Vitamin B, Reservoirs, Receptors, and Red-Cell Reactions JAMES E. LEKLEM Department of Niirrition and Food Management Oregon State University Corvallis, Oregon 97331-5103

INTRODUCTION Over the past sixty years there have been significant advances in our understanding of the role vitamin B6 plays in the body. In addition, the requirement for this vitamin has been examined,l,’ and recommendations for allowances have been put forth.3 The current amounts proposed are less than those previously recommended. Although the absolute change is not large (0.2 to 0.4 mg/d), such changes raise the question of how vitamin B, need is set. Some researchers feel the current RDA is more than adequate.2 This concept is based on body pools and associated turnover of these pools. Coburn has estimated that 2 pmol(0.34 mg) is the minimal requirement for a 70 kg adult. This minimal amount does not necessarily tell us what is needed for optimal health and for variation in macrodietary factors such as protein, carbohydrate, and micronutrients, such as riboflavin and As research moves (but does not leave) from understanding what the vitamin B, needs are for preventing a deficiency to understanding what the needs are for optimal health, taking into consideration nutrient-nutrient interaction and effects of specific physiological stressors, there are several questions that arise. I would raise three (related) questions related to needs above those centered around deficiency prevention. As these questions are raised, we must not forget to ask what the 2 Fmol minimum requirement suggested by Coburn* represents. These three questions are ( I ) Does the present RDA (at all ages) for vitamin B, result in tissue levels that lead to optimal health? ( 2 ) Does the present RDA for vitamin B6 provide for tissue levels that are preventive in terms of specific diseases? and (3) Are there needs for vitamin B, that go beyond that for maintenance of normal metabolism? Present data does not permit a full answer to these three interrelated questions. Recent conference^,^.^ including the present one, point to a growing interest in the use of vitamin B, for treatment and/or reduced risk of disease states. In addition, there are non-disease physiological situations that are to be considered. Physical exercise and the aging process are examples of this latter situation. If one goes beyond deficiency prevention, there are examples of “newer” suggested roles for vitamin B6. Several of these are listed in TABLE1. Space does not permit a full discussion of all of these, and the reader is referred to recent publicat for additional details. In considering the role and mechanism of action vitamin B, may have in these conditions, I have chosen to focus on the active form of vitamin B,, pyridoxal 5’-phosphate (PLP). The high reactivity of PLP is a unique property that leads to the possibility that vitamin B, has functions beyond that of a coenzyme. A further consideration relative to the list in TABLE 1 is the range in the amounts of vitamin B6 used. Doses of 20 to 30% of the RDA to 50-75 times the RDA for vitamin B, have been employed. Thus, there is the 34



question of whether vitamin B, is considered to be functioning as a nutrient or having more of a pharmacologic effect. The three areas discussed below are ones in which either of these possibilities exist. These three areas are the reservoirs of vitamin B,, vitamin Bh and steroid-receptor interaction, and effect of vitamin B, on red cell reactions.

METABOLISM AND FUNCTiON Before proceeding to the role of vitamin B, in these three areas, a brief description of the metabolism and functions of vitamin B, pfovides a framework for understanding other possible roles for this vitamin. Vitamin B, exists as three separate forms in foods: pyridoxine, pyridoxamine, and pyridoxal. In addition to each being present as the phosphorylated form, there also is a glucoside form of pyridoxine that exists in variable amounts in plant foods.' Subsequent to dephosphorylation, the three forms are absorbed by a nonsaturable, passive process.8 At high intakes there may be a saturable component, however.9 Detailed balance studies of intakes >50 mg are lacking. After absorption

Newer Suggested Roles for Vitamin B, in Disease States and Selected Pathological Conditions"


Premenstrual syndrome (PMS) Carpal tunnel syndrome (CTS) Modification of steroid action Diabetes: altering glycosylation Immune function Calcium channel blocker For some of these conditions there is limited evidence for supplemental vitamin B, being therapeutic.

