Vitamin B12 (Cyanocobalamin)

Introduction

A kind of vitamin B₁₂ called cyanocobalamin is used to treat and prevent vitamin B₁₂ insufficiency, with the exception of situations in which cyanide toxicity is present.

The deficiency can be brought on by intestinal cancer, fish tapeworm, pernicious anemia, or after stomach surgery. It can be used topically, intramuscularly, or as a nasal spray.

In general, cyanocobalamin is well tolerated. Itching, upset stomach, diarrhea, and nausea are examples of minor adverse effects.

Anaphylaxis is one serious adverse effect that might occur, as can low blood potassium that causes heart failure. It is not advised to use in those with Leber’s illness or cobalt allergies.

There have been no reports of toxicity or overdose. Its somewhat decreased bioavailability makes it less desirable than hydroxocobalamin for treating vitamin B₁₂ insufficiency.

Research has indicated that it possesses antihypertensive properties. Being an essential nutrient, vitamin B₁₂ is needed for life but cannot be produced by the body.

In the 1940s, cyanocobalamin was first produced. It is sold over the counter and as a generic drug. With over 6 million prescriptions, it was the 105th most often prescribed drug in the US in 2020.

Medical Use

In order to ensure adequate serum levels of vitamin B₁₂, cyanocobalamin is typically administered following surgical removal of part or all of the stomach or intestine.

It is also used to treat thyrotoxicosis, bleeding disorders, cancer, liver and kidney diseases, pernicious anemia, and vitamin B₁₂ deficiency (caused by inadequate dietary intake or difficulty absorbing owing to hereditary or other causes).

Patients on gastric bypass who have had a portion of their small intestine bypassed are frequently prescribed cyanocobalamin injections.

which makes it more difficult for them to obtain vitamin B₁₂ through food or supplements. To assess a person’s capacity to absorb vitamin B₁₂, the Schilling test is also conducted using cyanocobalamin.

When intravenous hydroxycobalamin is used to treat cyanide poisoning, the body also produces cyanocobalamin, which is subsequently eliminated through the urine.

Side Effects

An allergic reaction such as hives, breathing difficulties, facial redness, swelling of the arms, hands, feet, ankles, or lower legs, intense thirst, and diarrhea are among the potential side effects of cyanocobalamin injection.

Headache, lightheadedness, leg pain, itching, or rash are examples of less serious adverse effects.

When megaloblastic anemia is treated with B vitamins, such as cyanocobalamin, in conjunction with a concurrent vitamin B₁₂ shortage, there is a risk of hypokalemia because of enhanced erythropoiesis, or the creation of red blood cells, and subsequent potassium uptake by the cells when the anemia resolves.

Patients with Leber’s disease who receive cyanocobalamin treatment may experience severe ocular atrophy, which could result in blindness.

Chemistry

The “generic descriptor” name for all of the vitamin B₁₂ vitamins is vitamin B₁₂. Cyanocobalamin can be converted by any animal, including humans, into any of the active forms of vitamin B₁₂.

Because cyanocobalamin is the most air-stable of the B₁₂ forms, it is one of the most widely produced vitamins in the vitamin B₁₂ family (the family of compounds that function as B₁₂ when placed into the body).

After being created by bacterial fermentation, it is the easiest to purify and crystallize. It can be found as an amorphous red powder or as dark red crystals.

When cyanocobalamin is anhydrous, it is hygroscopic and only sporadically soluble in water. (1:80).

It can withstand brief autoclaving at 121 °C (250 °F). In light, the coenzymes of vitamin B₁₂ become unstable.

To create the physiologically active forms, additional groups (adenosyl, methyl) replace the cyanide ligand after ingestion. The kidney transforms the cyanide into thiocyanate, which is then eliminated.

Chemical Reactions

Cobalt typically appears in the trivalent form, Co(III), in the cobalamin. The cobalt center, on the other hand, is reduced to Co(II) or even Co(I) under reducing circumstances.

These are typically represented as B₁₂ and B₁₂, for reduced and super reduced, respectively. Cyanocobalamin can be converted into B₁₂ and B₁₂ via controlled potential reduction, chemical reduction with zinc in acetic acid, sodium borohydride in alkaline solution, or thiol action.

Without oxygen, both B₁₂ and B₁₂ remain stable for an infinite amount of time. In solution, B₁₂ appears orange-brown, whereas B₁₂ appears purple in artificial light and bluish-green in natural daylight.

One of the species that is known to be the most nucleophilic in aqueous solution is B₁₂. This characteristic makes it possible to easily produce cobalamin analogs with various substituents by attacking alkyl and vinyl halides with nucleophiles.

For instance, cyanocobalamin can be reduced to B₁₂ and then its analog cobalamin can be created by adding the appropriate alkyl halides, acyl halides, alkene, or alkyne.

The main impediment to the synthesis of the B₁₂ coenzyme analogs is steric hindrance. Neopentyl chloride and B₁₂, for instance, do not react, but the secondary alkyl halide analogs are too unstable to be separated.

