THE B VITAMINS
Vitamin B is a group of 8 different water-soluble vitamins: B1, B2, B3, B5, B6, B7, B9 and B12. These vitamins are very much interconnected in terms of their functions in the body: They play very important roles as coenzymes for various enzymes in the body – for example in energy metabolism, the immune system, and the nervous system and several of them are also important for DNA synthesis and DNA reconstruction.
Many studies have been done with the various B vitamins – especially B6, B9 and B12, but much is not yet known – for example, what the optimal intake of each of the vitamins is. Since they are part of very complex systems in the body and are interconnected, it can be difficult to study them individually. They are generally found in many foods, so deficiency is not often seen in countries with a good and varied food supply. As supplements, they are often found in the form of B vitamin complex, where all or more of them are included.
In relation to the skin, the B vitamins – as in the rest of the body – have important functions, but usually only some of them are used in cosmetics: Primarily B3 in the form of Niacinamide and B5 in the form of Panthenol and to a lesser extent B7 in the form of Biotin and B12 in the form of Cyanocobalamin.
PUCA - PURE & CARE anvender D-Panthenol og Niacinamide i flere af sine produkter.
Produkter med VITAMIN B
B1, B2, B3, B5, B6, B7, B9 og B12 – funktioner og systemer i kroppen
The B vitamins were discovered in the years between 1910 and 1937 – the first to be discovered was B1. A number of other substances were also discovered in addition to the current 8 B vitamins, which at the time were thought to be vitamins and therefore they were assigned a number in the series. It has since been shown that these substances did not meet the requirements to be classified as a vitamin (a vital micronutrient that the body cannot produce itself at all or to a sufficient degree) and therefore today there are "gaps" in the number series.
De 8 B vitaminer er kemisk meget forskellige stoffer – og flere af dem forekommer i forskellige former, som kroppen generelt er god til at omdanne. Nogle af dem betegnes oftest ved deres B-nummer – fx B12 (Cobalamin), mens andre oftest betegnes med deres almindelige navn – fx Biotin (B7). Fælles for dem er at de alle er vandopløselige og indbyrdes forbundet i deres funktioner i kroppen, hvor de er coenzymer. Da de er vandopløselige mikronæringsstoffer, bliver de normalt relativt let udskilt via urinen, så der er generelt ikke risiko for overdosis. De sjældne bivirkninger man har registreret ved kosttilskud og/eller injektioner meget høje doser over lang tid, er generelt reversible.
Deficiency is usually not seen in countries with a well-functioning and versatile food supply, but malnutrition does occur in countries with a lack thereof. There is also some research that suggests that it may occur in richer countries due to overprocessed food, where the vitamins have been broken down during processing. In some countries, therefore, there are rules or recommendations for, for example, enriching wheat flour, corn flour and rice with some of the B vitamins.
The B vitamins are produced primarily by plants and certain microorganisms. Most of them are found in legumes, whole grains, vegetables, and fruits, but in relation to food they are found in the highest concentration in meat, eggs and dairy products, as they have been concentrated here through the food chain. In this context, B12 is a bit special as it is not found in many plant products, which is why vegetarians and vegans may need supplements of this B vitamin. Some other groups that may need a supplement of the B vitamins are older and very active people, due to poorer absorption in the body and very high consumption in the body's energy metabolism, respectively. A very large alcohol intake can also be inhibitory to the absorption and effect of several of the B vitamins in the body, so deficiency conditions can occur with alcohol addicts. Finally, pregnant and lactating women generally have a greater need for the B vitamins, and B9 (folic acid) is especially recommended for pregnant women and people planning to become pregnant, as deficiency in the early fetal stage has been proven to be associated with neural tube defects.
In order to appreciate how important the B vitamins are for the body, it is necessary to know a little about how the body works biochemically. It is a very comprehensive topic, because the body is an extremely complex network of many biochemical pathways, cycles and patterns that affect each other. Metabolism is the term for the biochemical processes that break down what we consume into usable substances and energy, convert it into substances that need to be used and ensure that what the body does not need can be excreted*. It really requires many different chemical processes to handle all the different substances that you ingest through the mouth and airways – and the vast majority of these chemical reactions are regulated and catalyzed by enzymes. Therefore, enzymes are crucial for the maintenance of life.
Many enzymes need a cofactor (excipient) to function optimally. Such cofactors can be divided into small inorganic ions and more complex organic substances, which are called coenzymes – among these are the B vitamins. Thus, the B vitamins are necessary for a lot of enzymes to function as they help to convert substances in the body to e.g. energy, hormones, DNA, RNA, neurotransmitters and substances for the immune system and cell division. In this way, the B vitamins influence many functions in the body – especially the vital energy supply to each cell. The absence of the various B vitamins can cause very different symptoms such as fatigue, muscle weakness, skin lesions, mental confusion, balance problems, sensitive skin to the sun, hair loss, dementia, and anemia. Some of these symptoms are related to the brain and nervous system, which is not so strange, as the brain is the organ in the body that has the highest metabolic activity – the brain makes up approx. 2% of the body's weight, but accounts for over 20% of the body's total energy consumption. The importance of the B vitamins for the brain is also seen in the fact that they all have special transport mechanisms across the blood-brain barrier and there is a higher concentration in the brain than, for example, in the blood.
