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1.
Am J Emerg Med ; 46: 799.e1-799.e2, 2021 08.
Article in English | MEDLINE | ID: mdl-33597094

ABSTRACT

Chronic nitrous oxide abuse is a known cause of myeloneuropathy. Nitrous oxide irreversibly inactivates vitamin B12 causing demyelination of the dorsal spinal columns, clinically indistinguishable from that which is caused by vitamin B12 deficiency. We report a 37-year-old female who presented with ataxia, loss of lower extremity proprioception, demyelination of her cervical dorsal spinal columns, and other laboratory and physical exam findings consistent with nitrous oxide abuse. The patient reported daily use in excess of 500 nitrous oxide cartridges, also known as "whippits". Nitrous oxide myeloneuropathy should be included in the differential diagnoses for emergency medicine physicians when evaluating a patient with bilateral neurologic deficits and ataxia.


Subject(s)
Analgesics, Non-Narcotic/adverse effects , Myelitis, Transverse/chemically induced , Nitrous Oxide/adverse effects , Substance-Related Disorders/complications , Adult , Emergency Service, Hospital , Female , Humans , Magnetic Resonance Imaging , Myelitis, Transverse/diagnosis , Myelitis, Transverse/diagnostic imaging , Spinal Cord/diagnostic imaging , Vitamin B 12/antagonists & inhibitors , Vitamin B 12 Deficiency/chemically induced , Vitamin B 12 Deficiency/complications
2.
Chemistry ; 26(67): 15438-15445, 2020 Dec 01.
Article in English | MEDLINE | ID: mdl-32956545

ABSTRACT

The recently delineated structure- and reactivity-based concept of antivitamins B12 has begun to bear fruit by the generation, and study, of a range of such B12 -dummies, either vitamin B12 -derived, or transition metal analogues that also represent potential antivitamins B12 or specific B12 -antimetabolites. As reviewed here, this has opened up new research avenues in organometallic B12 -chemistry and bioinorganic coordination chemistry. Exploratory studies with antivitamins B12 have, furthermore, revealed some of their potential, as pharmacologically interesting compounds, for inducing B12 -deficiency in a range of organisms, from hospital resistant bacteria to laboratory mice. The derived capacity of antivitamins B12 to induce functional B12 -deficiency in mammalian cells and organs also suggest their valuable potential as growth inhibitors of cancerous human and animal cells.


Subject(s)
Antimetabolites , Vitamin B 12 , Animals , Antimetabolites/chemistry , Antimetabolites/pharmacology , Humans , Neoplasms/drug therapy , Vitamin B 12/antagonists & inhibitors , Vitamin B 12/chemistry , Vitamins/antagonists & inhibitors , Vitamins/chemistry
3.
Cells ; 8(12)2019 11 24.
Article in English | MEDLINE | ID: mdl-31771278

ABSTRACT

Cobalamin deficiency is an important health problem. The major non-hematological symptoms of hypocobalaminemia are nervous system disorders, but the molecular and cellular mechanisms underlying this phenomenon have not yet been fully explained. Increasing scientific evidence is stressing the pivotal role of astrocyte dysfunction in the pathogenesis of a wide range of neurological disorders. In light of the above, the aim of this study was to develop an in vitro model of cobalamin deficiency by optimizing the conditions of astrocyte culture in the presence of vitamin B12 antagonist, and then the model was used for multidirectional analysis of astrocyte homeostasis using image cytometry, immunoenzymatic and colorimetric assays, and fluorescence spectroscopy. Our results indicated that long-term incubation of normal human astrocytes with hydroxycobalamin(c-lactam) causes an increase of extracellular homocysteine level, a reduction of cell proliferation, and an accumulation of cells in the G2/M cell cycle phase. Moreover, we observed dramatic activation of caspases and an increase of catalase activity. Interestingly, we excluded extensive apoptosis and oxidative stress. The study provided significant evidence for astrocyte homeostasis disturbance under hypocobalaminemia, thus indicating an important element of the molecular mechanism of nervous system diseases related to vitamin B12 deficiency.


