Cyanocobalamin Hydroxocobalamin

Vitamin B12 is the name which has been used since its first introduction by Rickes and his colleagues in 1948 (Rl). However, vitamin B12 is a generic term which includes cyanocobalamin, hydroxocobalamin, adenosylcobala-min, and methylcobalamin. This group of compounds has been called co-balamins or corrinoids, the generic term used for all compounds containing a... 

The term cobalamins embraces this series of compounds, which includes classical vitamin B12 itself (cyanocobalamin), hydroxocobalamin, nitritocobalamin, thiocyanatocobalamin, and others. 

FIGURE 10.3 Structural formula of vitamin B[2 and partial structures of vitamin B[2 compounds. The partial structures of vitamin B,2 compounds show only those portions of the molecule that differ from vitamin B[2. 1 — 5 -deoxyadenosylcobalamin, 2 — methylcobal-amin, 3 — hydroxocobalamin, 4 — cyanocobalamin, 5 — benzimidazolyl cyanocobamide, 6 — pseudovitamin B[2, 7 — 5-hydroxybenzimidazolyl cyanocobamide, 8 — p-cresolyl cyanocobamide. 

The fibroblasts do not convert cyanocobalamin or hydroxocobalamin to methylcobalamin or adenosyl-cobalamin, resulting in diminished activity of both N5-methyltetrahydrofolate homocysteine methyltransferase and methylmalonyl-CoA mutase. Supplementation with hydroxocobalamin rectifies the aberrant biochemistry. The precise nature of the underlying defect remains obscure. Diagnosis should be suspected in a child with homocystinuria, methylmalonic aciduria, megaloblastic anemia, hypomethioninemia and normal blood levels of folate and vitamin B12. A definitive diagnosis requires demonstration of these abnormalities in fibroblasts. Prenatal diagnosis is possible. 

Cyanide is usually found in compounds (substances formed by joining two or more chemicals). Cyanide can interact with metals and other organic compounds (compounds that include carbon). Sodium cyanide and potassium cyanide are examples of simple cyanide compounds. Cyanide can be produced by certain bacteria, fungi, and algae, and is found in a number of foods and plants. In your body, cyanide can combine with a chemical (hydroxocobalamin) to form vitamin B12 (cyanocobalamin). In certain plant foods, including almonds, millet sprouts, lima beans, soy,... 

The metabolism of cyanide has been studied in animals. The proposed metabolic pathways shown in Figure 2-3 are (1) the major pathway, conversion to thiocyanate by either rhodanese or 3-mercapto-pyruvate sulfur transferase (2) conversion to 2-aminothiazoline-4-carboxylic acid (Wood and Cooley 1956) (3) incorporation into a 1-carbon metabolic pool (Boxer and Richards 1952) or (4) combining with hydroxocobalamin to form cyanocobalamin (vitamin B12) (Ansell and Lewis 1970). Thiocyanate has been shown to account for 60-80% of an administered cyanide dose (Blakley and Coop 1949 Wood and Cooley 1956) while 2-aminothiazoline-4-carboxylic acid accounts for about 15% of the dose (Wood and Cooley 1956). The conversion of cyanide to thiocyanate was first demonstrated in 1894. Conversion of cyanide to thiocyanate is enhanced when cyanide poisoning is treated by intravenous administration of a sulfur donor (Smith 1996 Way 1984). The sulfur donor must have a sulfane sulfur, a sulfur bonded to another sulfur (e.g., sodium thiosulfate). During conversion by rhodanese, a sulfur atom is transferred from the donor to the enzyme, forming a persulfide intermediate. The persulfide sulfur is then transferred... 

The ability of cyanide to form complexes with some metallic ions such as cobalt is the basis for the reaction with hydroxocobalamin that yields cyanocobalamin. Cyanocobalamin (vitamin B12), which contains cyanide and cobalt, is essential for the health of mammalian organisms. 

Cyanide s binding to metallic ions is also employed in a reaction with cobalt-containing compounds that yields cyanocobalamin (see Section 2.6). Cobalt compounds generally are not used because of their toxicity however, Co2EDTA (Klimmek et al. 1983) and hydroxocobalamin (Benabid et al. 1987 Mengel et al. 1989 Mushett et al. 1952) have been used as antidotes both in clinical and laboratory trials. Cardiac toxicity from Co2EDTA use under clinical conditions has raised caution in its clinical use, as the cardiac... 

Hydroxocobalamin - Hydroxocobalamin (vitamin B- 2a) is more highly protein bound and is retained in the body longer than cyanocobalamin. However, it has no advantage over cyanocobalamin. 

