Skip to main content
SpringerLink
Log in

Investigation of vitamin B6 inadequacy, induced by exposure to the anti-B6 factor 1-amino d-proline, on plasma lipophilic metabolites of rats: a metabolomics approach

  • Original Contribution
  • Published:
European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Purpose

Vitamin B6 status in the body is affected by several factors including dietary supply of the antivitamin B6 factor, 1-amino d-proline (1ADP), which is present in flaxseed. Owing to the prevalence of moderate B6 deficiency in the general population, a co-occurrence of 1ADP may lead to a further deterioration of B6 status. To this end, we applied a nontargeted metabolomics approach to identify potential plasma lipophilic biomarkers of deleterious effect of 1ADP on moderately vitamin B6-deficient rats using a high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.

Methods

Twenty-four rats were fed with a semi-purified diet containing pyridoxine·HCl (PN·HCl) either 7 mg/kg diet (optimal B6) or 0.7 mg/kg diet (moderate B6). The rats were divided into four treatments (n = 6), and one treatment in each B6 diet group was also fed ad libitum with 10 mg/kg diet of synthetic 1ADP. After 5 weeks of study, plasma was collected from the rats and lipophilic metabolites were extracted using acetonitrile as a solvent for analysis.

Results

Ten potential plasma lipophilic biomarkers were identified out of >2500 detected entities, which showed significant differences between the treatments. Plasma glycocholic acid, glycoursodeoxycholic acid, murocholic acid, N-docosahexaenoyl GABA, N-arachidonoyl GABA, lumula, nandrolone and orthothymotinic acid concentrations were significantly elevated, while plasma cystamine and 3-methyleneoxindole concentrations were significantly reduced as a result of either low B6 status or 1ADP or their interaction.

Conclusion

Changes in these metabolites revealed a potential defect in pathways linked with the biosynthesis and metabolism of bile acid components, N-acyl amino acids, analgesic androgens, anti-inflammatory and neuroprotective molecules. We also noted that the changes in these biomarkers can be alleviated by the application of adequate vitamin B6.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

1ADP:

1-Amino d-proline

ASBT:

Apical sodium-dependent bile acid transporter

Ar-EA:

N-Arachidonoyl ethanolamide

CYP:

Cytochrome P450

FAAH:

Fatty acid amide hydrolase

FXR:

Farnesoid X receptor

HPLC–QTOF-MS:

High-performance liquid chromatography/quadrupole time-of-flight mass spectrometry

NAGABA:

N-Arachidonoyl γ-butyric acid

NDGABA:

N-Docosahexaenoyl γ-aminobutyric acid

NTCP:

Sodium taurocholate co-transporting polypeptide

OATP:

Organic anion transporting polypeptide

OST:

Solute transporters

PLP:

Pyridoxal 5′-phosphate

PN·HCl:

Pyridoxine·hydrochloride

SULT:

Sulfotransferase

UGT:

UDP-glucuronosyltransferase

References

  1. Selhub J, Bagley LC, Miller J, Rosenberg IH (2000) B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr 71:614S–620S

    CAS  Google Scholar 

  2. Spinneker A, Sola R, Lemmen V, Castillo MJ, Pietrzik K, González-Gross M (2007) Vitamin B6 status, deficiency and its consequences—an overview. Nutr Hosp 22:7–24

    CAS  Google Scholar 

  3. Hellmann H, Mooney S (2010) Vitamin B6: a molecule for human health? Molecules 15:442–459

    Article  CAS  Google Scholar 

  4. Martinez M, Cuskelly GJ, Williamson J, Toth JP, Gregory JF III (2000) Vitamin B-6 deficiency in rats reduces hepatic serine hydroxymethyltransferase and cystathionine ß-synthase activities and rates of in vivo protein turnover, homocysteine remethylation and transsulfuration. J Nutr 130:1115–1123

    CAS  Google Scholar 

  5. Zhang Z, Kebreab E, Jing M, Rodriguez-Lecompte JC, Kuehn R, Flintoft M, House JD (2009) Impairments in pyridoxine-dependent sulphur amino acid metabolism are highly sensitive to the degree of vitamin B6 deficiency and repletion in the pig. Animal 3:826–837