Subject(s)
Astrocytes , Vitamin B 12 Deficiency , Vitamin B 12/physiology , Astrocytes/cytology , Astrocytes/metabolism , Caspases/metabolism , Catalase/metabolism , Cell Proliferation/physiology , Cells, Cultured , G2 Phase Cell Cycle Checkpoints/physiology , Homeostasis , Humans , Vitamin B 12/antagonists & inhibitors
4.
J Phys Chem Lett ; 10(18): 5484-5489, 2019 Sep 19.
Article in English | MEDLINE | ID: mdl-31483136

ABSTRACT

Polarized transient X-ray absorption near-edge structure (XANES) was used to probe the excited-state structure of a photostable B12 antivitamin (Coß-2-(2,4-difluorophenyl)-ethynylcobalamin, F2PhEtyCbl). A drop-on-demand delivery system synchronized to the LCLS X-ray free electron laser pulses was implemented and used to measure the XANES difference spectrum 12 ps following excitation, exposing only ∼45 µL of sample. Unlike cyanocobalamin (CNCbl), where the Co-C bond expands 15-20%, the excited state of F2PhEtyCbl is characterized by little change in the Co-C bond, suggesting that the acetylide linkage raises the barrier for expansion of the Co-C bond. In contrast, the lower axial Co-NDMB bond is elongated in the excited state of F2PhEtyCbl by ca. 10% or more, comparable to the 10% elongation observed for Co-NDMB in CNCbl.


Subject(s)
Coordination Complexes/chemistry , Models, Molecular , Vitamin B 12/antagonists & inhibitors , Carbon/chemistry , Cobalt/chemistry , Kinetics , Molecular Conformation , Photochemical Processes , Quantum Theory , Thermodynamics , X-Rays
5.
Phys Chem Chem Phys ; 19(45): 30310-30315, 2017 Nov 22.
Article in English | MEDLINE | ID: mdl-29125158

ABSTRACT

Biologically active forms of cobalamins are crucial cofactors in biochemical reactions and these metabolites can be inhibited by their structurally similar analogues known as antivitamins B12. Phenylethynylcobalamin (PhEtyCbl) or 4-ethylphenylcobalamin (EtPhCbl) exemplify recently synthesized and structurally characterized antivitamins B12. Herein, DFT and TD-DFT studies of EtPhCbl are provided to explore its photochemical behavior, which may lead to design of arylcobalamins that can be used as therapeutic agents in light activated drug applications. To understand the photolability of EtPhCbl, a potential energy surface (PES) for the photodissociation of the Co-C bond was constructed. The S1 PES contains two energy minima, one being metal-to-ligand charge transfer (MLCT) and another the ligand-field (LF) state. There are two possible pathways for photodissociation: the first pathway (path A) involves initially lengthening the Co-C bond from the MLCT minimum and then elongation of Co-NIm while the second pathway (path B) involves the lengthening of the Co-NIm bond through the MLCT region followed by the lengthening of the Co-C bond through the LF region. It is shown that photodissociation involving path A is not energetically favorable whereas preferable photodissociation of the Co-C bond involves path B.


Subject(s)
Vitamin B 12/analogs & derivatives , Vitamin B 12/antagonists & inhibitors , Ligands , Light , Metals , Photochemistry , Vitamin B 12/chemistry
6.
Angew Chem Int Ed Engl ; 56(26): 7387-7392, 2017 06 19.
Article in English | MEDLINE | ID: mdl-28544088

ABSTRACT

B12 antivitamins are important and robust tools for investigating the biological roles of vitamin B12 . Here, the potential antivitamin B12 2,4-difluorophenylethynylcobalamin (F2PhEtyCbl) was prepared, and its 3D structure was studied in solution and in the crystal. Chemically inert F2PhEtyCbl resisted thermolysis of its Co-C bond at 100 °C, was stable in bright daylight, and also remained intact upon prolonged storage in aqueous solution at room temperature. It binds to the human B12 -processing enzyme CblC with high affinity (KD =130 nm) in the presence of the cosubstrate glutathione (GSH). F2PhEtyCbl withstood tailoring by CblC, and it also stabilized the ternary complex with GSH. The crystal structure of this inactivated assembly provides first insight into the binding interactions between an antivitamin B12 and CblC, as well as into the organization of GSH and a base-off cobalamin in the active site of this enzyme.


