Английская Википедия:Cyanocobalamin

Содержание

Текст

Текст

Текст

Текст

Текст

Текст

Текст

Текст

Текст

Шаблон:Short description Шаблон:Use dmy dates Шаблон:Infobox drug Cyanocobalamin is a form of [[Vitamin B12|vitamin Шаблон:Chem]] used to treat and prevent [[vitamin B12 deficiency|vitamin Шаблон:Chem deficiency]] except in the presence of cyanide toxicity. The deficiency may occur in pernicious anemia, following surgical removal of the stomach, with fish tapeworm, or due to bowel cancer. It is used by mouth, by injection into a muscle, or as a nasal spray.

Cyanocobalamin is generally well tolerated. Minor side effects may include diarrhea, nausea, upset stomach, and itchiness. Serious side effects may include anaphylaxis, and low blood potassium resulting in heart failure. Use is not recommended in those who are allergic to cobalt or have Leber's disease. No overdosage or toxicity has been reported. It is less preferred than hydroxocobalamin for treating vitamin Шаблон:Chem deficiency because it has slightly lower bioavailability. Some study have shown that it has an antihypotensive effect. Vitamin Шаблон:Chem is an essential nutrient meaning that it cannot be made by the body but is required for life.

Cyanocobalamin was first manufactured in the 1940s. It is available as a generic medication and over the counter. In 2021, it was the 110th most commonly prescribed medication in the United States, with more than 5Шаблон:Nbspmillion prescriptions.

Medical use

Cyanocobalamin is usually prescribed after surgical removal of part or all of the stomach or intestine to ensure adequate serum levels of vitamin Шаблон:Chem. It is also used to treat pernicious anemia, [[Vitamin B12 deficiency|vitamin Шаблон:Chem deficiency]] (due to low intake from food or inability to absorb due to genetic or other factors), thyrotoxicosis, hemorrhage, malignancy, liver disease and kidney disease. Cyanocobalamin injections are often prescribed to gastric bypass patients who have had part of their small intestine bypassed, making it difficult for Шаблон:Chem to be acquired via food or vitamins. Cyanocobalamin is also used to perform the Schilling test to check ability to absorb vitamin Шаблон:Chem.Шаблон:R

Cyanocobalamin is also produced in the body (and then excreted via urine) after intravenous hydroxycobalamin is used to treat cyanide poisoning.

Side effects

Possible side effects of cyanocobalamin injection include allergic reactions such as hives, difficult breathing; redness of the face; swelling of the arms, hands, feet, ankles or lower legs; extreme thirst; and diarrhea. Less-serious side effects may include headache, dizziness, leg pain, itching, or rash.Шаблон:R

Treatment of megaloblastic anemia with concurrent vitamin Шаблон:Chem deficiency using Шаблон:Chem vitamers (including cyanocobalamin), creates the possibility of hypokalemia due to increased erythropoiesis (red blood cell production) and consequent cellular uptake of potassium upon anemia resolution.Шаблон:R When treated with cyanocobalamin, patients with Leber's disease may develop serious optic atrophy, possibly leading to blindness.Шаблон:R

Chemistry

Vitamin Шаблон:Chem is the "generic descriptor" name for any vitamers of vitamin Шаблон:Chem. Animals, including humans, can convert cyanocobalamin to any one of the active vitamin Шаблон:Chem compounds.Шаблон:R

Cyanocobalamin is one of the most widely manufactured vitamers in the vitamin Шаблон:Chem family (the family of chemicals that function as Шаблон:Chem when put into the body), because cyanocobalamin is the most air-stable of the Шаблон:Chem forms. It is the easiest to crystallize and therefore easiest to purify after it is produced by bacterial fermentation. It can be obtained as dark red crystals or as an amorphous red powder. Cyanocobalamin is hygroscopic in the anhydrous form, and sparingly soluble in water (1:80). It is stable to autoclaving for short periods at Шаблон:Convert. The vitamin Шаблон:Chem coenzymes are unstable in light. After consumption the cyanide ligand is replaced by other groups (adenosyl, methyl) to produce the biologically active forms. The cyanide is converted to thiocyanate and excreted by the kidney.

Chemical reactions

Файл:Various reduced forms of Cyanocobalamin.jpg

Reduced forms of Cyanocobalamin, with a Co(I) (top), Co(II) (middle), and Co(III) (bottom)

In the cobalamins, cobalt normally exists in the trivalent state, Co(III). However, under reducing conditions, the cobalt center is reduced to Co(II) or even Co(I), which are usually denoted as Шаблон:Chem and Шаблон:Chem, for reduced and super reduced, respectively.

Шаблон:Chem and Шаблон:Chem can be prepared from cyanocobalamin by controlled potential reduction, or chemical reduction using sodium borohydride in alkaline solution, zinc in acetic acid, or by the action of thiols. Both Шаблон:Chem and Шаблон:Chem are stable indefinitely under oxygen-free conditions. Шаблон:Chem appears orange-brown in solution, while Шаблон:Chem appears bluish-green under natural daylight, and purple under artificial light.Шаблон:R

Шаблон:Chem is one of the most nucleophilic species known in aqueous solution.Шаблон:R This property allows the convenient preparation of cobalamin analogs with different substituents, via nucleophilic attack on alkyl halides and vinyl halides.Шаблон:R

