deficiency mainly impacts children, specifically in developing countries where they may lack access to a well-rounded diet. However, pregnancy and lactation also puts one at risk for vitamin A deficiency.
Symptoms of vitamin A deficiency include dry skin, delayed growth in children, chest and throat infections, and even infertility issues. Left unchecked, deficiency can lead to blindness. This is due to vitamin A’s vital role in maintaining the healthy functioning of rods, a cell type found within the eye.
Conclusion
Over 100 years of research inform what we know about vitamin A’s necessity to life. For instance, we know that there is a delicate balance to the amount of vitamin A that enables crucial body and organ functions to proceed smoothly. This vitamin plays a huge role not only in the nutrition industry, but also in the skincare industry. As science continues to advance, there is promise in gaining a better understanding of the mechanism of vitamin A in the body and improving the synthesis of its artificial forms.