into the intestinal cell, each of the three forms can be converted to its phosphorylated form; however, they enter the circulation in mainly the nonphosphorylated form. The liver takes up the three forms and each is ultimately converted to PLP. In addition to PL, pyridoxine (PN) and pyridoxamine (PM) are converted to PNP and PMP by a kinase. These latter two phosphorylated forms are then converted to the active coenzyme, PLP, by way of a flavin mononucleotide-dependent oxidase reaction. Pyridoxal is converted to 4-pyridoxic acid (4-PA) by an aldehyde oxidase (another riboflavin-dependent (FAD) reaction). This reaction is irreversible, and urinary 4-PA is the major metabolic product of vitamin B,." The interconversion of the various forms of vitamers of B, is tightly regulated to ensure that the intracellular concentration of PLP is not too high.'.'' The quantitative aspects of vitamin B, metabolism in human liver has been determined" and recently reviewed.'* When considering the use of pyridoxine (as the hydrochloride) for supplementation (and food fortification), it is important to recognize that the three forms are quantitatively metabolized to a different Compared to an oral dose of PN, more of an equimolar dose of PL is converted to 4-PA and less to PLP. l 3 The liver is considered to be the primary source of PLP in the plasma. For this B6 vitamer, however, PL is thought to be the form that is transported across cell



membranes. All three nonphosphorylated forms are taken up by cells; however, some tissues such as muscle have a low PNP (PMP)oxidase activity, and thus PL is the only form that contributes to PLP levels in muscle. The red cell is not a tissue as such but is considered an important contributor to vitamin B6metabolism and transport.15316 A majority of the total vitamin B6 in plasma exists as PLP (75% of total) bound to albumin. RESERVOIRS There is a growing appreciation that although vitamin B, is a water soluble vitamin, there is significant storage within the muscle. Also, there are numerous pools of vitamin B6 within the body. Coburn and associates have studied these body pools and estimated the turnover of vitamin B6.*These studies have been done in rats, and using compartmental modeling, he has found that even 75 pools do not adequately model all the vitamers in every tissue. Based on literature value^,'^"^'^ an estimate of the amounts in several of the body pools is given in TABLE 2. Within a given tissue, there are no doubt multiple pools distributed in the cytoplasm, mitochondria, and nucleus. Binding affinity of TABLE 2. Estimated Body Pools of Vitamin B,"



Amount pmol/pool

Blood plasma Erythrocyte Liver Muscle Other tissues

0.12-0.24 0.08-0.20 18-24 800- 1000 15 nmol/g

These data are based on data from Coburn" and Leklem.'

PLP to specific proteins will influence the relative availability of vitamin €3, within and between tissues. As is evident in TABLE 2, of the tissues in the body, muscle tissue is the major pool. A majority of this pool is PLP bound to glycogen phosphorylase. The circulating pools of vitamin B6 are quite small and respond quickly to a change in vitamin B6 intake.13,14,16 The question of what conditions affect the availability of the pools of vitamin B, to other tissues is an important one. Also, to what extent do these pools change with a change in vitamin B, intake? Muscle vitamin B, content in adults does not change significantly with a decrease in vitamin B, intake, but a supplement of 0.95 mmol/day (160 mg) of pyridoxine to men increased total vitamin B, in muscle from 28 2 10 to 35 2 10 nmol/g (25% increase). The vitamin B, in muscle of rats appears to respond to decreased caloric intake" but not a decrease in the intake of vitamin B,. In studies in my laboratory, we have seen increased 4-PA urinary excretion in fasted rats the first and second day of fasting compared to non-fasted days (50% increase). Thus, vitamin B6 was being lost from tissues at a time when there was no intake of the vitamin. The exact source of this loss is not known but may have come from muscle or liver pools. Strenuous exercise in humans can be viewed as a condition of short-term



caloric deprivation. During and immediately following exercise, we and others have observed increased plasma levels of PLP.20-22This increase ranges from 10-35% and has been observed with running and cycling at values of 60-80% to VO, maximum. In addition, we have observed a significant decrease in plasma PLP concentration 30and 60 min following the end of the exercise. These decreases are as great or greater than the increase observed immediately following exercise. When these changes are viewed together, we see there is a significant flux (10-20 nmol/L over 2 hours) in persons with pre-exercise PLP concentrations of 35-55 nmol/L. The source of this PLP has been postulated to be either muscleZoor liver.*' Studies to date do not permit us to determine which is the source. We have observed, however, an increased excretion of 4-PA in trained women compared to untrained women. Although the difference was only about 1.0 pmollday (0.17 mg/day), this suggests that the changes observed in plasma PLP with exercise result in net loss of vitamin B,.22 Such a loss should be considered in establishing vitamin B, requirements.

