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. 1996 Jul 1;98(1):177–184. doi: 10.1172/JCI118763

The effect of a subnormal vitamin B-6 status on homocysteine metabolism.

J B Ubbink 1, A van der Merwe 1, R Delport 1, R H Allen 1, S P Stabler 1, R Riezler 1, W J Vermaak 1
PMCID: PMC507414  PMID: 8690790

Abstract

Homocysteine, an atherogenic amino acid, is either remethylated to methionine or metabolized to cysteine by the transsulfuration pathway. The biochemical conversion of homocysteine to cysteine is dependent upon two consecutive, vitamin B-6-dependent reactions. To study the effect of a selective vitamin B-6 deficiency on transsulfuration, we performed oral methionine load tests on 22 vitamin B-6-deficient asthma patients treated with theophylline (a vitamin B-6 antagonist) and 24 age- and sex-matched controls with a normal vitamin B-6 status. Both groups had normal circulating vitamin B-12 and folate concentrations. Methionine loading resulted in significantly higher increases in circulating total homocyst(e)ine (P < 0.01) and cystathionine (P < 0.05) concentrations in vitamin B-6-deficient patients compared with controls. 6 wk of vitamin B-6 supplementation (20 mg/d) significantly (P < 0.05) reduced post-methionine load increases in circulating total homocyst(e)ine concentrations in deficient subjects, but had no significant effect on the increase in total homocyst(e)ine concentrations in controls. The increases in post-methionine load circulating cystathionine concentrations were significantly (P < 0.01) reduced in both groups after vitamin supplementation. It is concluded that a vitamin B-6 deficiency may contribute to impaired transsulfuration and an abnormal methionine load test, which is associated with premature vascular disease.