Subject(s)
Glutathione/chemistry , Vitamin B 12/antagonists & inhibitors , Catalytic Domain , Crystallography, X-Ray , Fluorine/chemistry , Humans , Hydrolysis , Kinetics , Models, Molecular , Molecular Structure , Spectrum Analysis/methods , Substrate Specificity , Temperature , Vitamin B 12/chemistry , Vitamin B 12/pharmacology
7.
Chemistry ; 21(32): 11280-7, 2015 Aug 03.
Article in English | MEDLINE | ID: mdl-26139567

ABSTRACT

B12 -antimetabolites are compounds that counteract the physiological effects of vitamin B12 and related natural cobalamins. Presented here is a structure- and reactivity-based concept of the specific 'antivitamins B12 ': it refers to analogues of vitamin B12 that display high structural similarity to the vitamin and are 'locked chemically' to prevent their metabolic conversion into the crucial organometallic B12 -cofactors. Application of antivitamins B12 to healthy laboratory animals is, thus, expected to induce symptoms of B12 -deficiency. Antivitamins B12 may, hence, be helpful in elucidating still largely puzzling pathophysiological phenomena associated with B12 -deficiency, and also in recognizing physiological roles of B12 that probably still remain to be discovered.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antimetabolites/chemistry , Antimetabolites/metabolism , Antineoplastic Agents/chemistry , Physiological Phenomena/drug effects , Vitamin B 12/antagonists & inhibitors , Vitamin B 12/metabolism , Vitamins/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Humans , Models, Molecular , Vitamin B 12/chemistry , Vitamins/chemistry , Vitamins/metabolism
8.
Chembiochem ; 16(9): 1264-78, 2015 Jun 15.
Article in English | MEDLINE | ID: mdl-26013037

ABSTRACT

Antivitamins represent a broad class of compounds that counteract the essential effects of vitamins. The symptoms triggered by such antinutritional factors resemble those of vitamin deficiencies, but can be successfully reversed by treating patients with the intact vitamin. Despite being undesirable for healthy organisms, the toxicities of these compounds present considerable interest for biological and medicinal purposes. Indeed, antivitamins played fundamental roles in the development of pioneering antibiotic and antiproliferative drugs, such as prontosil and aminopterin. Their development and optimisation were made possible by the study, throughout the 20th century, of the vitamins' and antivitamins' functions in metabolic processes. However, even with this thorough knowledge, commercialised antivitamin-based drugs are still nowadays limited to antagonists of vitamins B9 and K. The antivitamin field thus still needs to be explored more intensely, in view of the outstanding therapeutic success exhibited by several antivitamin-based medicines. Here we summarise historical achievements and discuss critically recent developments, opportunities and potential limitations of the antivitamin approach, with a special focus on antivitamins K, B9 and B12 .


Subject(s)
4-Hydroxycoumarins/pharmacology , Anticoagulants/pharmacology , Folic Acid Antagonists/pharmacology , Indenes/pharmacology , Vitamin B 12/antagonists & inhibitors , Vitamin K/antagonists & inhibitors , Vitamins/antagonists & inhibitors , 4-Hydroxycoumarins/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anticoagulants/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Bacteria/drug effects , Bacterial Infections/drug therapy , Drug Discovery , Folic Acid/metabolism , Folic Acid Antagonists/chemistry , Humans , Indenes/chemistry , Models, Molecular , Neoplasms/drug therapy , Vitamin B 12/metabolism , Vitamin K/chemistry , Vitamin K/metabolism , Vitamin K/pharmacology , Vitamins/metabolism
9.
Dent Assist ; 82(4): 12, 14-6, 18-9; quiz 20-1, 2013.
Article in English | MEDLINE | ID: mdl-24003604

ABSTRACT

This course will teach the desirable characteristics of nitrous oxide, indications and contraindications for N2O/O2 use, as well as facts and myths surrounding chronic exposure to nitrous oxide, the biologic effects associated with high levels of the gas, and ways to assess and minimize trace gas contamination in an outpatient setting.


Subject(s)
Anesthesia, Dental/methods , Anesthetics, Inhalation , Conscious Sedation/methods , Nitrous Oxide , Anesthetics, Inhalation/adverse effects , Anesthetics, Inhalation/analysis , Anesthetics, Inhalation/pharmacology , Drug and Narcotic Control , Gas Scavengers , Humans , Nitrous Oxide/adverse effects , Nitrous Oxide/analysis , Nitrous Oxide/pharmacology , Occupational Exposure , United States , United States Occupational Safety and Health Administration , Vitamin B 12/antagonists & inhibitors
10.
Endocr J ; 60(12): 1275-80, 2013.
Article in English | MEDLINE | ID: mdl-24018893

