Vitamin Bg deficiency

Isoniazid Take this drug 1 hour before or 2 hours after meals. However, if gastric upset occurs, take isoniazid with food. Notify the primary health care provider of weakness, yellowing of the skin, loss of appetite, darkening of the urine, skin rashes, or numbness or tingling of the hands or feet. Avoid tyrainine-containing foods (see Chap. 31). To prevent pyridoxine (vitamin Bg) deficiency, 6 to 50 mg of pyridoxine daily may be prescribed. 

Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially in transamination and decarboxylation. It is also the cofactor of glycogen phosphorylase, where the phosphate group is catalytically important. In addition, vitamin Bg is important in steroid hormone action where it removes the hormone-receptor complex from DNA binding, terminating the action of the hormones. In vitamin Bg deficiency, this results in increased sensitivity to the actions of low concentrations of estrogens, androgens, cortisol, and vitamin D. 

Vitamin Bg deficiency, iron deficiency, and lead poisoning all can cause anemia. These three conditions are summarized and compared in Ihble 1-17-6. 

The terminology vitamin Bg covers a number of structurally related compounds, including pyridoxal and pyridoxamine and their 5 -phosphates. Pyridoxal 5 -phosphate (PLP), in particular, acts as a coenzyme for a large number of important enzymic reactions, especially those involved in amino acid metabolism. We shall meet some of these in more detail later, e.g. transamination (see Section 15.6) and amino acid decarboxylation (see Section 15.7), but it is worth noting at this point that the biological role of PLP is absolutely dependent upon imine formation and hydrolysis. Vitamin Bg deficiency may lead to anaemia, weakness, eye, mouth, and nose lesions, and neurological changes. 

Pyridoxine vitamin Bf) deficiency symptoms are generally expressed as alterations in the skin, blood, and central nervous system. Symptoms include sensory neuritis, mental depression, and convulsions. Hypochromic, sideroblastic anemia also may result. Since pyridoxine is required for the conversion of tryptophan to diphos-phopyridine and triphosphopyridine nucleotides, pellagralike symptoms can occur with vitamin Bg deficiency. This deficiency is found most often in conjunction with other B complex deficiencies. 

Pyridoxal phosphate has a clear role in lipid metabolism as the coenzyme for the decarboxylation of phosphatidylserine, leading to the formation of phosphatidylethanolamine, and then phosphatidylcholine (Section 14.2.1), and membrane lipids from vitamin Bg-deficient animals are low in phosphatidylcholine (She et al., 1995). It also has a role, less well defined, in the metabolism of polyunsaturated fatty acids vitamin Bg deficiency results in reduced activity of A desaturase and impairs the synthesis of eicosapentanoic and docosahexanoic acids (Tsuge et al., 2000). 

As discussed in Section 9.3.3, pyridoxal phosphate is involved in the regulation of gene expression, terminating the responses to steroid hormones and inactivating some tissue-specific transcription factors. There is decreased synthesis of pancreatic digestive enzymes in vitamin Bg deficiency, although the synthesis of other pancreatic proteins is unaffected (Dubick et al., 1995). 

It is apparent that abnormally increased excretion of kynurenine metabolites after a test dose of tryptophan cannot necessarily be regarded as evidence of vitamin Bg deficiency. This means that the tryptophan load test is unreliable as an index of status in epidemiological studies, although it is (probably) reliable in depletion/repletion studies to determine requirements. 

The metabolism of methionine, shown in Figure 9.5, includes two pyri-doxal phosphate-dependent steps cystathionine synthetase and cystathionase. Cystathionine synthetase is litde affected by vitamin Bg deficiency,... 

Central effects on blood pressure regulation as a result of decreased synthesis of brain GABA and serotonin (5-hydroxytryptamine). Glutamate decarboxylase activity in the nervous system is especially sensitive to vitamin Bg depletion, possibly as a result of mechanism-dependent inactivation by transamination. Although there is no evidence that aromatic amino acid decarboxylase activity is reduced in vitamin Bg deficiency, there is reduced formation of serotonin in the central nervous system. 

Increased sympathetic nervous system activity. There is evidence of elevated plasma concentrations of adrenaline and noradrenaline in vitamin Bg-deficient animals. 

Increased uptake of calcium by arterial smooth muscle, leading to increased muscle tone, and hence increased circulatory resistance and blood pressure. This could reflect increased sensitivity of vascular smooth muscle to calcitriol (vitamin D) action in vitamin Bg deficiency the membrane calcium-binding protein is regulated by vitamin D, and vascular tissue has calcitriol receptors. 

Deficiency of vitamins Bg, B12, or folate are aU associated with elevated plasma homocysteine, with vitamin Bg deficiency as a result of impaired activity of cystathionine synthetase (Section 9.5.5) and folate and vitamin B12 as a result of impaired activity of methionine synthetase (Section 10.3.4). In subjects with apparently adequate intakes of vitamins Bg and B12, supplements of these two vitamins have little or no effect on fasting plasma homocysteine, although additional vitamin Bg reduces the plasma concentration of homocysteine after a test dose of methionine. By contrast, supplements of... 

In vitamin Bg-deficient experimented emimals, there are skin lesions (e.g., acrodynia in the rat) emd fissures or ulceradon at the corners of the mouth emd over the tongue, as well as a number of endocrine abnormalides defects in the metabolism of tryptophan (Secdon 9.5.4), methionine (Section... 

The observation of a chronic urticaria in two sisters who excreted abnormal amounts of xanthurenic acid after a 10-g DL-tryptophan load indicated to Knapp et al. (K6) that constitutional genetic factors may be involved in vitamin Bg-deficiency symptoms. This was borne out by a very high xanthurenic acid level during a similar test on another family. 