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Selected References

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  1. Allen R. H., Stabler S. P., Savage D. G., Lindenbaum J. Elevation of 2-methylcitric acid I and II levels in serum, urine, and cerebrospinal fluid of patients with cobalamin deficiency. Metabolism. 1993 Aug;42(8):978–988. doi: 10.1016/0026-0495(93)90010-l. [DOI] [PubMed] [Google Scholar]
  2. Allen R. H., Stabler S. P., Savage D. G., Lindenbaum J. Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. FASEB J. 1993 Nov;7(14):1344–1353. doi: 10.1096/fasebj.7.14.7901104. [DOI] [PubMed] [Google Scholar]
  3. Andersson A., Brattström L., Israelsson B., Isaksson A., Hamfelt A., Hultberg B. Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status. Eur J Clin Invest. 1992 Feb;22(2):79–87. doi: 10.1111/j.1365-2362.1992.tb01940.x. [DOI] [PubMed] [Google Scholar]
  4. Araki A., Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr. 1987 Nov 27;422:43–52. doi: 10.1016/0378-4347(87)80438-3. [DOI] [PubMed] [Google Scholar]
  5. BINKLEY F., CHRISTENSEN G. M., JENSEN W. N. Pyridoxine and the transfer of sulfur. J Biol Chem. 1952 Jan;194(1):109–113. [PubMed] [Google Scholar]
  6. Blanchard J., Harvey S., Morgan W. J. A rapid and specific high-performance liquid chromatographic assay for theophylline in biological fluids. J Chromatogr Sci. 1990 Jun;28(6):303–306. doi: 10.1093/chromsci/28.6.303. [DOI] [PubMed] [Google Scholar]
  7. Boers G. H., Fowler B., Smals A. G., Trijbels F. J., Leermakers A. I., Kleijer W. J., Kloppenborg P. W. Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts. Hum Genet. 1985;69(2):164–169. doi: 10.1007/BF00293290. [DOI] [PubMed] [Google Scholar]
  8. Boers G. H., Smals A. G., Trijbels F. J., Fowler B., Bakkeren J. A., Schoonderwaldt H. C., Kleijer W. J., Kloppenborg P. W. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med. 1985 Sep 19;313(12):709–715. doi: 10.1056/NEJM198509193131201. [DOI] [PubMed] [Google Scholar]
  9. Bostom A. G., Jacques P. F., Nadeau M. R., Williams R. R., Ellison R. C., Selhub J. Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study. Atherosclerosis. 1995 Jul;116(1):147–151. doi: 10.1016/0021-9150(95)05529-6. [DOI] [PubMed] [Google Scholar]
  10. Brattström L. E., Israelsson B., Jeppsson J. O., Hultberg B. L. Folic acid--an innocuous means to reduce plasma homocysteine. Scand J Clin Lab Invest. 1988 May;48(3):215–221. doi: 10.3109/00365518809167487. [DOI] [PubMed] [Google Scholar]
  11. Brattström L., Israelsson B., Lindgärde F., Hultberg B. Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathionine beta-synthase deficiency. Metabolism. 1988 Feb;37(2):175–178. doi: 10.1016/s0026-0495(98)90014-2. [DOI] [PubMed] [Google Scholar]
  12. Brattström L., Israelsson B., Norrving B., Bergqvist D., Thörne J., Hultberg B., Hamfelt A. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment. Atherosclerosis. 1990 Feb;81(1):51–60. doi: 10.1016/0021-9150(90)90058-q. [DOI] [PubMed] [Google Scholar]
  13. Clarke R., Daly L., Robinson K., Naughten E., Cahalane S., Fowler B., Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991 Apr 25;324(17):1149–1155. doi: 10.1056/NEJM199104253241701. [DOI] [PubMed] [Google Scholar]
  14. Dudman N. P., Wilcken D. E., Wang J., Lynch J. F., Macey D., Lundberg P. Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology. Arterioscler Thromb. 1993 Sep;13(9):1253–1260. doi: 10.1161/01.atv.13.9.1253. [DOI] [PubMed] [Google Scholar]
  15. GIBSON J. B., CARSON N. A., NEILL D. W. PATHOLOGICAL FINDINGS IN HOMOCYSTINURIA. J Clin Pathol. 1964 Jul;17:427–437. doi: 10.1136/jcp.17.4.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Glueck C. J., Shaw P., Lang J. E., Tracy T., Sieve-Smith L., Wang Y. Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients. Am J Cardiol. 1995 Jan 15;75(2):132–136. doi: 10.1016/s0002-9149(00)80061-2. [DOI] [PubMed] [Google Scholar]