VITAMIN B6 AND STEROID RECEPTOR INTERRELATIONSHIPS One of the more intriguing and newer areas of vitamin B, research is the relationship between PLP and steroid hormone action. A recent review by Allgood and Cidlowski provides an excellent perspective on this interrelationship.23Because PLP is a highly reactive molecule, it is capable of reacting with amine groups.' In particular, PLP reacts with the E amino group of lysine to form a Schiff base. This reaction is key in understanding the PLP-steroid receptor effects. Earlier studies of vitamin B6 receptor interaction found that PLP was an effective compound for extracting steroid receptors from the nuclei of tissues on which the steroid acts.24Subsequent work indicated that under conditions in which there are physiologically relevant concentrations of PLP, reversible reactions occur with receptors for estrogen, androgen, progesterone, and g l u c o c o r t i ~ o i d sThe .~~~~~ review of Allgood and Cidlowski summarizes their work and that of others and points to vitamin B, (as PLP) functioning as a modulator of steroid hormone action. Their work can be summarized as follows: (1) PLP acts to moderate two properties of steroid receptors, the binding of steroid to DNA and the nuclear localization of steroids. ( 2 ) PLP is specific in its effect of altering the conformation of the glucocorticoid receptor. (3) PLP affects several properties of steroid hormone receptors by way of a direct interaction of PLP with the receptor and not through receptor-associated protein^.^ The in uiuo action of PLP does not appear to involve .~ are in a change in receptor number or binding capacity of the h ~ r m o n e There uiuo effects of steroids that are altered depending on vitamin B, status. As an example, the induction of tyrosine aminotransferase by glucocorticoid administration is increased when there is a decreased intake of vitamin B,. In earlier work, by Leklem and Brown (unpublished), we have observed an increased induction (20-30%) of tryptophan oxygenase (a non-vitamin B,-dependent enzyme) by cortisol in vitamin B,-deficient rats as compared to vitamin B6-adeqUate rats. The precise mechanism by which PLP modulates steroid hormone must await further work. There is the strong possibility, however, that vitamin B6 modifies the endocrine system by way of interaction of PLP with steroid receptors. One of the potential clinical situations in which this interaction may play a role is premenstrual syndrome (PMS). This syndrome affects many women and presents with a variety of symptoms. As many as 10% of the women have premenstrual



symptoms that adversely affect their lives.27There are a number of nutritional and hormonal therapies that have been used for treating this syndrome.28These include vitamin E, magnesium, vitamin B,, and progesterone. These compounds have been used singly and in various combinations and resulted in equally variable outcomes. Because of the relative lack of consistency in design and range of intake\ used, it is not possible to make a definitive statement as to the efficacy of vitamin B, as a treatment for PMS. A review by Kleijnen et al. summarizes the 12 controlled trials in which vitamin B, was used singly.29These authors concluded that the evidence of positive effects of vitamin B, is weak.

VITAMIN B6 AND THE RED CELL 'The human red cell (erythrocyte) contains the necessary enzymes to convert the three forms of vitamin B, (pyridoxine, pyridoxal, and pyridoxamine) to the active coenzyme, PLP.3'' Pyridoxine is known to be rapidly taken up by the red cell and converted to PLP." Inasmuch as there is both stromal and soluble phosphatase activity in the red cell, the PLP can be converted to PL and the PL can exit the red cell. This PL, once in the plasma, could be taken up by other tissues and converted to PLP. By this mechanism, the red cell could serve a transport role for delivery of vitamin B, to tissues. The extent to which this does or does not occur is not known. Currently, the liver is still considered the primary source of circulating PLP and probably PL.' In considering the role that the red cell plays in vitamin Bh metabolism, it is important to consider the binding of PLP and PL to proteins within the red cell. PLP binds tightly to the p chain of hemoglobin, and PL binds to the alpha chain.j' Because of this binding, especially for PLP, the subsequent availability of PL (from hydrolysis of PLP) would appear to be limited. The binding of PL would also h i t its availability. 'the binding of PLP and PL to hemoglobin affects the oxygen affinity. As a result of PLP binding to the chain of deoxyhemoglobin, there is decreased oxygen affinity, whereas pyridoxal binding to the alpha chain results in an increase in oxygen affinit~.~' This differential affect thus makes it difficult to predict what effect increased vitamin B, levels in the red cell might have, if any, on oxygen delivery to tissues.