Ud over at være coenzymer er nogle af B vitaminerne også udgangsstoffer for dannelse af andre vigtige stoffer – fx B5 (Pantotensyre) som er forløber for det vigtige stof coenzym A (CoA). Dette stof er bl.a. vigtig i syntesen og oxidation af fedtsyrer og spiller en vigtig rolle i reaktionsmønstret kaldet citronsyrecyklussen eller krebs cyklus, som er kroppens centrale reaktionsmønster til energiudnyttelse af stoffer fra både kulhydrater, fedt og proteiner – dette foregår inde i mitokondrierne i alle kroppens celler. Kort fortalt omdannes kulhydrater, fedt og proteiner via en række enzymprocesser (flere af dem med B vitaminer som coenzymer) til stoffer som kan indgå i citronsyrecyklussen – primært Acetyl coenzym A, som via denne cyklus af reaktioner omdannes til andre stoffer. Reaktionerne i citronsyrecyklussen katalyseres af 8 forskellige enzymer (igen med B vitaminer som coenzymer i nogle af dem) og undervejs frigives elektroner i form af stofferne NADH** og FADH2***. Også her er B vitaminerne centrale da disse to stoffer indeholder henholdsvis B3 (Niacin) og B2 (Riboflavin) vitaminerne. NADH og FADH2 transporterer elektronerne over til en anden særlig reaktionsproces, kaldet elektrontransportkæden eller respirationskæden, som foregår over den indre membran i mitokondrierne inde i cellerne. Denne proces involverer Coenzym Q, Cytochrom C og fem særlige proteinkomplekser, som bruger elektronerne fra NADH og FADH2 og oxygen til at pumpe protoner (H+) over den indre membran, hvilket giver en elektrokemisk protongradient (og danner vand). Denne gradient driver det sidste proteinkompleks i kæden til at producere ATP**** – kroppens energi-valuta. Både dyr og planter har netop dette molekyle, ATP som deres energi-valuta, som bruges til alle energikrævende processer – fx muskelbevægelser, nerveimpulser og DNA-syntese. Citronsyrecyklussen og elektrontransportkæden er blot to af mange reaktionsmønstre som involverer B vitaminerne, man kunne også nævne folat-cyklus og den koblede methionin-cyklus, som fx er centrale for DNA- og RNA-syntesen og regulering – her er B9 (Folat) og B12 (Cobalamin) centrale komponenter. Der er kort sagt rigtig mange reaktionsmønster i kroppen, som er forbundet på forskellige måder – nogle af de centrale har behov for B vitaminerne.
Although it has been many years since the B vitamins were discovered, much is still not known about this complex group of substances. For instance, it’s difficult to determine what the optimal dose is for each of them, because many factors play a role in, for example, the uptake and the utilization of nutrients. Dosage recommendations are slightly different in different countries and age groups – the recommendations given here are approximate values for adults.
I det følgende vil hver af de 8 B vitaminer blive beskrevet – med lidt mere fokus på dem, som normalt bruges i kosmetik – det skal dog siges at alle 8 B vitaminer i dag er lovlige at bruge i kosmetik i EU.
* En illustration af hvor kompleks metabolismen er kan ses her: https://upload.wikimedia.org/wikipedia/commons/a/a8/Human_Metabolism_-_Pathways.jpg
** NADH is an abbreviation for Nicotinamide Adenine Dinucleotide, which can carry electrons via Hydrogen.
*** FADH2 er den reducerede form af Flavin Adenine Dinucleotide (FAD), som bærer elektroner via Hydrogen
**** ATP står for AdenosinTriPhosphat.
The recommended daily dose for B1 is approx. 1.1 mg/day for adults – slightly higher for pregnant and lactating women. In Europe, the recommendation is calculated based on how much energy you consume: 0.1 mg per megajoule. For B1, no UL (Upper Limit) – max oral dose – has been calculated as there is not enough data and it has been evaluated that it is not necessary because B1 is very safe to ingest. Allergic reaction and nausea have only been observed after injection of very high doses of B1.
Deficiency of B1 can start with non-specific symptoms such as fatigue, poorer memories, sleep disorders and constipation and develop into the disease Beriberi, with symptoms like muscle weakness, high blood pressure, mental confusion, heart rhythm disorders and a particular form of dementia. In addition, skin lesions, itching, rashes, and inflammation may occur. Alcoholism can result in B1 deficiency; It has been found that up to 80% of alcohol abusers lack B1 due to impaired nutrient intake, reduced absorption of B1 and impaired utilization in the cells.
Good sources of B1 are e.g. whole grains, legumes, some meat (e.g. pork), fish, dairy products, nuts and green vegetables. In some countries such as some African countries and India, foods like wheat flour, rice and corn flour are enriched with B1 as it is easily degraded during processing. In food sources, B1 is found, for example, in the form of Thiamin phosphate esters, which are easily hydrolyzed in the intestine to Thiamin, which is taken up over the intestinal wall. In the blood and cells, much of it is bound to proteins. You have a small stock of B1 of about 25-30 mg, which is primarily located in muscles, heart, brain, liver, and kidneys – this means that if you suddenly stop taking B1, deficiency symptoms will only come after 2-3 weeks for adults.
In the body, B1 is found both in the form of Thiamin and in various phosphorylated forms – e.g. the primary active form, which is Thiamin Pyrophosphate (TPP). TTP acts as a coenzyme, for example for the enzyme, which converts pyruvate to Acetyl Coenzyme A. Acetyl Coenzyme A is the input molecule for the citric acid cycle and also an important molecule in the synthesis of fatty acids, steroids and the neurotransmitter Acetylcholine. In addition, TPP is also a coenzyme for enzymes involved in the metabolism of carbohydrates, fats and proteins and one of the enzymes in the citric acid cycle. B1 also has a role in membrane structures and synapse formation in the nervous system and in cellular differentiation.
Thiamine is a colorless water-soluble substance that decomposes in alkaline conditions and at high temperatures. The structural formula is shown in Figure 1, which shows that it is a relatively small molecule with two ring structures containing both nitrogen and sulfur. It is biosynthesized, for example, by bacteria and some protozoa, plants and fungi. Industrially, B1 and derivatives are synthesized and sold as medicines or supplements. It is not used very much in cosmetics. It has been said that Thiamin should be able to act as an insect repellent, but it has been concluded in a major review that this is not the case. However, it cannot be ruled out that Thiamine can reduce subjective symptoms due to insect bites.
Figure 1: B1 – Thiamine
The recommended daily dose of B2, which has previously been called Vitamin G, is approx. 1.4 mg/day for adults – slightly higher for pregnant and lactating women. No UL (Upper Limit) has been calculated, as not enough sufficient data is available, and it is not found to be necessary because B2 is very safe to ingest. It has only been observed that very high doses can cause abdominal pain and diarrhea.