ABSTRACT

Aim of the study was to clarify the relationship between metformin-induced vitamin B12 (B12) deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes. Serum B12 concentrations, homocysteine plasma levels, the presence of retinopathy and history of macroangiopathy (stroke or coronary heart disease) were analyzed in patients without renal dysfunction (serum creatinine<115 µmol/L). Firstly, B12 status was analyzed in 62 consecutive metformin-treated patients. Secondly, the relationship between B12, homocysteine and vascular complications was analyzed in 46 metformin-treated and 38 age- and sex-matched non-metformin-treated patients. Among the 62 consecutive metformin-treated patients, B12 was deficient (<150 pmol/L) in 8 (13%) and borderline-deficient (150-220 pmol/L) in 18 (29%): the larger the metformin dosage, the lower the B12 (P=0.02, Spearman's ρ=-0.30). There were independent correlations between metformin use and B12 lowering (P=0.02, r = -0.25), and B12 lowering and elevation of homocysteine (P<0.01, r=-0.34). Elevation of homocysteine was a risk for retinopathy (P=0.02, OR 1.26, 95%CI 1.04-1.52). There was no significant relation between homocysteine and macroangiopathy. Correlation between B12 and homocysteine was stronger in metformin-treated (P<0.01, r=-0.48) than non-metformin-treated (P=0.04, r=-0.38) patients. In ten B12 deficient patients, B12 supplementation (1,500 µg/day) for 2.2±1.0 months with continued use of metformin raised B12 levels: 152±42 and 299±97 pmol/L before and after treatment, respectively (P<0.01). Metformin-induced B12 lowering in diabetes was associated with elevation of homocysteine, and hyperhomocysteinemia was independently related to retinopathy. Metformin-induced B12 deficiency was correctable with B12 supplementation.


Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Angiopathies/chemically induced , Hyperhomocysteinemia/chemically induced , Hypoglycemic Agents/adverse effects , Metformin/adverse effects , Vitamin B 12 Deficiency/chemically induced , Aged , Coronary Disease/chemically induced , Coronary Disease/complications , Coronary Disease/epidemiology , Coronary Disease/physiopathology , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetic Angiopathies/complications , Diabetic Angiopathies/epidemiology , Diabetic Angiopathies/physiopathology , Diabetic Retinopathy/chemically induced , Diabetic Retinopathy/complications , Diabetic Retinopathy/epidemiology , Diabetic Retinopathy/physiopathology , Dietary Supplements , Dose-Response Relationship, Drug , Female , Homocysteine/agonists , Homocysteine/blood , Humans , Hyperhomocysteinemia/complications , Hyperhomocysteinemia/epidemiology , Hyperhomocysteinemia/physiopathology , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Japan/epidemiology , Male , Metformin/administration & dosage , Metformin/therapeutic use , Middle Aged , Prevalence , Risk Factors , Severity of Illness Index , Stroke/chemically induced , Stroke/complications , Stroke/epidemiology , Stroke/physiopathology , Vitamin B 12/antagonists & inhibitors , Vitamin B 12/blood , Vitamin B 12/therapeutic use , Vitamin B 12 Deficiency/complications , Vitamin B 12 Deficiency/diet therapy , Vitamin B 12 Deficiency/epidemiology
12.
Dent Assist ; 79(4): 22-3, 26, 28-30; quiz 32, 34, 2010.
Article in English | MEDLINE | ID: mdl-20853735

ABSTRACT

Nitrous oxide/oxygen sedation remains a viable option for managing a patient's pain and anxiety in the dental office. There are several advantages to its use and relatively few contraindications. Knowing how to minimize the operator's exposure to the gas is also an important consideration. N2O/O2 sedation has a long-standing history of safety and success and it is likely that this type of sedation will be used far into the future. It is necessary to educate the entire office team on the biohazard issues of nitrous oxide safety in the dental office and keep abreast of sound scientific literature in this area. Many states are starting to include nitrous oxide administration and monitoring in their state practice acts for dental assistants. Refer to your state practice act for current requirements in your location.