One of the potential consequences of PLP binding to hemoglobin may be an alteration in the amount of glycated hemoglobin. In persons with diabetes mellitus, the amount of glycated hemoglobin is considered an indicator of long-term glucose control. The presence of high levels glycated hemoglobin is indicative of a reversible Amadori product by way of a nonenzymatic p r o ~ e s s .Solomon ~ ~ . ~ ~and coworkers have found that administration of high-dose vitamin B, (150 mg of PN-hydrochloride per day) for six weeks resulted in decreased levels of hemoglobin A lc.35 This level of supplementation also decreased erythrocyte hemoglobin 0, affinity (PSO). These observations suggest vitamin B, supplementation has a beneficial role for persons with diabetes. Are there other metabolic changes in diabetes that might affect glycosylation or have other adverse effects? Several studies have found that



a significant proportion of people with either type I or type I1 diabetes mellitus have low plasma levels of B, v i t a m e r ~ . Related ~ ~ - ~ ~to this is the observation that acute ingestion of glucose depresses plasma PLP concentration 20-30% within 1-2 hours following a glucose load.39 The mechanism for this decrease is not known but may be related to insulin ~ e n s i t i v i t yand ~ ~ increased release of alkaline phosphatase from cell membrane^.^^ Persons with diabetes mellitus have an elevated plasma (serum) alkaline phosphatase (AP) activity.42This elevated AP activity may in part explain the decreased plasma PLP level observed in diabetes mellitus. The lower circulating PLP levels in persons with diabetes may have an effect on several cellular processes that could in turn have adverse clinical effects. FIGURE 1 illustrates several of these possibilities. Space does not permit a detailed explanation of each of these. The cellular processes/systems affected by PLP have


DaTe Neuropathy Vascular Cataracts Retinopathy

Altered Methionine Metabolism


\Abnormal Tryptophan Metabolism $.

Methionine Metabolites Vascular Damage Cardiovascular Risk




XA-insulin complex

B~~~~~~ t



Insulin Sensitivity

FIGURE 1. Interrelationshipsbetween diabetes mellitus and vitamin B6.These interrelationships are presented as hypotheses, and not all have been tested experimentally.

been previously discussed. Included in the hypotheses presented in FIGURE 1 are effects of changes in PLP levels on glycosylated proteins, red cell metabolism, the immune system, tryptophan metabolism, and methionine metabolism. These are hypotheses, and not all of these potential effects have been experimentally tested in persons with diabetes. I do hope they provide provocative discussion and ideas for further research. REFERENCES 1.

LEKLEM, J. E. 1991. Vitamin B-6. In Handbook of Vitamins. 2nd ed. L. J. Machlin, Ed.: 341-392. Dekker. New York.