Deficiency of B2 is rare and usually accompanied by a deficiency of other vitamins and nutrients – people at risk of deficiency are alcohol addicts, vegetarians and people who are very physically active. The deficiency condition is called ariboflavinosis, which manifests itself in, for example, lesions in the mouth or lips, inflammation of the mucous membranes of the mouth, sore throat, hair loss, inflammation of the skin and increased sensitivity to sunlight. It has also been seen that deficiency can inhibit the metabolism of minerals and iron, which is important for the production of hemoglobin and red blood cells, for example.
Good sources of B2 are, for example, meat, fish, poultry, eggs, dairy products, legumes, green vegetables, mushrooms, wild rice and almonds. As for B1, there are some countries in Africa, America and India where, for example, wheat flour and corn flour are enriched with B2. In foods, B2 is primarily protein-bound and is released via enzyme reactions before being absorbed across the gut.
I kroppen findes B2 i form af Riboflavin og de to aktive former er FAD* of FMN**. Dvs Riboflavin er precursor for FMN og FAD, som begge er vigtige coenzymer fx i energiproduktionen og som kroppen kan omdanne til hinanden efter behov. B2 er involveret i citronsyrecyklussen i form af FAD som transporterer elektroner til elektrontransportkæden for at danne ATP. Det er også involveret i flere reaktionstrin som finder sted før citronsyrecyklussen i omsætningen af proteiner og fedt og i aktiveringen af andre vitaminer (fx B3, B6 og B9) og i dannelsen af det meget vigtige antioxidant Glutathion og dannelsen af antistoffer – omkring 70-80 enzym-reaktioner i mennesket understøttes af B2-deriverede coenzymer. På den måde er B2 vigtigt for fx immunforsvaret og dannelsen af energi som er grundlæggende for alle cellerne. Desuden har B2 en antioxidativ og antiinflammatorisk funktion og er involveret i bibeholde en normal niveau af homocystein – en aminosyre, som ved høje niveauer indikerer forhøjet risiko for hjerte-kar-sygdom og derfor bruges som markør dertil.
Several animal experiments suggest that B2 can also affect pain experiences, and some suggest that in combination with other drugs it can reduce migraine attacks – however, there are not many studies with people regarding this possible property. It is excreted in the urine and gives the urine the yellow color.
Riboflavin er i ren form et vandopløseligt, gul-orange fast stof med en svag lugt og en bitter smag. Det er rimelig varmestabil, men det nedbrydes af sollys og bliver da en pro-oxidant (fotosensibilisator), således at det kan gøre skade på det væv det er i kontakt med. Det er derfor relevant at medtage antioxidanter, hvis Riboflavin skal anvendes i en form i lys – eller beskytte Riboflavin på en måde, såsom ved indkapsling. Figur 2 viser strukturen af Riboflavin, som er et relativt lille molekyle med tre ringstrukturer og en sidekæde. Biosyntesen af Riboflavin finder sted i bakterier, svampe og planter. Industrielt fremstilles det i dag især ved fermenteringsmetoder, hvor man bruger visse svampe-arter eller GMO-bakterier. Det bruges til medicin, kosttilskud og som tilsætningsstof i fødevarer (E101) – bl.a. til at give farve til fødevarer. Desuden har et dyreforsøg vist, at Riboflavin kan reducere histamin-induceret*** kløe – ved oralt indtag. Riboflavin bruges ikke særlig meget i kosmetik, men er fx tilladt som farvestof.
Figure 2: B2 – Riboflavin
* FAD står for Flavin Adenine Dinucleotide
** FMN is the abbreviation Flavin MonoNucleotide
*** Histamin er en at det bedst kendte mediatorer af proinflammation i huden fx ved insektbid og er det primære endogene kløe-inducerende stof.
The recommended daily dose of B3 is 11-16 mg/day for adults and a UL has been set – a max oral dose of 35 mg/day – mostly based on the fact that B3 can cause a temporary redness in the skin if more than 100 mg is ingested. However, cases of nausea, vomiting, headache, itchy and burning sensation in the skin as well as diarrhea and in very rare cases liver damage at very high doses above 1000 mg have also been observed.
The body can produce B3 from the essential amino acid tryptophan in the liver, but generally not to a sufficient degree and therefore B3 is categorized as a vitamin and food is the primary source of B3. Lack of B3 (and tryptophan) causes the disease pellagra, which was discovered in 1937 – this is why the compound previously was named vitamin PP, which stood for "Pellagra Preventive". The most visible symptoms are hyperpigmentation, eczema, and inflammation of the skin – primarily on sun-exposed areas. Other symptoms include diarrhea, inflammation of the mouth, aggression, weakness, mental confusion, difficulty concentrating, sleep problems and dementia. Severe deficiency can result in death.
Good sources of B3 are, for example, meat, fish such as tuna and salmon, poultry, nuts, legumes, vegetables, whole grains and seeds. In some countries, foods such as wheat flour are enriched with B3 or a B3 derivative. Vitamin B3 is Niacin, which is often called Nicotinic Acid. The most common derivative, which is often the substance used (e.g. in cosmetics and supplements) is Nicotinamide, which is also called Niacinamide. Chemically, the substances are very similar – the only difference is that the OH group in Niacin has been replaced by an NH2 group in Niacinamide (see Figure 3). The body can utilize Niacin and Niacinamide equally, but Niacinamide does not have the same effect in relation to the fact that Niacin has been shown to modify the lipid balance in the body and does not give the same side effects at high doses – such as flushing of the skin.