    Article  CAS  Google Scholar 

  6. Allgood VE, Cidlowski JA (1992) Vitamin B6 modulates transcriptional activation by multiple members of the steroid hormone receptor superfamily. J Biol Chem 267:3819–3824

    CAS  Google Scholar 

  7. Cake MH, DiSorbo DM, Litwack G (1978) Effect of pyridoxal phosphate on the DNA binding site of activated hepatic glucocorticoid receptor. J Biol Chem 253:4886–4891

    CAS  Google Scholar 

  8. Isomaa V, Pajunen AE, Bardin CW, Janne OA (1982) Nuclear androgen receptors in the mouse kidney: validation of a new assay. Endocrinology 111:833–843

    Article  CAS  Google Scholar 

  9. Nishigori H, Moudgil VK, Toft D (1978) Inactivation of avian progesterone receptor binding to ATP-Sepharose by pyridoxal 5′-phosphate. Biochem Biophys Res Commun 80:112–118

    Article  CAS  Google Scholar 

  10. Buyukokuroglu ME, Gepdiremen A, Tastekin A, Ors R (2007) Pyridoxine may protect the cerebellar granular cells against glutamate-induced toxicity. Int J Vitam Nutr Res 77:336–340

    Article  CAS  Google Scholar 

  11. Cabrini L, Bochicchio D, Bordoni A, Sassi S, Marchetti M, Maranesi M (2005) Correlation between dietary polyunsaturated fatty acids and plasma homocysteine concentration in vitamin B6-deficient rats. Nutr Metab Cardiovasc Dis 15:94–99

    Article  CAS  Google Scholar 

  12. Iwami T, Okada M (1982) Stimulation of cholesterol metabolism in pyridoxine-deficient rats. J Nutr Sci Vitaminol (Tokyo) 28:77–84

    Article  CAS  Google Scholar 

  13. Shah SN, Patricia VJ, Kummerow FA (1960) The effect of pyridoxine on cholesterol metabolism. J Nutr 72:81–86

    CAS  Google Scholar 

  14. Klosterman JH (1974) Vitamin B6 antagonists of natural origin. J Agric Food Chem 22–1:13–16

    Article  Google Scholar 

  15. Prasad K (2009) Flaxseed and cardiovascular health. J Cardiovasc Pharmacol 54:369–377

    Article  CAS  Google Scholar 

  16. Klosterman HJ, Lamoureux GL, Parsons JL (1967) Isolation, characterization, and synthesis of linatine. A vitamin B6 antagonist from flaxseed (Linum usitatissimum). Biochemistry (NY) 6:170–177

    Article  CAS  Google Scholar 

  17. Mayengbam S, Yang H, Barthet V, Aliani M, House JD (2014) Identification, characterization, and quantification of an anti-pyridoxine factor from flaxseed using ultrahigh-performance liquid chromatography-mass spectrometry. J Agric Food Chem 62:419–426

    Article  CAS  Google Scholar 

  18. Sasaoka K, Ogawa T, Moritoki K, Kimoto M (1976) Antivitamin B6 effect of 1 aminoproline on rats. Biochim Biophys Acta 428:396–402

    Article  CAS  Google Scholar 

  19. Leklem JE (1990) Vitamin B-6: a status report. J Nutr 120:1503–1507

    CAS  Google Scholar 

  20. Morris MS, Picciano MF, Jacques PF, Selhub J (2008) Plasma pyridoxal 5′-phosphate in the US population: the national health and nutrition examination survey, 2003–2004. Am J Clin Nutr 87:1446–1454

    CAS  Google Scholar 

  21. Bruce SJ, Tavazzi I, Parisod V, Rezzi S, Kochhar S, Guy PA (2009) Investigation of human blood plasma sample preparation for performing metabolomics using ultrahigh performance liquid chromatography/mass spectrometry. Anal Chem 81:3285–3296