S. P. 1990. Location and turnover of vitamin B, pools and vitamin B6 require2. COBURN, ments of humans. Ann. N.Y. Acad. Sci. 585: 76-85. 3. Recommended Dietary Allowances. 10th ed. 1989. Natl. Acad. Sci., Natl. Res. Council. Washington, D.C. & T. D. SHULTZ.1985. The effect of dietary protein on 4. MILLER,L. T., J. E. LEKLEM the metabolism of vitamin B-6 in humans. J. Nutr. 115: 1663-1672. Eds. 1988. Clinical and Physiological Applications 5. LEKLEM,J. E. & R. D. REYNOLDS, of Vitamin B-6. Liss. New York. K., Ed. 1990. Vitamin B6. Ann. N.Y. Acad. Sci. 585. 6. DAKSHINAMURTI, 7. KABm, H., J. E. LEKLEM& L . T. MILLER.1983. Measurement of glycosylated vitamin B-6 in foods. J. Food. Sci. 48: 1422-1425. L . M. 1985. I n Vitamin B-6: Its Role in Health and Disease. R. D. 8. HENDERSON, Reynolds & J. E. Leklem, Eds.: 22-23. Liss. New York. 1979. Transport and metabolism H., M. W. H A M M& L. M. HENDERSON. 9. MEHANSHO, of pyridoxal and pyridoxal phosphate in the small intestine of the rat. J. Nutr. 109: 1542-1551. 10. SHULTZ,T. D. & J. E. LEKLEM.1981. Urinary 4-pyridoxic acid, urinary vitamin B-6 and plasma pyridoxal phosphate as measures of vitamin B-6 status. I n Methods in Vitamin B-6 Nutrition. J. E. Leklem & R. D. Reynolds, Eds.: 297-320. Plenum. New York. A. H., J. M. HENDERSON, E. WANG,B. W. MCDONALD & W. J. MILLIKAN. 11. MERRILL, 1984. Metabolism of vitamin B-6 by human liver. J. Nutr. 114: 1664-1674. 1990. Vitamin B6 metabolism by human 12. MERRILL,JR., A. H. & J. M. HENDERSON. liver. Ann. N.Y. Acad. Sci. 585: 110-117. & L . T. MILLER.1980. The metabolism of small doses 13. W o z E N s K i , J. R., J. E . LEKLEM of vitamin B-6 in men. J. Nutr. 110 275-285. J. E. 1988. Vitamin B-6 metabolism and function in humans. I n Clinical and 14. LEKLEM, Physiological Applications of Vitamin B-6. J. E. Leklem & R. D. Reynolds, Eds.: 3-28. Liss. New York. 1984. Effect of binding to hemoglobin and albumin 15. INK, S. L . & L . M. HENDERSON. on pyridoxal transport and metabolism. J. Biol. Chem. 259: 5833-5837. B. B., G. M. PERRY,J. E. CLEMENTS & M. F. GREANY. 1989. Rapid uptake 16. ANDERSON, and clearance of pyridoxine by red blood cells in uiuo. Am. J. Clin. Nutr. 50: 1059-63. W. E. SCHALTENBRAND 17. COBURN,S. P., D. L. LEWIS,W. J. FINK,J. D. MAHUREN, & D. L. COSTILL.1988. Human vitamin B-6 pools estimated through muscle biopsies. Am. J. Clin. Nutr. 48: 291-294. S. P., P. J. ZIEGLER,D. L . COSTILL,J. D. MAHUREN et al. 1991. Response 18. COBURN, of vitamin B-6 content of muscle to changes in vitamin B-6 intake in men. Am. J. Clin. Nutr. 53: 1436-1442. 19. BLACK,A. L., B. M. GUIRARD & E. E. SNELL.1978. The behavior of muscle phosphorylase as a reservoir for vitamin B-6 in the rat. J. Nutr. 108: 670-677. 1983. Increased plasma pyridoxal5’-phosphate in male 20. L.EKLEM,J. E. & T. D. SHULTZ. adolescents after a 4500-meter run. Am. J. Clin. Nutr. 48: 541-548. & P. A. DEUSTER. A,, R. D. REYNOLDS, B. L. SMOAK,V. G. VILLANUEVA 21. HOFMANN, 1991. Plasma pyridoxal5’-phosphate concentrations in response to ingestion of water or glucose polymer during a 2-h run. Am. J. Clin. Nutr. 53: 84-89. 22. MANORE,M., J. E. LEKLEM& M. C. WALTER.1987. Vitamin B-6 metabolism as affected by exercise in trained and untrained women fed diets differing in carbohydrate and vitamin B-6 content. Am. J. Clin. Nutr. 46: 995-1004. 23. ALLGOOD,V. E. & J. A. CIDLOWSKI.1991. Novel role for vitamin B-6 in steroid hormone action: a link between nutrition and the endocrine system. J. Nutr. Biochem. 2: 523-534. 24. COMPTON,M. M. & J. A. CIDLOWSKI. 1986. Vitamin B-6 and glucocorticoid action. Endocrin. Rev. 7: 140-148. 25. DISORBO, D. M., D. S. PHELPS,V. S. OHL& G. LITWACK. 1980. Pyridoxine deficiency influences the behavior of the glucocorticoid receptor complex. J. Biol. Chem. 255: 3866-3870. 26. BUNCE,G. E. & M. VESSAL.1987. Effect of zinc andlor pyridoxine deficiency upon


27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.