Subject(s)
Anesthesia, Dental/methods , Anesthetics, Inhalation , Conscious Sedation/methods , Nitrous Oxide , 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/antagonists & inhibitors , Anesthetics, Inhalation/adverse effects , Anesthetics, Inhalation/analysis , Body Burden , Contraindications , DNA/biosynthesis , Dental Waste/analysis , Humans , Nitrous Oxide/adverse effects , Nitrous Oxide/analysis , Occupational Exposure , Oxygen/administration & dosage , Vitamin B 12/antagonists & inhibitors
13.
Neurol Sci ; 30(1): 75-6, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19169627
15.
Rev Neurol (Paris) ; 156(6-7): 665-7, 2000 Jul.
Article in French | MEDLINE | ID: mdl-10891804
16.
Neurosci Lett ; 288(3): 191-4, 2000 Jul 21.
Article in English | MEDLINE | ID: mdl-10889340

ABSTRACT

Vitamin B12 is implicated in methylation processes. Myelin basic protein is methylated on one arginine group. A defect in methylation could produce an unstable protein, leading to neurological disorders. In order to study myelin basic protein, we have developed the cultures of newborn rat oligodendrocytes in vitamin B12-depleted medium. As these cells do not grow without serum, vitamin B12 is always present. We overcame this problem by using OH-cobalamin c-lactam, an antagonist of B12. To ensure that the system was vitamin B12 deficient, we measured the concentrations of homocysteine and methylmalonic acid whose accumulations reflect a vitamin B12 deficiency. Methylmalonic acid was measured by mass spectrometry and homocysteine by HPLC. We obtained a powerful model for studying the influence of B12 deficiency on the synthesis of myelin compounds.


Subject(s)
Oligodendroglia/drug effects , Oligodendroglia/metabolism , Peripheral Nervous System Diseases/metabolism , Vitamin B 12 Deficiency/metabolism , Vitamin B 12 Deficiency/pathology , Vitamin B 12/analogs & derivatives , Vitamin B 12/antagonists & inhibitors , Vitamin B 12/metabolism , Vitamin B 12/pharmacology , Animals , Animals, Newborn , Cells, Cultured , Culture Media, Conditioned/metabolism , Homocysteine/metabolism , Humans , Methylmalonic Acid/metabolism , Peripheral Nervous System Diseases/etiology , Peripheral Nervous System Diseases/pathology , Rats , Rats, Wistar , Vitamin B 12 Deficiency/complications
17.
Rev Neurol ; 29(1): 36-8, 1999.
Article in Spanish | MEDLINE | ID: mdl-10528308

ABSTRACT

INTRODUCTION: Nitrous oxide is a commonly used anaesthetic agent. One complication of this is due to its capacity to inactivate cobalamin. Therefore, in patients with poor reserves of vitamin B12, neurological and hematological alterations may be induced after a short period of exposure to nitrous oxide. CLINICAL CASE: A 69 year old man was anesthetized for three hours with 50% nitrous oxide during a surgical operation. Two weeks later he complained of severe mixed, mainly sensory polyneuropathy and was unable to walk. On diagnostic studies, vitamin B12 levels were found to be 18 pg/ml. The Shilling test confirmed that there was lack of intrinsic factor. In the preoperative studies a striking increase in motor conduction velocity was observed. Neurophysiological studies showed that there was mixed polyneuropathy, predominantly axonal. After starting treatment with hydroxycobalamin there was marked improvement and the patient became able to walk unaided. CONCLUSION: Since nitrous oxide may cause serious neurological alterations in patients with subclinical deficits of cobalamin, which may not always be accompanied by hematological changes, we consider the need for determination of plasma levels of vitamin B12 and if possible, of methylmalonic acid and homocysteine in elderly patients who are to have general anesthetics involving nitrous oxide.


Subject(s)
Anesthetics, Inhalation/adverse effects , Demyelinating Diseases/chemically induced , Nitrous Oxide/adverse effects , Postoperative Complications/chemically induced , Vitamin B 12 Deficiency/chemically induced , Vitamin B 12/antagonists & inhibitors , Aged , Axons/pathology , Blood Vessel Prosthesis Implantation , Humans , Intrinsic Factor/deficiency , Male , Nitrous Oxide/pharmacology , Paraplegia/chemically induced , Postoperative Complications/prevention & control , Preoperative Care , Sensation Disorders/chemically induced , Vitamin B 12/analysis
18.
Leuk Lymphoma ; 31(1-2): 21-37, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9720712