B3 is found in the body in the form of Niacin and Niacinamide – and these are precursors to the coenzymes: NAD+ and NADP+* – i.e. Niacinamide is part of the chemical structure of NAD+ and NADP+. These coenzymes are important in over 40 redox reaction processes, which take place in all cells in the body. They are found in this oxidized form and in their reduced forms – NADH and NADPH, where they carry a Hydrogen atom with associated electrons which can be passed on in other reactions such as in the electron transport chain and thus act as a form of energy transport and storage. NAD+/NADH is primarily involved in the breakdown of carbohydrates, proteins, alcohol and lipids and in the citric acid cycle, while NADP+/NADPH is more involved in the constructive reactions of e.g. fatty acids and cholesterol (which is an important part of steroid hormones) and in the (re)activation of the important antioxidant Glutathione. In addition, they are involved in DNA repair reactions and in the formation of components for the immune system and have anti-inflammatory properties. As they are generally very important for energy metabolism, it is especially areas in the body with a very high energy consumption and high cell turnover that are affected by deficiency: the brain, intestines, and skin.
Both Niacin and Niacinamide are absorbed easily and quickly from the stomach and small intestine and unlike many other vitamins, the uptake is not reduced with increasing dose, so even doses of 3 g grams are absorbed almost completely. Niacinamide is the primary form in the blood, and this is converted in the liver to NAD+, which can then be converted to NADP+ – and these can be hydrolyzed back to Niacinamide and Niacin. Like the other B vitamins, B3 is excreted primarily in the urine.
In nature, B3 is biosynthesized in both plants and animals – also most often from the amino acid Tryptophan, although some organisms can use other molecules as starting material. Industrially, Niacin and Niacinamide can be chemically synthesized via various reaction pathways.
Niacin and Niacinamide are relatively small water-soluble molecules, which in pure form are colorless, solids and not particularly heat stable. It is most often Niacinamide that is used in both medicine, dietary supplements and in cosmetics, as Niacin can dilate the blood vessels and thereby give an unintended flushing of the skin, which is reversible.
I forhold til huden er Niacinamide nok det B-vitamin, som bruges allermest i kosmetik og med god grund – det har mange veldokumenterede og positive egenskaber i huden og det har været anvendt i kosmetik i over 50 år med kun meget få rapporter om bivirkninger, så det er både virksomt og meget sikkert at bruge i kosmetik. I kosmetik anvendes normalt 2-5 % Niacinamide for at have effekt og det er også de niveauer man har brugt i de fleste studier. Man har vist, at Niacinamide kan absorberes – både i in vitro forsøg med en såkaldt Franz diffusion cell (som er en meget anvendt metode til at vurdere hudgennemtrængelighed) og in vivo ved at måle at NADPH øges i huden efter påsmøring. Man har desuden påvist at niveauet af NADH og NADPH i huden falder med alderen. Det er ikke helt klarlagt om Niacinamide omdannes i huden til Niacin og det er muligt at Niacin har nogle flere virkninger, men den uønskede rødme-effekt gør at Niacin ikke er særlig egnet til kosmetik og langt de fleste studer er udført med Niacinamide. Studierne har bl.a. vist at Niacinamide kan have en positiv effekt i forhold til akne, rynker, pigmentpletter og styrke hudbarrieren. Derudover har Niacinamide også været med i studier omkring sårheling og hudsygdomme som cancer, psoriasis og rosacea. Man kender ikke i detaljer alle mekanismerne bag de mange gode egenskaber, men sandsynligvis spiller den fundamentale rolle af Niacinamide som precursor for NAD(H) og NADP(H) en signifikant rolle i mange af dens egenskaber for kroppen og huden. Man har påvist, at NADPH har en antioxidativ virkning, hvilket har indflydelse på flere aspekter i kroppen og huden – fx kollagenstatus – og det er kendt at oxidativ stress spiller en vigtig rolle i mange forskelle hudproblemer og sygdomme. I det følgende vil mange af Niacinamides kosmetiske og dermatologiske interessante egenskaber blive præsenteret.
Improving the skin barrier: The skin barrier is fundamental to a functional skin; a poor skin barrier can contribute to several different skin problems such as sensitive skin, eczema, dry skin and contact allergy. Therefore, an improvement in the skin barrier can prevent and reduce such problems. It has been shown that Niacinamide can improve the skin barrier by upregulating the synthesis of ceramides and other important intercellular lipids such as fatty acids and cholesterol in the skin. For example, a placebo-controlled in vivo study has shown that when using a topical product containing 2% Niacinamide for 4 weeks, the amount of ceramides and free fatty acids in the upper layer of the skin (stratum corneum) increased significantly compared to the same topical formulation without Niacinamide (placebo). The scientists could also measure a clear reduction in TEWL**, which is a measure of how much water evaporates from the skin and thus a measure of the skin barrier. Another way that Niacinamide improves the skin barrier is by stimulating keratinocyte differentiation and thereby increasing the epidermal turnover. Finally, it is seen that Niacinamide can increase the thickness and moisture capacity of the stratum corneum, which also contributes to an improved skin barrier.
Reduction of acne and skin inflammation: Niacinamide can regulate the formation of lipids (sebum) in the sebaceous glands and has a potent anti-inflammatory effect, which are two important factors in the development of acne. Several in vivo experiments have been performed with topical products containing 2-5% Niacinamide for 4-8 weeks, which have shown a positive effect on acne. In vitro, Niacinamide has been shown to inhibit the synthesis of inflammatory mediators such as prostaglandins and interleukin-8 in keratinocytes and in skin models irradiated with UV light. In a clinical in vivo trial it has been shown that 5% Niacinamide applied to the skin before UV irradiation reduces the redness (inflammation) that would otherwise be induced.
Reduce pigmentation: Melanin is a group of substances that give color to the skin and protect against the sun's rays. They are produced in the melanocytes and from there via so-called melanosomes transferred to keratinocytes. Studies suggest that Niacinamide inhibits this transfer and thereby reduces the pigmentation of the skin. Several in vivo experiments have been made with topical products containing 5% Niacinamide over 4-12 weeks, which gives a significant reduction in the area of pigment spots and clarity – and furthermore improves the structure of the skin. For example, a placebo-controlled study of 50 people with sun-damaged skin showed that applying a topical product with 5% Niacinamide for 12 weeks had a number of positive effects on the skin: It reduced fine lines, wrinkles and pigment spots and improved skin elasticity. The reduction of pigment spots appears to be dose-dependent and reversible.
