Pyridoxine deficiency response

Isoniazid is bactericidal for growing tubercle bacilli, is absorbed orally, and is metabolized by acetylation. It is a structural analogue of pyridoxine and may cause pyridoxine deficiency, peripheral neuritis and, in toxic doses, pyridoxine-responsive convulsions. Its mechanism of action is not known. 

Lakshmi, R. et al., Effect of riboflavin or pyridoxine deficiency on inflammatory response, Indian. J. Biochem. Biophys., 28, 481, 1991. 

Cystathionine P-synthase deficiency is an autosomal recessive trait (Fig. 47.1). It is the most common cause of homocystinuria and is the second most treatable disorder of amino acid metabolism. Some patients respond to pyridoxine treatment but others are pyridoxine non-responsive. Orally administered betaine often lowers serum homocysteine concentrations. 

Elevations of serum iron occur in various other pathological conditions hemolytic anemia, lead toxicity, pyridoxine deficiency, pernicious anemia, acute liver necrosis, and iron poisoning. Serum transferrin levels usually decrease in these cases and the percent saturation increases in response to increased iron in the extracellular fluid. Desferrioxamine, a siderophote from actinomycetes, has been used to treat patients with acute iron toxicity (30,31]. The toxicity of iron was reviewed in a previous volume of this series [6]. 

In cats, pyridoxine deficiency is associated with the formation of calcium oxalate calculi in the kidneys. The magnesium and pyridoxine levels in the diet are related. Diets low in magnesium are responsible for increased incidence and severity of the oxalate lithiasis in the kidney, and the effect of the low-magnesium diet is counteracted by the administration of pyridoxine. These observations made in animals may have some relevance to the development of lithiasis in humans. Patients with recurring calcium oxalate stones in the kidney secrete more xanthurenic and pyridoxic acid than normal individuals, suggesting that lithiasis may result from deficient pyridoxine metabolism, possibly due to accelerated breakdown of the coenzyme. If other signs of pyridoxine deficiency develop, one must assume that the accelerated breakdown occurs only in a few organs, probably only in the kidneys. 

Although it is possible to describe the clinicopatho-logical manifestations of pyridoxine deficiency and the metabolic role of pyridoxal phosphate, each pathological alteration cannot be explained by a specific metabolic alteration. Deficiency of a vitamin involved in several steps of the intermediary metabolism of amino acids is bound to be associated with severe clinicopath-ological changes, but the specific metabolic alterations responsible for the anemia and convulsions in pyridoxine deficiency have not been identified. y-Amino butyric acid, cystathione, sphingosine, and 5-hydroxy-tryptamine are compounds abundant in the brain. Pyridoxal phosphate is involved in their metabolic formation. Is there any correlation between the role of pyridoxal phosphate in the metabolism of these compounds and the development of convulsions and ataxia in pyridoxine deficiency Is the role of pyridoxine phosphate in the intermediary metabolism of sulfur amino acid related to the development of seborrheic dermatitis ... 

Figure 1. Effect of Repeated Antigenic Stimuli upon Antibody Response in Pyridoxine-deficient and Control Rats. Injections of Diphtheria Toxoid Given at Times Indicated by the Arrows. Animals were Fed the Pyridoxine-deficient or the Control Diet during the Entire Course of the Study, and were on Experiment for Four Weeks Prior to the First Toxoid Injection, Figures on the Ordinate Represent Reciprocal Titers. Used by Permission, from Axelrod (1958), Copyright by the American Society for Clinical Nutrition, Inc,...

Effect of Pyridoxine-deficiency upon Circulating Antibody Response to Alum-precipated Diphtheria Toxoid ... 

Figure 4. Growth Responses of Recipient CBA/J mice. Periods during which the Purified Control (Complete) and Pyridoxine-deficient Diets were Fed are Indicated by the Unbroken and Broken Lines, Respectively. DB Refers to Deoxypyridoxine, A Single Injection of 0.5 ml of a Suspension of Splenic Cells (0.8 to 1,0 X 10 Cells) was Administered Intraperitoneally at the Indicated Times. Used by Permission, from Axelrod and Trakatellis (1964). Copyright by Academic Press.

The development of a method suitable for the study of antibody synthesis by individual cells has facilitated investigations of antibody synthesis at the cellular level (Jerne and Nordin, 1963). With this procedure, we have demonstrated a dramatic reduction in the number of antibody-forming cells in the spleens of pyridoxine-deficient rats immunized with sheep erythrocytes (Figure 6) (Kumar and Axelrod, 1968). This decreased cellular immune response was independent of the inanition associated with the deficiency and was... 