ABSTRACT

The vitamin B12 antagonist cyanocobalamin [c-lactam] was cytotoxic to cultured human leukemia cells, grown in methylfolate, homocysteine, and vitamin B12, but not in the presence of methionine. Small concentrations of methionine were effective in restoring the growth rate in a dose-dependent fashion, confirming methionine deficiency as the cytotoxic principle. Cyanocobalamin [c-lactam] prevented utilization of the methyl group of methylfolate, but no evidence of folate deficiency developed in long-term culture. High concentrations of non-methylated folate were unable to reverse the cytotoxicity, excluding a methylfolate 'trap' as the cause. Low concentrations of serine in the medium induced transient biochemical megaloblastosis. Cyanocobalamin [c-lactam] caused this to occur earlier, and persist. In high concentrations of serine, the inhibitor caused only transient changes in deoxyuridine suppression. Homocysteine cannot be remethylated without vitamin B12, and condensation with serine is the only other excretory pathway for this toxic amino acid. We hypothesize that impaired DNA synthesis in vitamin B12 deficiency is the result of diverting serine away from thymidylate synthesis, into homocysteine metabolism.


Subject(s)
Leukemia/drug therapy , Vitamin B 12/antagonists & inhibitors , 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/antagonists & inhibitors , Cell Survival/drug effects , Enzyme Inhibitors/pharmacology , HL-60 Cells , Humans , K562 Cells , Linear Models , Logistic Models , Methylmalonyl-CoA Mutase/drug effects , Structure-Activity Relationship
19.
AJNR Am J Neuroradiol ; 19(5): 894-6, 1998 May.
Article in English | MEDLINE | ID: mdl-9613506

ABSTRACT

We describe a case of myeloneuropathy resulting from nitrous oxide abuse. MR imaging of the spine revealed symmetric abnormal signal in the posterior columns of the cervical cord. Myeloneuropathy is caused by inactivation of vitamin B12 by nitrous oxide. This syndrome can also be seen in patients with borderline vitamin B12 deficiency who have recently been anesthetized with nitrous oxide.


Subject(s)
Nitrous Oxide/poisoning , Spinal Cord Diseases/chemically induced , Substance-Related Disorders/complications , Adult , Humans , Magnetic Resonance Imaging , Male , Neck , Spinal Cord/pathology , Spinal Cord Diseases/diagnosis , Spinal Cord Diseases/drug therapy , Vitamin B 12/antagonists & inhibitors , Vitamin B 12/therapeutic use
20.
Blood ; 89(12): 4600-7, 1997 Jun 15.
Article in English | MEDLINE | ID: mdl-9192785

ABSTRACT

The [c-lactam] derivative of cobalamin antagonizes vitamin B12 in vivo. Therefore, we investigated its effects in tissue culture to develop a model in which to study vitamin B12-deficient hemopoiesis. HL60 cells were cultured in medium containing either methionine or L-homocysteine thiolactone, and various concentrations of 5-methyltetrahydrofolate or pteroylglutamic acid. In medium with L-homocysteine thiolactone, 5-methyltetrahydrofolate, and dialyzed serum, cyanocobalamin [c-lactam] caused cell death, reversible by additional vitamin B12. Pteroylglutamic acid did not prevent this cytotoxic effect. Methionine completely protected cells against cyanocobalamin [c-lactam] for periods of up to 4 months of culture, irrespective of the folate source. Cyanocobalamin [c-lactam] reversibly impaired the incorporation of 5-[14CH3]-tetrahydrofolate and [1-(14)C] propionic acid by intact cells, consistent with inhibition of methionine synthase and methylmalonyl-CoA mutase. A substantial proportion of 5-[14CH3]-tetrahydrofolate uptake could not be suppressed by methionine and may, therefore, have occurred outside of the methionine synthase pathway. These findings are the first indication that cyanocobalamin [c-lactam] antagonizes vitamin B12 in vitro and causes cell death from methionine deficiency. The model should be valuable for investigating the biochemical pathology of vitamin B12-deficient hemopoiesis. The results suggest that methylfolate is not trapped when methionine synthase is inhibited in HL60 cells, but they do not disprove the methylfolate trap hypothesis as applied to normal blood cells.


Subject(s)
Enzyme Inhibitors/pharmacology , HL-60 Cells/drug effects , Hydroxocobalamin/pharmacology , Methionine/pharmacology , Vitamin B 12/antagonists & inhibitors , 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/antagonists & inhibitors , Cell Death/drug effects , Folic Acid/pharmacology , Homocysteine/analogs & derivatives , Homocysteine/pharmacology , Humans , Hydroxocobalamin/antagonists & inhibitors , Methionine/deficiency , Methylmalonyl-CoA Mutase/antagonists & inhibitors , Propionates/metabolism , Tetrahydrofolates/metabolism
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