Reduction of yellowing of the skin, which can come with age: Yellowing of the skin may be due to a series of spontaneous oxidative reactions between proteins and sugar molecules – called Millard reactions or protein glycation. This results in cross-linked proteins which can accumulate in the skin matrix and give a yellowish color. It is believed that it is the antioxidant properties of Niacinamide or the derivatives NAD+ and NADP+ that enable Niacinamide to inhibit this yellowing of the skin, as it occurs due to oxidative stress.
Reducere rynker og fine linier og forbedrer hudens elasticitet: Rynker og fine linjer opstår især som følge af mindre fugt i huden, tyndere hud og pga. reduktion af vigtige dermale komponenter så som collagen, elastik og andre proteiner i huden. In vitro har man vist at Niacinamide som precursor for NAD+ og NADP+ stimulerer hudens syntese af kollagen, keratin, fillagin og involucrin. Det er bekræftet in vivo at Niacinamide øger udtrykket af kollagen (type I, III og V), elastin og fibrillin (1 og 2) og reducer nogle af metalloproteinaser (MMP 1, 3 og 9) og elastase, som er enzymer, der nedbryder hhv kollagne og elastin i huden – både i hud som ikke blev UV-bestråling og hud, som blev udsat for UVA-bestråling. Flere placebo-kontrollerede in vivo studier med Niacinamide i koncentrationer på 2,5-5% har vist at kunne reducere rynker og fine linjer og forbedre hudens elasticitet.
Figure 3: B3 – Niacin
* NAD+ står for Nicotinamide Adenine Dinucleotide. NADP+ står for Nicotinamide Adenine Dinucleotide Phosphate.
** TEWL står for Trans Epidermal Water Loss
The recommended daily dose of B5 is 5 mg/day for adults and slightly higher for breast-feeding women. No UL has been set as it is a very safe compound to ingest, also in high quantities. B5 deficiency is very rare, but can cause symptoms such as fatigue, lethargy, nausea, acne, sensory disturbances and muscle cramps – all reversible symptoms. Vitamin B5 is one substance: Pantothenic acid – the name comes from the Greek "Pantos" which means "from everywhere" as this substance is found (in small amounts) in almost all foods.
Good sources of B5 are, for example, dairy products, eggs, fish, potatoes, tomatoes, whole grains, sunflower seeds, avocados and mushrooms. As with the other B vitamins, there is usually not much left of this vitamin after processing wheat into wheat flour and rice into rice flour – especially not if the outer layer of the grain has been removed. However, since it is found in so many foods, deficiency is very rare and therefore there is no requirement for food enrichment in any countries.
In the body, B5 is the precursor to the very important coenzyme A – often abbreviated CoA. As mentioned, CoA is essential in many reactions in, for example, the metabolism of fats, proteins and carbohydrates and in the form of Acetyl CoA it is also directly involved in the citric acid cycle and is thus an important source of energy. Acetyl CoA is also involved in the biosynthesis of e.g. steroid hormones, phospholipids, the hormone melatonin and the neurotransmitter acetylcholine. In this way, B5 is very important for the body in many aspects. In foods, B5 is found primarily in the form of CoA or bound to proteins. In the intestines, B5 is released, after which it can be absorbed over the intestine and can be included in the biosynthesis of CoA. B5 is not stored in the body and like the other B vitamins it is excreted primarily via the urine.
In nature, B5 is biosynthesized in plants and some bacteria from e.g. the amino acids Aspartate and Valine. Industrially, B5 can be produced via chemical synthesis, and it can also be isolated from bacteria. Pantothenic acid (B5) is in pure form slightly yellowish crystals without fragrance and is not very stable to acid, base or heat – it is a relatively small molecule; see the structural form in Figure 4. Therefore, more stable derivatives such as Calcium Pantothenate and the alcohol derivative Panthenol, which the body can convert to Pantothenic acid, are often used. B5 is included in both medicine, dietary supplements and cosmetics.
In relation to cosmetics, it is usually Panthenol* that is used, and many studies have been done with this substance, which show positive properties in relation to use on the skin. 1-5% Panthenol is typically used in products for the skin and studies have shown that the substance can be absorbed relatively quickly into the skin and can be converted to pantothenic acid. The substance is hygroscopic, which means that it can bind water to itself and is thus good at retaining moisture in the skin and absorbing moisture to the skin. The moisture in the skin plays a crucial role for the skin's many physiological and mechanical properties and for the appearance of the skin. Studies have also shown that Panthenol can, for example, improve the skin barrier, stimulate wound healing, reduce skin irritation, and have anti-inflammatory properties. Mechanisms of action behind all these properties have not been fully elucidated, but some of them are because Panthenol (B5 derivative) is a precursor to Coenzyme A (CoA). Panthenol is also a very safe and mild substance and has, for example, been used on sensitive skin, eczema skin and small children with irritation in the diaper area without giving any kind of irritation – on the contrary with positive results. A study has also shown that Panthenol does not adversely affect the skin microbiota.
En dårlig hudbarriere og manglende fugt i huden spiller en vigtig rolle i mange hudproblemer og derved kan et stof som Panthenol have en positiv effekt på flere forskellige hudproblemer og på rask hud ved at forbedre og opretholde en god hudbarriere og fugtigheden. En mulig mekanisme bag – ud over den hygroskopiske egenskab – er at CoA medvirker i syntesen af lipider som er vigtige komponenter i hudens yderste lag (stratum corneum) og hudbarrieren og muligvis ved at fremmer den epidermale differentiering, hvilket også er vigtigt i forbindelse med sårheling. Både in vitro og In vivo forsøgt har vist, at Panthenol (5 %) fremmer sårheling. Ligeså har flere in vivo forsøg på forskellige slags skadet hud med 2,5-5 % Panthenol i 7-28 dage vist signifikant forbedring på hudens fugtighed og barrieren. Et studie med rask hud har fx vist at hudens tolerance overfor irritanter blev øget – formodentlig ved at bibeholde en god barriere og fugtighed i huden. Panthenol har været brugt med succes i topikale produkter i over 70 år.