    Article  CAS  Google Scholar 

  22. Gregory III JF, Park Y, Lamers Y, Bandyopadhyay N, Chi Y-Y, Lee K, Kim S, da Silva V, Hove N, Ranka S, Kahveci T, Muller KE, Stevens RD, Newgard CB, Stacpoole PW, Jones DP (2013) Metabolomic analysis reveals extended metabolic consequences of marginal vitamin B-6 deficiency in healthy human subjects. PLoS One 8(6):e63544. doi:10.1371/journal.pone.0063544

  23. Lamers Y, Coats B, Ralat M, Quinlivan EP, Stacpoole PW, Gregory JF (2011) Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women. J Nutr 141:835–842

    Article  CAS  Google Scholar 

  24. Mayengbam S, Raposo S, Aliani M, House D, James (2015) Oral exposure to the anti-pyridoxine compound 1-amino d-proline further perturbs homocysteine metabolism through the transsulphuration pathway in moderately vitamin B6-deficient rats. J Nutr Biochem 26:241–249

    Article  CAS  Google Scholar 

  25. Lv Y, Liu X, Yan S, Liang X, Yang Y, Dai W, Zhang W (2010) Metabolomic study of myocardial ischemia and intervention effects of Compound Danshen Tablets in rats using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. J Pharm Biomed Anal 52:129–135

    Article  CAS  Google Scholar 

  26. Lamers Y, Williamson J, Ralat M, Quinlivan EP, Gilbert LR, Keeling C, Stevens RD, Newgard CB, Ueland PM, Meyer K, Fredriksen A, Stacpoole PW, Gregory JF III (2009) Moderate dietary vitamin B-6 restriction raises plasma glycine and cystathionine concentrations while minimally affecting the rates of glycine turnover and glycine cleavage in healthy men and women. J Nutr 139:452–460

    Article  CAS  Google Scholar 

  27. Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P (2009) Bile acids as regulatory molecules. J Lipid Res 50:1509–1520

    Article  CAS  Google Scholar 

  28. Xu X, Lu Y, Chen L, Chen J, Luo X, Shen X (2013) Identification of 15d-PGJ2 as an antagonist of farnesoid X receptor: molecular modeling with biological evaluation. Steroids 78:813–822

    Article  CAS  Google Scholar 

  29. Benz C, Angermuller S, Tox U, Kloters-Plachky P, Riedel HD, Sauer P, Stremmel W, Stiehl A (1998) Effect of tauroursodeoxycholic acid on bile-acid-induced apoptosis and cytolysis in rat hepatocytes. J Hepatol 28:99–106

    Article  CAS  Google Scholar 

  30. Hanus L, Shohami E, Bab I, Mechoulam R (2014) N-Acyl amino acids and their impact on biological processes. BioFactors 40:381–388

    Article  CAS  Google Scholar 

  31. Han B, Wright R, Kirchhoff AM, Chester JA, Cooper BR, Davisson VJ, Barker E (2013) Quantitative LC–MS/MS analysis of arachidonoyl amino acids in mouse brain with treatment of FAAH inhibitor. Anal Biochem 432:74–81

    Article  CAS  Google Scholar 

  32. Maccarrone M, Bari M, Di Rienzo M, Finazzi-Agro A, Rossi A (2003) Progesterone activates fatty acid amide hydrolase (FAAH) promoter in human T lymphocytes through the transcription factor Ikaros. Evidence for a synergistic effect of leptin. J Biol Chem 278:32726–32732

    Article  CAS  Google Scholar 

  33. Bousquet M, Gibrat C, Ouellet M, Rouillard C, Calon F, Cicchetti F (2010) Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases. J Neurochem 114:1651–1658

    Article  CAS  Google Scholar 

  34. Ebadi M (1981) Regulation and function of pyridoxal phosphate in CNS. Neurochem Int 3:181–205

    Article  CAS  Google Scholar 

  35. Ricciotti E, FitzGerald GA (2011) Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 31:986–1000

    Article  CAS  Google Scholar 

  36. Aihara K, Handa T, Oga T, Watanabe K, Tanizawa K, Ikezoe K, Taguchi Y, Sato H, Chin K, Nagai S, Narumiya S, Wells AU, Mishima M (2013) Clinical relevance of plasma prostaglandin F2α metabolite concentrations in patients with idiopathic pulmonary fibrosis. PLoS One 8:e66017