The strong coordination between the central cobalt atom and benzimidazole, which pulls it down into the corrin ring’s plane, may be the cause of this action.

The transient impact establishes the Co-C bond’s polarizability in this way. Nevertheless, H2O or hydroxyl ions take their place once the benzimidazole is separated from cobalt by quaternization with methyl iodide.

The modified B₁₂ then easily targets different secondary alkyl halides to yield the corresponding stable cobalamin analogs.

Column chromatography or phenol-methylene chloride extraction is typically used to extract and purify the products.

This process yields cobalamin analogs that include vinylcobalamin, carboxymethylcobalamin, and cyclohexylcobalamin, as well as the naturally occurring coenzymes methylcobalamin and cobamamide.

The potential applications of this reaction as a catalyst for organic reagents, photosensitized catalyst systems, and chemical dehalogenation are being investigated.

Production

Commercial cyanocobalamin is made by fermenting microorganisms. A combination of methylcobalamin, hydroxocobalamin, and adenosylcobalamin is produced through fermentation by different bacteria.

When potassium cyanide is added to these compounds along with heat and sodium nitrite, the result is cyanocobalamin.

Propionibacterium species are the preferred bacterial fermentation organisms for vitamin B₁₂ production since they do not produce any endotoxins or exotoxins and have been accorded GRAS status (generally considered as safe).

In the past, cyanocobalamin was once believed to be the physiological form. This was due to the fact that, during purification activated charcoal.

Columns following separation from the bacterial cultures, the hydroxocobalamin that the bacteria produced converted to cyanocobalamin (since cyanide is naturally contained
ed in activated charcoal).

The most common type of cyanocobalamin seen in medicinal preparations is derived from the stabilizing effect of cyanide.

In 2008, four companies—the French Sanofi-Aventis and three Chinese companies—produced 35 tons of vitamin B₁₂ worldwide.

Metabolism

Methylcobalamin, found in the cytosol, and adenosylcobalamin, found in mitochondria, are the two functional forms of vitamin B₁₂.

Cyanocobalamin, which is frequently included in multivitamins, is probably transformed into bioactive forms by the body.

Commercial supplement pills containing methylcobalamin and adenosylcobalamin are both accessible.

The MMACHC gene product catalyzes the dealkylation of alkylcobalamin, such as methylcobalamin and adenosylcobalamin, and the decyanation of cyanocobalamin.

Cobalamin reductases have also been linked to this role. The interconversion of cyano- and alkyl cobalamin is made possible by the MMACHC gene product and cobalamin reductases.

Fortified foods such as powdered breast milk, human breakfast cereals, energy drinks, and animal feed for fish, swine, and poultry also include cyanocobalamin.

Cigarette smoke contains nitric oxide and hydrogen cyanide, which render vitamin B₁₂ inactive.

Nitrous oxide, popularly referred to as laughing gas and utilized as a recreational and anesthetic drug, also renders vitamin B₁₂ inactive.

Heating in any way, including the microwave, renders vitamin B₁₂ inactive.

In The Cytosol

Methionine synthase in the methionine cycle needs methylcobalamin and 5-methyltetrahydrofolate to transfer a methyl group from 5-methyltetrahydrofolate to homocysteine.

Resulting in the production of tetrahydrofolate (THF) and methionine, which is utilized to produce SAMe.

DNA methylation, phospholipid membrane synthesis, choline, sphingomyelin, acetylcholine, and other neurotransmitters are all made possible by SAMe, the universal methyl donor.

In Mitochondria

Methionine synthase (PDB 1Q8J) and methylmalonyl-CoA mutase (PDB 4REQ[39]) are the enzymes that utilize B12 as an inherent cofactor.

Vitamin B₁₂ (as adenosylcobalamin) is needed for the metabolism of propionyl-CoA in the mitochondria in order to produce succinyl-CoA.

Elevated blood levels of methylmalonic acid (MMA) happen when a vitamin B₁₂ deficiency prevents the mitochondria from converting propionyl-CoA to succinyl-CoA.

Therefore, high homocysteine and MMA levels in the blood may both be signs of vitamin B12 insufficiency.

Adenosylcobalamin is required for the methylmalonyl-CoA mutase (MUT) enzyme as a cofactor. Propionyl-CoA, which is produced during the processing of protein and cholesterol, is changed into methylmalonyl-CoA by the MUT enzyme, which then produces succinyl-CoA.

Since vitamin B₁₂ produces succinyl-CoA, which is needed in mitochondria to make porphyrin and heme for the production of hemoglobin in red blood cells, vitamin B₁₂ is required to avoid anemia.

Absorption and Transport

Coeliac illness may be associated with inadequate absorption of vitamin B₁₂. Haptocorrin, intrinsic factor, and transcobalamin II are the three distinct protein molecules that are sequentially needed for the intestinal absorption of vitamin B₁₂.

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