Figure 4: B5 – Pantothenic acid
* Pantotensyre og dens derivater såsom Panthenol findes i to forskellige rummelige strukturer, som ofte har præfikset ”D” (står for ”dexter”) eller ”L” (står for ”laevus”). Det er D-versionerne som er biologisk aktive. Derfor anvendes ordet ”Dexpanthenol” nogle gange, når det er den rene D-panthenol, der er tale om.
- PYRIDOXINE, PYRIDOXAL OG PYRIDOXAMINE
The recommended daily dose of B6 is approx. 1.5 mg/day for adults and slightly higher for pregnant, breastfeeding women and the elderly, as B6 uptake generally decreases with age. In addition, the need for B6 is increased by a large intake of alcohol and protein. A UL of 100 mg/day has been set, which is based on reports of reversible sensory neuropathy following ingestion of more than 1000 mg/day for a longer period. Some studies suggest that a significant portion of the earth's population does not receive the recommended amount.
B6 deficiency can, for example, cause eczema, anemia, confusion, depression, a weaker immune system and elevated levels of the amino acid homocysteine in the blood, which is associated with cardiovascular disease. In addition, deficiency is associated with a variety of diseases such as diabetes, cardiovascular disease, cancer, and inflammation in the body. Conversely, for example, a clear relationship has also been seen with B6 intake and incidence of cancer in the form of the higher the intake the lower the incidence of cancer – the strongest correlation was seen with gastrointestinal cancer. However, it is not entirely clear whether B6 directly inhibits cancer or whether B6 is just a marker for healthy eating and other factors are actually the inhibitors of cancer.
Too high doses can cause headaches, numbness, and fatigue and some suggest that it can generate dangerous substances by UV radiation and cause neurological damage. Animal experiments point to an interaction between B6 and UV radiation, which may be responsible for a higher risk of skin cancer.
Good sources of B6 are e.g. fish, legumes, poultry, cereals and some fruits and vegetables.
B6 is not one single substance, but a group of 3 chemically related molecules: Pyridoxine, Pyridoxal Pyridoxamine (see the structures in Figure 5) and their phosphorylated derivative, which are biologically more active substances – of which the phosphorylated form of Pyridoxal, Pyridoxal 5'- phosphate, is the biologically most active form of B6. The body can convert the 6 forms into each other and thus from e.g. Pyridoxine, which is especially found in foods and supplements e.g. form the most active version, Pyridoxal 5 'phosphate.
In the body, B6 – primarily in the form of Pyridoxal 5 'phosphate – is a very important coenzyme for a number of enzymes; about 150 biochemical reactions need B6. Many of these reactions are related to the degradation of proteins as well as the biosynthesis and degradation of amino acids and neurotransmitters such as serotonin, dopamine, norepinephrine and melatonin. In addition, B6 is also involved in the metabolism of carbohydrates and fats and in the formation of hemoglobin, certain antibodies and hormones. So, the importance of B6 is not to be overlooked and research is being done on whether B6 and the enzymes it is coenzyme for can be targets for the treatment of various diseases - e.g., malaria, cancer, high blood pressure and diabetes. In addition to being a coenzyme, B6 is also an antioxidant that, for example, can inhibit lipid peroxidation with potency similar to Vitamin E. It has also been shown that B6 can inhibit the formation of Advanced Glycation Endproducts (AGE) and Advanced Lipoxygenation Endproducts (ALE), both of which are related to oxidative stress. These can accumulate and in the long run be harmful to various tissues in the body such as the heart, nerves, eyes and kidneys - it has also been seen that AGE accumulation in the skin is associated with aging of the skin.
B6 bliver biosyntetiseret i visse bakterier og gærceller, mens de fleste dyr inklusiv mennesket ikke kan og er dermed afhængig af at indtage det via maden. Nogle tarmbakterier kan danne B6, men ikke i tilstrækkelig grad. Industrielt kan B6 stofferne fremstilles ved kemisk syntese – de bruges fx i kosttilskud og i medicinsk øjemed til at forebygge mangel og fx også ved særlige typer af svampeforgiftning. B6 er ikke anvendt i særlige høj grad i kosmetik. Der er ikke helt klarhed om det har positive egenskaber ved topikal brug og desuden tyder noget på, at det kan være skadelig ved UV-bestråling.
Figure 5: B6 – Pyridoxine, Pyridoxal and Pyridoxamine
The recommended daily dose of B7, previously called Vitamin H, is approx. 30-40 µg/day for adults – a little higher for pregnant and breastfeeding women. Alcohol, some medications as well as certain congenital mutations in genes that are involved in the utilization of B7 may increase the need for B7. There is no UL – max oral dose, as there is no sufficient data to suggest that it is dangerous even at very high levels. A normal balanced diet usually covers the need for B7; therefore deficiency is very rare. Symptoms of deficiency are hair loss, weak nails, eczema, balance problems, cramps, lethargy, eye inflammation and depression.
Gode kilder til B7 er fx nødder, bønner, frø, lever, fuldkorn, laks, gær og æg (dog ikke rå æg da æggehviden indeholder proteinet avidin, som binder biotin og dermed forhindre optagelsen over tarmen). I fødevarer er B7 bundet til proteiner, hvorfra det bliver frigivet af enzymer i tarmen, således at Biotin-molekylet kan blive optages over primært tyndtarmen. Optagelsen er meget effektiv; så selv meget høje indtag af B7 bliver optaget over tarmen. Desuden findes der bakterier i tyktarmen som biosyntetiserer B7. Det er estimeret at disse bakterier producerer ca lige så meget B7 som en normalt kost indeholder, men det er ukendt hvor meget af denne B7-mængde som optages i kroppen. Fra tarmen kommer det med blodet til leveren. Optaget i leveren er afhængig af et bestemt transportør-protein, som også binder og transportere B5, hvilket vil sige at B5 og B7 konkurrer om pladsen i dette protein og dermed kan påvirke hinandens optag i leveren. Fra leveren bliver det via blodkarrene fordelt ud til alle kroppens væv. Udskillelse fra kroppen sker primært via urinen.