  17. Hopkins P. N., Wu L. L., Wu J., Hunt S. C., James B. C., Vincent G. M., Williams R. R. Higher plasma homocyst(e)ine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease. Arterioscler Thromb Vasc Biol. 1995 Sep;15(9):1314–1320. doi: 10.1161/01.atv.15.9.1314. [DOI] [PubMed] [Google Scholar]
  18. Kang S. S., Passen E. L., Ruggie N., Wong P. W., Sora H. Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Circulation. 1993 Oct;88(4 Pt 1):1463–1469. doi: 10.1161/01.cir.88.4.1463. [DOI] [PubMed] [Google Scholar]
  19. Kang S. S., Wong P. W., Bock H. G., Horwitz A., Grix A. Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations. Am J Hum Genet. 1991 Mar;48(3):546–551. [PMC free article] [PubMed] [Google Scholar]
  20. Kang S. S., Wong P. W., Norusis M. Homocysteinemia due to folate deficiency. Metabolism. 1987 May;36(5):458–462. doi: 10.1016/0026-0495(87)90043-6. [DOI] [PubMed] [Google Scholar]
  21. Kang S. S., Wong P. W., Susmano A., Sora J., Norusis M., Ruggie N. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet. 1991 Mar;48(3):536–545. [PMC free article] [PubMed] [Google Scholar]
  22. Kang S. S., Zhou J., Wong P. W., Kowalisyn J., Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet. 1988 Oct;43(4):414–421. [PMC free article] [PubMed] [Google Scholar]
  23. Kanwar Y. S., Manaligod J. R., Wong P. W. Morphologic studies in a patient with homocystinuria due to 5, 10-methylenetetrahydrofolate reductase deficiency. Pediatr Res. 1976 Jun;10(6):598–609. doi: 10.1203/00006450-197606000-00008. [DOI] [PubMed] [Google Scholar]
  24. Malinow M. R., Nieto F. J., Szklo M., Chambless L. E., Bond G. Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The Atherosclerosis Risk in Communities Study. Circulation. 1993 Apr;87(4):1107–1113. doi: 10.1161/01.cir.87.4.1107. [DOI] [PubMed] [Google Scholar]
  25. McCully K. S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969 Jul;56(1):111–128. [PMC free article] [PubMed] [Google Scholar]
  26. Miller J. W., Nadeau M. R., Smith D., Selhub J. Vitamin B-6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats. Am J Clin Nutr. 1994 May;59(5):1033–1039. doi: 10.1093/ajcn/59.5.1033. [DOI] [PubMed] [Google Scholar]
  27. Miller J. W., Ribaya-Mercado J. D., Russell R. M., Shepard D. C., Morrow F. D., Cochary E. F., Sadowski J. A., Gershoff S. N., Selhub J. Effect of vitamin B-6 deficiency on fasting plasma homocysteine concentrations. Am J Clin Nutr. 1992 Jun;55(6):1154–1160. doi: 10.1093/ajcn/55.6.1154. [DOI] [PubMed] [Google Scholar]
  28. Mills J. L., McPartlin J. M., Kirke P. N., Lee Y. J., Conley M. R., Weir D. G., Scott J. M. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet. 1995 Jan 21;345(8943):149–151. doi: 10.1016/s0140-6736(95)90165-5. [DOI] [PubMed] [Google Scholar]
  29. Murphy-Chutorian D. R., Wexman M. P., Grieco A. J., Heininger J. A., Glassman E., Gaull G. E., Ng S. K., Feit F., Wexman K., Fox A. C. Methionine intolerance: a possible risk factor for coronary artery disease. J Am Coll Cardiol. 1985 Oct;6(4):725–730. doi: 10.1016/s0735-1097(85)80473-3. [DOI] [PubMed] [Google Scholar]
  30. Pancharuniti N., Lewis C. A., Sauberlich H. E., Perkins L. L., Go R. C., Alvarez J. O., Macaluso M., Acton R. T., Copeland R. B., Cousins A. L. Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease. Am J Clin Nutr. 1994 Apr;59(4):940–948. doi: 10.1093/ajcn/59.4.940. [DOI] [PubMed] [Google Scholar]
  31. Park Y. K., Linkswiler H. Effect of vitamin B6 depletion in adult man on the excretion of cystathionine and other methionine metabolites. J Nutr. 1970 Jan;100(1):110–116. doi: 10.1093/jn/100.1.110. [DOI] [PubMed] [Google Scholar]
  32. Savage D. G., Lindenbaum J., Stabler S. P., Allen R. H. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med. 1994 Mar;96(3):239–246. doi: 10.1016/0002-9343(94)90149-x. [DOI] [PubMed] [Google Scholar]
  33. Selhub J., Jacques P. F., Bostom A. G., D'Agostino R. B., Wilson P. W., Belanger A. J., O'Leary D. H., Wolf P. A., Schaefer E. J., Rosenberg I. H. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995 Feb 2;332(5):286–291. doi: 10.1056/NEJM199502023320502. [DOI] [PubMed] [Google Scholar]