G4. Gershoff, S. N., and Faragalla, F. F., Endogenous oxalate synthesis and glycine, serine, deoxypyridoxine interrelationships in vitamin Bg-deficient rats. ]. Biol. Chem. 234, 2391-2393 (1959). 

K6. Knapp, A., Kupke, G, and Gassmann, B., Excretion of tryptophan metabolites in a family with essential vitamin Bg deficiency. Emaehruttgsforschung 3, 546-553 (1958) Chem. Abstr. 53, 14257 (1959). 

SIO. Sue, C. L., Relation between vitamin Bg deficiency and blood poisoning in pregnancy. Sheng Li K o Hsueh Ti Chin. Chan. 1, 366-375 (1957) Chem. Abstr. 55, 10620 (1961). 

In pronounced vitamin Bg deficiency due to alcohol abuse, GPT formation may be inhibited, so that GPT activities appear misleadingly low. 

In 20-25% of cases, side effects are observed, depending mainly on the dose (hypersensitivity reactions, aphthous lesions, arthralgia, nausea, fever). All in all, treatment of Wilson s disease with penicillamine is considered to be successful and safe. If jrenicill-amine is not well tolerated or if serious side effects are observed (e.g. kidney or bone-marrow damage, polyneuropathy, pemphigus), treatment must be discontinued. Penicillamine usually causes pyridoxin deficiency, so that substitution (25—40 mg/day) is recommended, particularly as chronic liver damage also leads to vitamin Bg deficiency. If necessary, electrolytes and trace elements also have to be substituted. 

Most of the vitamin in the body is eventually degraded to pyridoxic acid (PX) and excreted in the urine. Vitamin Bg deficiency can result in a decrease in the amoimt of PX excreted, as illustrated by the data in Table 9.4. Human subjects who had consinned a Bg-sufficient diet were fed a Bg-deficient diet for 45 days. The results... 

Isonicotinyl hydrazide (INH), one of the most effective drugs against tuberculosis, is inhibitory to pyridoxal kinase, the enzyme that converts pyridoxal to PLP. Apparently, the drug reacts with pyridoxal to form a hydrazone which blocks the enzyme. Pyridoxal kinase is not the primary target of INH in mycobacteria. However, patients on long-term isonicotinyl hydrazide therapy sometimes suffer symptoms of vitamin Bg deficiency. ... 

Abnormal response to a metabolic load, such as the inability to metabolize a test dose of histidine in folate deficiency (Section 10.10.4), or tryptophan in vitamin Bg deficiency (Section 9.5.4), tdthough at normal levels of intake there may be no metabolic impairment... 

In vitamin Bg-deficient experimental animals, there are skin lesions (e.g., acrodynia in the rat) and fissures or ulceration at the corners of the mouth and over the tongue, as well as a number of endocrine abnormcdities defects in the metabolism of Uyptophan (Section 9.5.4), methionine (Section 9.5.5), and other amino acids hypochromic microcytic anemia (the first step of heme biosynthesis is pyridoxal phosphate dependent) changes in leukocyte count and activity a tendency to epileptiform convulsions and peripheral nervous system damage resulting in ataxia and sensory neuropathy. There is also impairment of immune responses, as a result of reduced activity of serine hydroxymethyltransferase and hence reduced avtdlability of one-carbon substituted folate for nucleic acid synthesis (Section 10.3.3). It has been suggested... 

The rates of synthesis and catabolism of some pyridoxal phosphate-dependent enzymes are altered in deficiency. For exttmple, within a few days of feeding a vitamin Be-free diet to animals, there is a fall in the activity of cysteine sulfinate decarboxylase in liver after 2 weeks, the amount of the enzyme protein has fallen to extremely low levels. It is likely that these enzymes are sacrificed to release pyridoxal phosphate for other, more essential enzymes. Other enzymes show the opposite response - apparent induction of the apoenzyme in vitamin Bg deficiency, presumably in an attempt to trap as much of the available pyridoxal phosphate as possible. Sato tmd coworkers (1996) demonstrated increased catabolism of apocystathionase in vitamin Be deficiency, but no decrease in the amount of immunoreactive protein in the liver, as a result of increased transcription. 

Prolonged systemic therapy with EDTA has resulted in zinc and vitamin Bg deficiencies. Furthermore, febrile reactions with headache, myalgia, nausea, vomiting, lachrymation, nasal lesions, glycosuria, hypotension, and electrocardiographic (ECG or EKG) changes have been reported. 

Although several mechanisms have been proposed to be responsible for causing CRS, none has been extensively studied. One hypothesis has been that the effects are due to an immediate hypersensitivity reaction. Since no IgE-mediated reaction has been documented, there is no direct evidence that this is the case. Another hypothesis is that vitamin Bg deficiency plays a role in the response because the symptoms were prevented by supplementing individuals with the vitamin. Since glutamate can be converted to acetylcholine by the tricarboxylic acid cycle, it has also been proposed that the effects are due to an increase in acetylcholine levels. It has been noted that after MSG ingestion, there is a decrease in cholinesterase levels. Due to inadequate investigations, it is not currently known if any or all of these mechanisms are responsible for CRS. The neurotoxicity of MSG, demonstrated after exposure... 

A deficiency of vitamin Bg alone is uncommon, and it is more usual to expect the problem to occur in association with deficits in other vitamins of the B-complex. As with other water-soluble vitamins that function as coenzymes, the relative affinity of the coenzyme for a given apoenzyme and the extent to which a particular holoenzyme-catalyzed reaction is essential are reflected in the progressive symptomatology of deficiency of the vitamin. Investigations of the consequences of vitamin Bg deficiency in the human use... 

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