In the body Biotin is coenzyme for 5 carboxylase enzymes, which play key roles in the metabolism of both fats, carbohydrates and proteins – for example in the formation of sugar molecules from pyruvate and amino acids, the biosynthesis of fats and the formation of proteins such as keratin. Keratin is the main component in e.g. hair and nails, which is why Biotin deficiency is linked to hair and nail growth. In addition, Biotin can bind to specific proteins that affect the transcription of genes.
B7 biosyntetiseres af planter og bakterier. Industrielt bliver det primært fremstillet ved kemisk syntese. Det er et relativt lille molekyle – se Figur 6. I ren form er det et hvidt eller farveløst, vandopløseligt pulver, som er rimelig varmestabilt. Det bruges især i kosttilskud og desuden fx i medicin, bioteknologiske metoder til fx at isolere proteiner og også lidt i kosmetik. Formålet i kosttilskud og kosmetik er ofte at styrke hår og negle, men der er ikke klar evidens for dens virkning. Der er især lavet studier med Biotin som kosttilskud, der dog tyder på at det statistisk set ikke har nogen reel virkning for raske personer –nogle studier viser, at personer, som har en form for sygdom, der gør at de ikke udnytter Biotin godt nok, kan have en positiv virkning på hår og negle af at tage biotin som kosttilskud.
Figure 6: B7 – Biotin
- FOLATE (FOLIC ACID)
B9, formerly called Vitamin M, has a recommended daily dose of approx. 400 µg/day for adults – 600/500 µg/day for pregnant and lactating women respectively. UL - max oral dose - is set to be 1000 µm/day for adults; this applies to dietary supplements, as it has been assessed that there is no risk of high intake via the diet. The reason for the UL is because very high doses can hide a deficiency of vitamin B12, which can cause a form of anemia. Deficiency of B9 can also result in anemia however, as well as symptoms such as fatigue, shortness of breath, sores on the tongue, change in the color of the skin and hair, elevated levels of homocysteine, diarrhea and depression. Deficiency in pregnant women can cause birth defects such as neural tube defects. In addition, B9 deficiency has been linked to an increased risk of a number of cancers.
Good sources of B9 are, for example, asparagus, spinach, broccoli, nuts, lentils, chickpeas, milk and offal such as chicken livers. In several countries, there are requirements or proposals to enrich foods with B9 – such as wheat flour, corn flour and rice. B9 is the most common fortified vitamin. The reason is in particular that B9 is relatively unstable, and several studies have shown that part of the earth's population does not receive the recommended dose.
The term B9 is usually used for Folate (Folic acid) – shown in Figure 7 – but is also often used for very similar substances, which are often called folates - e.g. folacin, and folic acid and are the active and primary forms in the body. "Folate" is sometimes used a little differently depending on whether the subject is chemistry, biochemistry or nutrition. The word "folic acid" is often used for the synthetically produced forms, while the natural forms are often called folates. The natural folates usually contain several glutamate units in a chain, which are broken down in the body into folic acid. In the body it is found in several different forms: the primary active forms are Tetrahydrofolic acid (Tetrahydrofolate; THF) and Methyltetrahydrofolate (5-MTHF, also known as Levomefolic acid) – the latter of which is the most common in the blood.
B9 in the form of folic acid is thus a precursor to THF and 5-MTHF, which are coenzymes for a number of enzymes that are necessary in, for example, biosynthesis, repair and methylation of DNA and RNA. These are very basic functions for cell division, maintenance, growth and e.g. the production of red blood cells – so it is not difficult to imagine that e.g. deficiency during pregnancy can have fatal consequences for the fetus and deficiency in adults can also have severe consequences. THF and 5-MTHF are also involved in the conversion of the amino acid homocysteine to the essential amino acid methionine. B9 and B12 are particularly connected in the two coupled reaction patterns folate cycle and methionine cycle, so that lack of one affects the effect of the other. These two also have a special connection to iron, as a deficiency of B9 or B12 can hide a deficiency of iron - thus these three substances should be in balance.
B9 is biosynthesized in plants, fungi, certain protozoa and bacteria. Industrially, it is usually produced by chemical synthesis and often in the form of more stable derivatives - which is used in dietary supplements, for example. The natural forms of B9 are not very stable to heat and light - especially not in a low pH environment. During UV irradiation, it degrades i.a. to a substance that can be harmful to cells, so it is debated whether B9 is ideal to use in topical products – some studies are looking at the possibility of using more stable versions, which in the skin could be converted to the active substance. It is believed that the melanin of the skin has a protective effect on B9 in the skin in relation to UV radiation.
However, since UV radiation can damage the skin's DNA and B9 is important for DNA repairs, it is possible that B9 could benefit the skin. A study with both in vitro and in vivo experiments has shown that B9 can enter the skin (via a suitable protective cream vehicle) and that it did not damage the skin. In the same study, it was shown that UV radiation can affect the cells to express higher levels of certain intracellular proteins that contribute to the uptake of B9.
I dag er B9 ikke anvendt meget i kosmetik, selvom nogle studier tyder på at det kunne have en positiv virkning – fx har et in vitro forsøg vist, at Folsyre sammen med Kreatin accelererede hudens genopbygning og et in vivo forsøg har vist, at Folsyre sammen med Kreatin havde en beskyttende effekt overfor UV-inducerede DNA-skader og øgede hudens fasthed og reducerede rynker – sandsynligvis delvist som følge af en øget collagen densitet.