oestrogen retention and oestrogen receptor distribution in the rat uterus. 3. Steroid Biochem. 26: 303-308. REID,R. L. 1985. Premenstrual syndrome. Curr. Probl. Obstet. Gynecol. Fertil. 8 7-9. O'BRIEN,P. M. S. 1982. The premenstrual syndrome. A review of the present status of therapy. Drugs 24: 140-151. J., G . T. RIET& P. KNIPSCHILD. 1990. Vitamin B-6 in the treatment of the KLEIJNEN, premenstrual syndrome-a review. Br. J. Obstet. Gynecol. 97: 847-852. 1980. Transport and accumulation of pyridoxine MEHANSHO, H. & L . M. HENDERSON. and pyridoxal by erythrocytes. J. Biol. Chem. 255: 11901-11907. C. BAUER& R. BENESCH.1973. Pyridoxal BENESCH,R. E., S. YUNG,T. SUZUKI, compounds as specific reagents for the alpha and /3 N-termini of hemoglobin. Proc. Natl. Acad. Sci. USA 70: 2595-2599. REYNOLDS, R. D. & C. L. NATTA.1985. Vitamin 8-6 and sickle cell anemia. In Vitamin B-6: Its Role in Health and Disease. R. D. Reynolds & J. E. Leklem, Eds.: 301-316. Liss. New York. KOENIC,R. J. & A . CERAMI.1980. Hemoglobin A l c and diabetes mellitus. Annu. Rev. Med. 31: 29-34. & A. CERAMI.1986. Nonenzymatic glycosylation: role VLASSARA, H., M. BROWNLEE in the pathogenesis of diabetic complications. Clin. Chem. 32: B37-B41. SOLOMON, L. R. & K. COHEN.1989. Erythrocyte O2 transport and metabolism and effects of vitamin B-6 therapy in type I1 diabetes mellitus. Diabetes 38: 881-886. DAVIS,R. E., J . S . CALDER& D. H . CURNOW.1976. Serum pyridoxal and folate concentrations in diabetes. Pathology 8: 151-156. HOLLENBECK, C. B., J . E . LEKLEM,M. C. RIDDLE& W. E. CONNOR.1983. The composition and nutritional adequacy of subject-selected high carbohydrate, low fat diets in insulin-dependent diabetes mellitus. Am. J . Clin. Nutr. 3 8 41-51, HAMFELT,A. & L. SODERHJELM. 1983. Plasma pyridoxal phosphate in diabetes. Am. J . Clin. Nutr. 38: 841-842. 1990. Acute ingestion of glucose decreases LEKLEM,J . E. & C. B. HOLLENBECK. plasma pyridoxal 5'-phosphate and total vitamin B-6 concentration. Am. J. Clin. Nutr. 51: 832-836. HOLLENBECK, C. B., C. C. DONNER& J. E. LEKLEM. 1985. Evidence that the acute fall in plasma pyridoxal5'-phosphate following an oral glucose challenge is assocated with insulin sensitive glucose utilization (Abstract). Clin. Res. 33: 61A. ROMERO, G . , L . LUTTRELL, A. ROGOL,C. ZELLER,E . HEWLETT& J. LARNER.1988. Phosphatidylinositol-glycan anchors of membrane proteins: potential precursors of insulin mediators. Science 240: 509-51 1. GOLDBERG, D. M., J. V. MARTIN& A. H. KNIGHT.1976. Elevation of serum alkaline phosphatase activity and related enzymes in diabetes mellitus. Clin. Biochem. 10: 8-11.

DISCUSSION D. ROE (Carnell University, Ithaca, N Y ) : In your studies of vitamin B6 and exercise, you indicated that the effects you observed were acute. From the pictures that you showed, the studies were conducted in younger people. In these younger people did you find the mobilization of vitamin B6 to be acute? This was not so in the older persons we studied. As long as people are exercising daily, this persists. What did you find in your younger population? J. E. LEKLEM (Oregon State University, Corvallis, OR): We see this consistently in the younger population. We have seen it with running and with cycling. We have also conducted one study under water and found those changes in people