  34. Selhub J., Jacques P. F., Wilson P. W., Rush D., Rosenberg I. H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993 Dec 8;270(22):2693–2698. doi: 10.1001/jama.1993.03510220049033. [DOI] [PubMed] [Google Scholar]
  35. Selhub J., Miller J. W. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr. 1992 Jan;55(1):131–138. doi: 10.1093/ajcn/55.1.131. [DOI] [PubMed] [Google Scholar]
  36. Shin H. K., Linkswiler H. M. Tryptophan and methionine metabolism of adult females as affected by vitamin B-6 deficiency. J Nutr. 1974 Oct;104(10):1348–1355. doi: 10.1093/jn/104.10.1348. [DOI] [PubMed] [Google Scholar]
  37. Stabler S. P., Marcell P. D., Podell E. R., Allen R. H., Savage D. G., Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest. 1988 Feb;81(2):466–474. doi: 10.1172/JCI113343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Steegers-Theunissen R. P., Boers G. H., Trijbels F. J., Finkelstein J. D., Blom H. J., Thomas C. M., Borm G. F., Wouters M. G., Eskes T. K. Maternal hyperhomocysteinemia: a risk factor for neural-tube defects? Metabolism. 1994 Dec;43(12):1475–1480. doi: 10.1016/0026-0495(94)90004-3. [DOI] [PubMed] [Google Scholar]
  39. Stipanuk M. H. Metabolism of sulfur-containing amino acids. Annu Rev Nutr. 1986;6:179–209. doi: 10.1146/annurev.nu.06.070186.001143. [DOI] [PubMed] [Google Scholar]
  40. Ubbink J. B., Bissbort S., Vermaak W. J., Delport R. Inhibition of pyridoxal kinase by methylxanthines. Enzyme. 1990;43(2):72–79. doi: 10.1159/000468709. [DOI] [PubMed] [Google Scholar]
  41. Ubbink J. B., Delport R., Becker P. J., Bissbort S. Evidence of a theophylline-induced vitamin B6 deficiency caused by noncompetitive inhibition of pyridoxal kinase. J Lab Clin Med. 1989 Jan;113(1):15–22. [PubMed] [Google Scholar]
  42. Ubbink J. B., Delport R., Bissbort S., Vermaak W. J., Becker P. J. Relationship between vitamin B-6 status and elevated pyridoxal kinase levels induced by theophylline therapy in humans. J Nutr. 1990 Nov;120(11):1352–1359. doi: 10.1093/jn/120.11.1352. [DOI] [PubMed] [Google Scholar]
  43. Ubbink J. B., Hayward Vermaak W. J., Bissbort S. Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr. 1991 Apr 19;565(1-2):441–446. doi: 10.1016/0378-4347(91)80407-4. [DOI] [PubMed] [Google Scholar]
  44. Ubbink J. B., Serfontein W. J., de Villiers L. S. Stability of pyridoxal-5-phosphate semicarbazone: applications in plasma vitamin B6 analysis and population surveys of vitamin B6 nutritional status. J Chromatogr. 1985 Aug 9;342(2):277–284. doi: 10.1016/s0378-4347(00)84518-1. [DOI] [PubMed] [Google Scholar]
  45. Ubbink J. B., Vermaak W. J., Delport R., van der Merwe A., Becker P. J., Potgieter H. Effective homocysteine metabolism may protect South African blacks against coronary heart disease. Am J Clin Nutr. 1995 Oct;62(4):802–808. doi: 10.1093/ajcn/62.4.802. [DOI] [PubMed] [Google Scholar]
  46. Ubbink J. B., Vermaak W. J., van der Merwe A., Becker P. J., Delport R., Potgieter H. C. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr. 1994 Oct;124(10):1927–1933. doi: 10.1093/jn/124.10.1927. [DOI] [PubMed] [Google Scholar]
  47. Ubbink J. B., Vermaak W. J., van der Merwe A., Becker P. J. Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr. 1993 Jan;57(1):47–53. doi: 10.1093/ajcn/57.1.47. [DOI] [PubMed] [Google Scholar]
  48. Wilcken D. E., Reddy S. G., Gupta V. J. Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria. Metabolism. 1983 Apr;32(4):363–370. doi: 10.1016/0026-0495(83)90045-8. [DOI] [PubMed] [Google Scholar]
  49. Wu L. L., Wu J., Hunt S. C., James B. C., Vincent G. M., Williams R. R., Hopkins P. N. Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease. Clin Chem. 1994 Apr;40(4):552–561. [PubMed] [Google Scholar]
  50. van der Put N. M., Steegers-Theunissen R. P., Frosst P., Trijbels F. J., Eskes T. K., van den Heuvel L. P., Mariman E. C., den Heyer M., Rozen R., Blom H. J. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet. 1995 Oct 21;346(8982):1070–1071. doi: 10.1016/s0140-6736(95)91743-8. [DOI] [PubMed] [Google Scholar]

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