Figure 7: B9 – Folate (Folic acid)
Den anbefalede daglige dosis af B12 er på 2-4 µg/dag for voksne og lidt mere for gravide og ammende. Der er ikke en UL – max oral dosis, da man generelt mener at B12 er meget sikkert at indtage og let udskilles. Der er dog studier, som viser at meget høje doser kan give læsioner på huden og en form for akne-lignende udslæt – sammenhæng er dog ikke helt fastlagt. Man har heller ikke helt konsensus omkring hvilke koncentrationsgrænser i blodet af B12 der vurderes til at være for meget og for lidt. Man har set forhøjede niveauer af B12 i flere forskellige sygdomsstilstande; fx ved nogle typer af leukæmi, men har ikke klare årsagssammenhænge på plads.
Deficiency of B12 will often first manifest in the form of hyperpigmentation, changes in hair and nails and inflammation of the tongue. In addition, deficiency can cause fatigue, balance problems, shortness of breath, memory loss, elevated homocysteine, poorer immune system and in the long run a form of anemia, neuritis, reduction in cognitive abilities, psychosis, and reduced fertility. Deficiency is rarely due to too low an intake via the diet - however, vegetarians and vegans can be in deficit as B12 is mostly found in animal foods. The most common cause of deficiency is poor absorption, which is seen, for example, in the elderly and people who have reduced levels of proteins needed for absorption or have a too low level of stomach acid, which may be due to antacids. Deficiency of B12 is worldwide one of the most common vitamin deficiencies, which is why it is also relatively common and in some places a requirement to enrich foods such as plant milk, wheat flour, corn flour, bread, pasta and rice.
Good sources of B12 are animal foods, especially offal, eggs and fish. In addition, yeast and milk as well as seaweed and fermented foods with B12-containing microorganisms. It is only bacteria that can biosynthesize B12 and the reason why animal products contain B12; likewise, B12 is biosynthesized by some bacteria in the human colon, but how much is absorbed is not entirely known – the primary uptake occurs in the small intestine in humans.
B12, also called Cobalamin, is chemically a very complex vitamin, containing the metal Cobalt. It covers several very similar substances (cobalamins), of which Cyanocobalamin (shown in Figure 8) together with Methylcobalamin are the most common in e.g. dietary supplements. In the body, the two biologically active forms of B12 are Methylcobalamin and Adenosylcobalamin. Methylcobalamin is a coenzyme for the enzyme Methonine synthase, which converts homocysteine to Methonine, which is important in the also B9-dependent biosynthesis of the nucleic acids pyrimidines and purines, which are the starting materials for the biosynthesis of DNA and RNA. Adenosylcobalamin is the coenzyme for the enzyme Methylmalonyl CoA mutase, which is important in the breakdown of fatty acids and proteins. More generally, B12 is necessary for the normal functioning of the bone marrow, where the red blood cells are formed, the breakdown of fatty acids and proteins, the formation of DNA and RNA, the nervous system and it also affects the immune system.
I fødevarer er B12 oftest bundet til proteiner, hvilke det frigives fra i mavesækken eller i starten af tyndtarmen. For at beskytte B12 mod syren i mavesækken bindes det til det beskyttende protein Haptocorrin, som den igen frigives fra i tarmen, således at B12 er frit i tarmen. For at blive absorberet over tyndtarmvæggen og komme ud i blodet, skal det binde til endnu et protein, Intrinsic factor, som sørger for at det føres til leveren og derfra ud i blodet. Med blodet bliver B12 – som her primært er bundet til Haptocorrin igen – fordelt ud til resten af kroppens celler, hvor det igen bliver frigivet og kan omdannes til en aktiv form. Optagelsen af B12 er dermed ret kompleks og afhænger af flere proteiner, hvilket gør, at der er flere trin, som kan hæmme optagelsen – fx pga. mutationer i et af de proteiner som er nødvendige for optagelsen. Desuden er optagelsen ikke særlig effektiv (især ikke hos ældre) således at en relativ stor del af madens indhold af B12 bliver udskilt med afføringen. Det som optages i kroppen, bliver efter endt funktion udskilt med urinen. I leveren findes omkring 50 % af kroppens B12-indhold, hvor det udgør det største lager af B12 på omkring 2-5 mg hos voksne. Dette lager holder i flere år, hvorfor der går lang tid før man ser symptomer på mangel.
B12 is biosynthesized by some archaea and bacteria in the form of Methylcobalamin and Adenosylcobalamin. Industrially, B12 is most often produced via fermentation with certain bacteria followed by isolation and a chemical process to make it into Cyanocobalamin. It can also be synthesized, but it is a very complex synthetic route with over 60 steps, which is not profitable.
B12 is a relatively large and complex molecule that is water-soluble, light-sensitive and in pure form a deep red powder.
In dietary supplements and food enrichment, the Cyanocobalamin form in particular is used, as the Cyanide unit stabilizes the molecule. B12 is also found in medicines in the form of tablets and as an injection, which can be used in case of deficiency. As with everything else, there is a risk (albeit small) of side effects such as allergies and anaphylactic reaction – some people are sensitive to cobalt, for example.
In relation to the skin, both too much and too little B12 can result in skin issues. Some studies suggest that B12 may have a protective effect against eczema and inflammation of the skin – probably by reducing the production of nitric oxide (which, in too high amounts, is proinflammatory) and proinflammatory cytokines. When used topically, B12 itself has a very low skin permeability, which is why there are some studies that use special delivery systems such as liposomes to increase absorption. For example, a mouse study showed that liposomes containing Adenosylcobalamin in a hydrogel gave a better skin permeability and had a marked positive effect on induced atopic eczema. In a placebo-controlled study in people with atopic eczema, a cream containing 0.07% cyanocobalamin over 8 weeks showed a significant improvement in the condition compared to the same formulation without cyanocobalamin. And there are several studies that have shown that B12 can have a beneficial effect on eczema. B12 has also shown a positive effect in the form of an ointment with 0.07% Cyanocobalamin against mild-to-moderate plaque psoriasis.
Compared to cosmetics, B12 is not very widely used; perhaps because it gives a red color and because some studies suggest that too much B12 can aggravate acne. However, there are also studies that suggest that it may act as an antioxidant, be anti-inflammatory, as well as reduce itching and irritation of the skin.
Figure 8: B12 - Cyanocobalamin
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