Pyridoxine is present in food in the free form and as a glucoside, which may undergo partial hydrolysis in the gut lumen, or may be absorbed intact. Although pyridoxine is associated with the enzyme glycogen phosphorylase in muscles, it is not released in response to a dietary deficiency therefore it cannot be regarded as a storage form of the vitamin. 

Pyridoxine is indicated in vitamin B deficiency, for the treatment of some pyridoxine responsive anemia s and for isoniazid-induced neuropathy. It may relieve symptoms of pellagra when niacin fails. Long-term administration of large doses may produce neurotoxicity manifesting itself in progressive peripheral sensory neuropathy. 

AASA dehydrogenase deficiency (pyridoxine-responsive convulsions). 

The homocystinurias are a group of disorders involving defects in the metabolism of homocysteine. The diseases are inherited as autosomal recessive illnesses, characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine /3-synthase, which converts homocysteine to cystathionine (Figure 20.21). Individuals who are homozygous for cystathionine [3-synthase deficiency exhibit ectopia lentis (displace ment of the lens of the eye), skeletal abnormalities, premature arte rial disease, osteoporosis, and mental retardation. Patients can be responsive or non-responsive to oral administration of pyridoxine (vitamin B6)—a cofactor of cystathionine [3-synthase. Bg-responsive patients usually have a milder and later onset of clinical symptoms compared with B6-non-responsive patients. Treatment includes restriction of methionine intake and supplementation with vitamins Bg, B, and folate. 

Apparently the content of the active metabolite pyridoxamine S -phosphalc is lower in human than in mouse or hamster skin.120 When inflammatory response was assessed in a pyridoxine or riboflavin deficient rat model, data suggested enhanced inflammation in pyridoxine but not riboflavin... 

For prevention of disease in the elderly, the pregnant, or other susceptible groups, national fortification of food with vitamin B12 appears sensible and inexpensive but at present is not used and, in the absence of population screening s unlikely to be mandated by governmental edict. In general terms, the hematological manifestations of vitamin B12 deficiency are rapidly and fully correctable, although deficiencies of other micronutrients such as iron, folic acid, pyridoxine, copper, or vitamin C may be unmasked in the process and may limit the bone marrow s response until they are also corrected. 

Like glutathione reductase, pyridoxine oxidase is sensitive to riboflavin depletion. In normal subjects and in experimental animals, the EGR and pyridoxine oxidase activation coefficients are correlated, and both reflect riboflavin nutritional status. In subjects with glucose 6-phosphate dehydrogenase deficiency, there is an apparent protection of EGR, so that even in riboflavin deficiency it does not lose its cofactor, and the EGR activation coefficient remains within the normal range. The mechanism of this protection is unknown. In such subjects, the erythrocyte pyridoxine oxidase activation coefficient gives a response that mirrors riboflavin nutritional status (Clements and Anderson, 1980). 

Glutamate is utilized in metabolic interaaions with other amino acids and is formed into new proteins. One route by which glutamate can be removed is through reaaions that require vitamin B6 (pyridoxine), and individuals who are deficient in this vitamin may suffer greater effeas from excess MSG. Glutamate also has an important role in the brain where it acts as an excitatory neurotransmitter, increasing the aaivity of nerve cells, ft is responsible for most of the interactions between nerve cells in the brain, for example those involved in memory... 

One patient has been found with this deficiency (All). Hie patient, an infant, was mentally retarded, had a megaloblastic anemia and abnormally high levels of serum and erythrocyte folate. In spite of the high serum folate concentration there was a marked rise in the reticulocyte count when the patient was treated with folate. It was thought that the patient had impaired utilization of -methyltetrahydrofolate. Assay of liver W -methyltetrahy-drofolate transferase showed it to be reduced. It was suggested that folate accumulated at the N -methyltetrahydrofolate block and could therefore not be further utilized. Treatment with pteroylglutamic acid provided a means of producing active folate up to the point of the block. Unfortunately this patient was also treated with pyridoxine, and it is not clear which vitamin was responsible for the reticulocyte response. Further studies are required to determine the precise nature of this metabolic disorder. 

A8. Arakawa, T., Tamura, T., Higashi, O., Ohara, K., Tanno, K., Honda, Y., Narisawa, K., Konno, T., Wada, Y., Sato, Y., and Mizuno, T., Formiminotransferase deficiency syndrome associated with megaloblastic anaemia responsive to pyridoxine or folic acid. Tohoku J. Exp. Med. 94, 3-16 (1968). 

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