Vitamin B12 exists as hydroxocobalamin, adeno-sylcobalamin and cyanocobalamin. Cobalamins are found exclusively in food ingredients of animal origin like meat, liver and to a lesser degree in dairy products. Vitamin B12 is absorbed in the distal ileum under the influence of the glycoprotein intrinsic... 

Vitamin B12 consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide. Various organic groups may be covalently bound to the cobalt atom, forming different cobalamins. Deoxyadenosylcobalamin and methylcobalamin are the active forms of the vitamin in humans. Cyanocobalamin and hydroxocobalamin (both available for therapeutic use) and other cobalamins found in food sources are converted to the active forms. The ultimate source of vitamin Bi2 is from microbial synthesis the vitamin is not synthesized by animals or plants. The chief dietary source of vitamin Bi2 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products. Vitamin Bi2 is sometimes called extrinsic factor to differentiate it from intrinsic factor, a protein normally secreted by the stomach that is required for gastrointestinal uptake of dietary vitamin B12. 

Vitamin B12 for parenteral injection is available as cyanocobalamin or hydroxocobalamin. Hydroxocobalamin is preferred because it is more highly protein-bound and therefore remains longer in the circulation. Initial therapy should consist of 100-1000 meg of vitamin B12 intramuscularly daily or every other day for 1-2 weeks to replenish body stores. 

Parenteral 250, 500 meg vials for IV infusion Vitamin B12 (generic cyanocobalamin or hydroxocobalamin)... 

Hydroxocobalamin Cyanide Adult dose is 5 g IV over 15 minutes. Converts cyanide to cyanocobalamin. 

Treatment Conventional antidote kit consists of nitrites to induce methemoglobinemia (which binds cyanide) and thiosulfate (which hastens conversion of cyanide to less toxic thiocyanate) a newer antidote kit (Cyanokit) consists of concentrated hydroxocobalamin, which directly converts cyanide into cyanocobalamin... 

Treatment of cyanide poisoning includes rapid administration of activated charcoal (although charcoal binds cyanide poorly, it can reduce absorption) and general supportive care. The conventional antidote kit available in the USA includes two forms of nitrite (amyl nitrite and sodium nitrite) and sodium thiosulfate. The nitrites induce methemoglobinemia, which binds to free CI T creating the less toxic cyanomethemoglobin thiosulfate is a cofactor in the enzymatic conversion of CN to the much less toxic thiocyanate (SCINT). Recently, the FDA approved a concentrated form of hydroxocobalamin, which is now available as the Cyanokit (EMD Pharmaceuticals, Durham, North Carolina). Hydroxocobalamin (one form of vitamin B12) combines rapidly with CN to form cyanocobalamin (another form of vitamin B12). 

Vitamin B12 consists of a porphyrin-like ring structure, with an atom of Co chelated at its centre, linked to a nucleotide base, ribose and phosphoric acid (6.34). A number of different groups can be attached to the free ligand site on the cobalt. Cyanocobalamin has -CN at this position and is the commercial and therapeutic form of the vitamin, although the principal dietary forms of B12 are 5 -deoxyadenosylcobalamin (with 5 -deoxyadeno-sine at the R position), methylcobalamin (-CH3) and hydroxocobalamin (-OH). Vitamin B12 acts as a co-factor for methionine synthetase and methylmalonyl CoA mutase. The former enzyme catalyses the transfer of the methyl group of 5-methyl-H4 folate to cobalamin and thence to homocysteine, forming methionine. Methylmalonyl CoA mutase catalyses the conversion of methylmalonyl CoA to succinyl CoA in the mitochondrion. 

Cyanocobalamin, the form of vitamin B12 isolated initially, contains cyanide attached to cobalt. It occurs only in minor amounts, if at all, in nature but is generated through the addition of cyanide during the isolation. Hydroxocobalamin (vitamin B12a) containing OH in place of CN"does occur in nature. However, the predominant forms of the vitamin are the coenzymes in which an alkyl group replaces the CN of cyanocobalamin. 

The Bj2 vitamers consist of a group of organometallic compounds that have a common cor-rinoid structure and vary in the substituent bound to the central cobalt atom (Fig. 7) (167,168). The principal naturally occurring Bl2 vitamers are hydroxocobalamin (HOCbl), methylcobal-amin (MeCbl), and adenosylcobalamin (AdoCbl). Cyanocobalamin (CNCbl) is the form commonly used for clinical, pharmaceutical, and food fortification purposes, due to its greater relative stability. 

CNCbl = cyanocobalamin HOCbl = hydroxocobalamin MeCbl = methylcobalamin AdoCbl = adenosylcobalamin. Column specifications expressed as (length X ID, particle size manufacturer) when reported in original publication. n = number of determinations. 

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