that are diving. So with many different types of exercise we see it. We have seen a similar change with exercise in individuals 50-65 years of age. We have not been able to correlate the degree of change with any specific situation other than with differences in carbohydrate intake. I think, there, it has to do with the levels of glycogen phosphorylase that are present. J. C. SMITH(Beltsville Human Nutrition Center, Beltsville, M D ) : My question is about parameters for assessing vitamin B6 status. Would you comment on a pending procedure for assessing overall status? I chose not to look at status indicators for this presentation. Obviously LEKLEM: it is an important topic even for individuals taking large amounts of vitamin B,. The red cell PLP levels have been suggested as another measure. One of the problems you run into there is the fact that PLP is bound to hemoglobin and bound fairly tightly. The question is, What does that really mean? Maybe it is an indicator of long-term intake much like the red cell transaminase levels. One has to work out, however, some of the methods problems of extracting efficiently the PLP from the hemoglobin. Until that’s done, I really don’t think we can make a lot of definitive statements. I think a combination of plasma PLP, plasma pyridoxal, and the red cell PLP probably is useful, in addition to urinary excretion. D. RAITEN(Silver Spring, M D ) : Given what we’ve seen in various clinical situations with the changes in PLP levels, could you address the PLP issue a little bit further? LEKLEM:I was talking about PLP mainly as the cellular component that is active. but it is important to recognize that PL is probably the form that moves into cells and that also moves out of cells. A. J. FORLANO (Eldorado, T X ) : Dr. Leklem, you mentioned carpal tunnel syndrome. I know that there has been some medical indication that pyridoxine may be effective. Do you have any dosage recommendations on that particular disease? LEKLEM:Dr. John Ellis has treated patients over the years with B,, and he uses doses of 100 mg to 150 mg. I would only say that until there are at least one or two more well-done double-blind, placebo-controlled, large population-based studies that I would not publicly recommend any level of vitamin B6 for carpal tunnel syndrome. To do so suggests that, in fact, it works. We’re beginning to evaluate individuals with carpal tunnel syndrome and to look at nerve conduction. We will then randomize them into two groups so that we can begin to look at the situation. Vitamin B, is being prescribed, as I understand, by some physicians. Those individuals are using somewhere between 50-150 mg. F. COLBY( N e w York, N Y ) : You very briefly mentioned hormone-related cancers. Is this idea straight speculation? LEKLEM:It is pure speculation at the moment. In breast cancer patients, you do see decreased levels of plasma pyridoxal phosphate. I have not seen anybody try to relate that response to some of the antiestrogens. I was involved in a study a couple of years ago at the University of Wisconsin where people were treated with tamoxifen, and we measured the PLP levels, which were depressed in many cases. We’ve not analyzed the data completely, however, to see if there is some relationship. If it has an effect, it may act to minimize the action of estrogens and act like an antiestrogen. D. H. Kooss (Lorna Linda, CA): I wasn’t clear whether the lowering of the glycosolated hemoglobin was related to better diabetic control. LE.KLEM: In that particular study, they simply observed a lower amount of glycocolated protein. They didn’t see better control, per se, because the glucose levels didn’t drop. It simply suggested that there was some inhibition of glycosyla-



tion. There have been a number of studies done, however, where vitamin B, given to diabetics had no significant effect on glucose control. UNrDENTrFrED SPEAKER: Is the alleged lipid-lowering effect of vitamin B, solely through its ability to generate niacin? Or is there possibly another mechanism? LEKLEM: I don’t think it is due to niacin at all. I think it has to do with methionine metabolism, the levels of S-adenosylmethionine in the body, and what controls the levels and the potential impact it might have there. It may also be related to this hormone modulation effect, but I think more likely it is related to amino acid metabolism and specifically to methionine metabolism. J.-P. CURTAY (Paris, France): There have been some cases of neuropathy with excess vitamin B, administrated for a period of time. Some have suggested that it may be linked with a defect of phosphorylation that could be linked with deficiency of magnesium. Do you think this is plausible? LEKLEM: One would have to possess a mechanism for altering magnesium levels in the cell due to high levels of vitamin B6. In the literature there are two reports that I am aware of that suggest one can enhance magnesium levels by giving high levels of vitamin B,. We did a study with 10 mg of vitamin B6in women and observed no effect. CURTAY:Do you believe that the activation of pyridoxal in humans requires magnesium and eventually zinc and vitamin B,? LEKLEM:Yes. I think there is evidence in the literature about magnesium and zinc. We recently completed some animal studies that showed that we can modify PLP levels in tissues and in the circulation depending upon the amount of zinc and magnesium. E. J. HAWRYLEWICZ (Mercy Hospital and Medical Center, Chicago, IL): Very shortly, there will be very large-scale tamoxifen trials for prevention of breast cancer. In these trials, which will be very long-term, is it recommended that we should monitor vitamin B6 or supplement these patients with vitamin B6? LEKLEM: Yes, at least monitor PLP levels. I would want to take the data that we have accumulated, look at it more closely, and begin to do some subpopulation studies very soon to see whether there is some relationship. It may be that tamoxifen acts through the receptors for estrogen. Is that true? HAWRYLEWICZ: Presumably. LEKLEM:If that’s true, presumably one could minimize that effect by having a high level of vitamin B6 intake. Honestly, I just don’t know.

Vitamin B6. Reservoirs, receptors, and red-cell reactions.

Vitamin B, Reservoirs, Receptors, and Red-Cell Reactions JAMES E. LEKLEM Department of Niirrition and Food Management Oregon State University Corvalli...
626KB Sizes 0 Downloads 0 Views