For example, cyanocobalamin can be converted to its analog cobalamins via reduction to Шаблон:Chem, followed by the addition of the corresponding alkyl halides, acyl halides, alkene or alkyne. Steric hindrance is the major limiting factor in the synthesis of the Шаблон:Chem coenzyme analogs. For example, no reaction occurs between neopentyl chloride and Шаблон:Chem, whereas the secondary alkyl halide analogs are too unstable to be isolated.Шаблон:R This effect may be due to the strong coordination between benzimidazole and the central cobalt atom, pulling it down into the plane of the corrin ring. The trans effect determines the polarizability of the Co–C bond so formed. However, once the benzimidazole is detached from cobalt by quaternization with methyl iodide, it is replaced by Шаблон:Chem or hydroxyl ions. Various secondary alkyl halides are then readily attacked by the modified Шаблон:Chem to give the corresponding stable cobalamin analogs.Шаблон:R The products are usually extracted and purified by phenol-methylene chloride extraction or by column chromatography.Шаблон:R

Cobalamin analogs prepared by this method include the naturally occurring coenzymes methylcobalamin and cobamamide, and other cobalamins that do not occur naturally, such as vinylcobalamin, carboxymethylcobalamin and cyclohexylcobalamin.Шаблон:R This reaction is under review for use as a catalyst for chemical dehalogenation, organic reagent and photosensitized catalyst systems.Шаблон:R

Production

Cyanocobalamin is commercially prepared by bacterial fermentation. Fermentation by a variety of microorganisms yields a mixture of methylcobalamin, hydroxocobalamin and adenosylcobalamin. These compounds are converted to cyanocobalamin by addition of potassium cyanide in the presence of sodium nitrite and heat. Since multiple species of Propionibacterium produce no exotoxins or endotoxins and have been granted GRAS status (generally regarded as safe) by the United States Food and Drug Administration, they are the preferred bacterial fermentation organisms for vitamin Шаблон:Chem production.Шаблон:R

Historically, the physiological form was initially thought to be cyanocobalamin. This was because hydroxocobalamin produced by bacteria was changed to cyanocobalamin during purification in activated charcoal columns after separation from the bacterial cultures (because cyanide is naturally present in activated charcoal). Cyanocobalamin is the form in most pharmaceutical preparations because adding cyanide stabilizes the molecule.Шаблон:R

The total world production of vitamin B₁₂, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes.

Metabolism

The two bioactive forms of vitamin Шаблон:Chem are methylcobalamin in cytosol and adenosylcobalamin in mitochondria. Multivitamins often contain cyanocobalamin, which is presumably converted to bioactive forms in the body. Both methylcobalamin and adenosylcobalamin are commercially available as supplement pills. The MMACHC gene product catalyzes the decyanation of cyanocobalamin as well as the dealkylation of alkylcobalamins including methylcobalamin and adenosylcobalamin.Шаблон:R This function has also been attributed to cobalamin reductases.Шаблон:R The MMACHC gene product and cobalamin reductases enable the interconversion of cyano- and alkylcobalamins.Шаблон:R

Cyanocobalamin is added to fortifyШаблон:R nutrition, including baby milk powder, breakfast cereals and energy drinks for humans, also animal feed for poultry, swine and fish. Vitamin Шаблон:Chem becomes inactive due to hydrogen cyanide and nitric oxide in cigarette smoke. Vitamin Шаблон:Chem also becomes inactive due to nitrous oxide Шаблон:Chem commonly known as laughing gas, used for anaesthesia and as a recreational drug. Vitamin Шаблон:Chem becomes inactive due to microwaving or other forms of heating.Шаблон:R

In the cytosol

Methylcobalamin and 5-methyltetrahydrofolate are needed by methionine synthase in the methionine cycle to transfer a methyl group from 5-methyltetrahydrofolate to homocysteine, thereby generating tetrahydrofolate (THF) and methionine, which is used to make SAMe. SAMe is the universal methyl donor and is used for DNA methylation and to make phospholipid membranes, choline, sphingomyelin, acetylcholine, and other neurotransmitters.

In mitochondria

Файл:Odd-chain FA oxydation.png

Vitamin Шаблон:Chem adenosylcobalamin in mitochondrion—cholesterol and protein metabolism

The enzymes that use Шаблон:Chem as a built-in cofactor are methylmalonyl-CoA mutase (PDB 4REQШаблон:R) and methionine synthase (PDB 1Q8J).Шаблон:R

The metabolism of propionyl-CoA occurs in the mitochondria and requires Vitamin Шаблон:Chem (as adenosylcobalamin) to make succinyl-CoA. When the conversion of propionyl-CoA to succinyl-CoA in the mitochondria fails due to Vitamin Шаблон:Chem deficiency, elevated blood levels of methylmalonic acid (MMA) occur. Thus, elevated blood levels of homocysteine and MMA may both be indicators of [[vitamin B12 deficiency|vitamin Шаблон:Chem deficiency]].

Adenosylcobalamin is needed as cofactor in methylmalonyl-CoA mutase—MUT enzyme. Processing of cholesterol and protein gives propionyl-CoA that is converted to methylmalonyl-CoA, which is used by MUT enzyme to make succinyl-CoA. Vitamin Шаблон:Chem is needed to prevent anemia, since making porphyrin and heme in mitochondria for producing hemoglobin in red blood cells depends on succinyl-CoA made by vitamin Шаблон:Chem.

Absorption and transport

Inadequate absorption of vitamin Шаблон:Chem may be related to coeliac disease. Intestinal absorption of vitamin Шаблон:Chem requires successively three different protein molecules: haptocorrin, intrinsic factor and transcobalamin II.

See also

• Methylcobalamin
• Hydroxocobalamin
• Adenosylcobalamin
• Cobalamin biosynthesis