    Article  CAS  Google Scholar 

  37. Maranesi M, Barzanti V, Coccheri S, Marchetti M, Tolomelli B (1993) Interaction between vitamin B6 deficiency and low EFA dietary intake on kidney phospholipids and PGE2 in the rat. Prostaglandins Leukot Essent Fatty Acids 49:531–536

    Article  CAS  Google Scholar 

  38. Chang SJ (2000) Vitamin B6 antagonists alter the function and ultrastructure of mice endothelial cells. J Nutr Sci Vitaminol (Tokyo) 46:149–153

    Article  CAS  Google Scholar 

  39. Schanzer W (1996) Metabolism of anabolic androgenic steroids. Clin Chem 42:1001–1020

    CAS  Google Scholar 

  40. Kurling-Kailanto S, Kankaanpaa A, Hautaniemi J, Seppala T (2010) Blockade of androgen or estrogen receptors reduces nandrolone’s ability to modulate acute reward-related neurochemical effects of amphetamine in rat brain. Pharmacol Biochem Behav 95:422–427

    Article  CAS  Google Scholar 

  41. Zotti M, Tucci P, Colaianna M, Morgese MG, Mhillaj E, Schiavone S, Scaccianoce S, Cuomo V, Trabace L (2013) Chronic nandrolone administration induces dysfunction of the reward pathway in rats. Steroids 79:7–13

    Article  Google Scholar 

  42. da Silva VR, Ralat MA, Quinlivan EP, DeRatt BN, Garrett TJ, Chi YY, Nijhout HF, Reed MC, Gregory JF III (2014) Targeted metabolomics and mathematical modeling demonstrate that vitamin B-6 restriction alters one-carbon metabolism in cultured HepG2 cells. Am J Physiol Endocrinol Metab 143:1719–1727

    Google Scholar 

  43. Marozzi FJ, Malone MH (1968) Analgesic and anti-inflammatory evaluation of thymotic acid and certain homologs. J Pharm Sci 57:989–994

    Article  CAS  Google Scholar 

  44. Tuli V, Moyed HS, Stevenson D, Gordon I (1974) Antiviral activity of 3-methyleneoxindole. Antimicrob Agents Chemother 5:479–484

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Discovery Grants Program of the Natural Sciences and Engineering Research Council of Canada (NSERC; JDH and MA). Shyamchand Mayengbam was the recipient of a NSERC CREATE. J.D.H., S.M. and M.A. designed research; S.M. conducted research; S.M. and M.A. analyzed data; S.M. wrote the manuscript; J.D.H. and M.A. reviewed manuscript, and M.A. had primary responsibility for the final content. All authors read and approved the final manuscript.

Conflict of interest

Authors of this study declare no conflict of interests.

Ethical standard

The animal study was conducted according to the procedures approved by Animal User and Animal Care Committees, University of Manitoba and adhered to the guidelines of Canadian Council of Animal Care.

Author information

Authors and Affiliations

  1. Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada

    Shyamchand Mayengbam, James D. House & Michel Aliani

  2. Department of Animal Sciences, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada

    James D. House

  3. St-Boniface Hospital Research Centre, 351 Tache Avenue, Winnipeg, MB, R2H 2A6, Canada

    Michel Aliani

Authors
  1. Shyamchand Mayengbam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James D. House
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michel Aliani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michel Aliani.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 411 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mayengbam, S., House, J.D. & Aliani, M. Investigation of vitamin B6 inadequacy, induced by exposure to the anti-B6 factor 1-amino d-proline, on plasma lipophilic metabolites of rats: a metabolomics approach. Eur J Nutr 55, 1213–1223 (2016). https://doi.org/10.1007/s00394-015-0934-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-015-0934-x

Keywords

Search

Navigation