Skip to main content
SpringerLink
Log in

Quantitative analysis of absorption, metabolism, and excretion of benzoxazinoids in humans after the consumption of high- and low-benzoxazinoid diets with similar contents of cereal dietary fibres: a crossover study

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

Abstract

Purpose

Benzoxazinoids (BXs) are a group of wholegrain phytochemicals with potential pharmacological properties; however, limited information exists on their absorption, metabolism, and excretion in humans. The aim of this study was to investigate the dose-dependent uptake and excretion of dietary BXs in a healthy population.

Methods

Blood and urine were collected from 19 healthy participants from a crossover study after a washout, a LOW BX diet or HIGH BX diet, and analysed for 12 BXs and 4 phenoxazinone derivatives.

Results

We found that the plasma BX level peaked approximately 3 h after food intake, whereas BXs in urine were present even at 36 h after consuming a meal. No phenoxazinone derivatives could be detected in either plasma or urine. The dominant BX metabolite in both plasma and urine was 2-β-d-glucopyranosyloxy-1,4-benzoxazin-3-one (HBOA-Glc), even though 2-β-d-glucopyranosyloxy-4-hydroxy-1,4-benzoxazin-3-one (DIBOA-Glc) was the major component in the diet.

Conclusion

The dietary BX treatment correlated well with the plasma and urine levels, illustrating strong dose-dependent BX absorption, which also had a rapid washout, especially from the plasma compartment.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Carlsen SCK, Kudsk P, Laursen B, Mathiassen SK, Mortensen AG, Fomsgaard IS (2009) Allelochemicals in rye (Secale cereale L.): cultivar and tissue differences in the production of benzoxazinoids and phenolic acids. Nat Prod Commun 4:199–208

    CAS  Google Scholar 

  2. Niemeyer HM (2009) Hydroxamic acids derived from 2-hydroxy-2H-1,4-benzoxazin-3(4H)-one: key defense chemicals of cereals. J Agric Food Chem 57:1677–1696. doi:10.1021/jf8034034

    Article  CAS  Google Scholar 

  3. Adhikari KB, Tanwir F, Gregersen PL, Steffensen SK, Jensen BM, Poulsen LK, Nielsen CH, Høyer S, Borre M, Fomsgaard IS (2015) Benzoxazinoids: cereal phytochemicals with putative therapeutic and health-protecting properties. Mol Nutr Food Res. doi:10.1002/mnfr.201400717

    Google Scholar 

  4. Okarter N, Liu RH (2010) Health benefits of whole grain phytochemicals. Crit Rev Food Sci Nutr 50:193–208. doi:10.1080/10408390802248734

    Article  CAS  Google Scholar 

  5. Lutsey PL, Jacobs DRJ, Kori S, Mayer-Davis E, Shea S, Steffen LM, Szklo M, Tracy R (2007) Whole grain intake and its cross-sectional association with obesity, insulin resistance, inflammation, diabetes and subclinical CVD: the MESA study. Br J Nutr 98:397–405. doi:10.1017/S0007114507700715

    Article  CAS  Google Scholar 

  6. Georgoulis M, Kontogianni MD, Tileli N, Margariti A, Fragopoulou E, Tiniakos D, Zafiropoulou R, Papatheodoridis G (2014) The impact of cereal grain consumption on the development and severity of non-alcoholic fatty liver disease. Eur J Nutr 53:1727–1735. doi:10.1007/s00394-014-0679-y

    Article  CAS  Google Scholar 

  7. Ampatzoglou A, Williams CL, Atwal KK, Maidens CM, Ross AB, Thielecke F, Jonnalagadda SS, Kennedy OB, Yaqoob P (2015) Effects of increased wholegrain consumption on immune and inflammatory markers in healthy low habitual wholegrain consumers. Eur J Nutr. doi:10.1007/s00394-015-0836-y

    Google Scholar 

  8. Pedersen HA, Laursen B, Mortensen A, Fomsgaard IS (2011) Bread from common cereal cultivars contains an important array of neglected bioactive benzoxazinoids. Food Chem 127:1814–1820. doi:10.1016/j.foodchem.2011.02.070

    Article  CAS  Google Scholar 

  9. Hanhineva K, Rogachev I, Aura AM, Aharoni A, Poutanen K, Mykkanen H (2011) Qualitative characterization of benzoxazinoid derivatives in whole grain rye and wheat by LC-MS metabolite profiling. J Agric Food Chem 59:921–927. doi:10.1021/jf103612u

    Article  CAS  Google Scholar 

  10. Fomsgaard IS, Mortensen AG, Holm PB, Gregersen P (2010) Use of benzoxazinoids-containing cereal grain products for health-improving purposes, vol EP2265133 (A1), December 29

  11. Gents MB, Nielsen ST, Mortensen AG, Christophersen C, Fomsgaard IS (2005) Transformation products of 2-benzoxazolinone (BOA) in soil. Chemosphere 61:74–84. doi:10.1016/j.chemosphere.2005.03.068

    Article  CAS  Google Scholar 

  12. Krogh SS, Mensz SJM, Nielsen ST, Mortensen AG, Christophersen C, Fomsgaard IS (2006) Fate of benzoxazinone allelochemicals in soil after incorporation of wheat and rye sprouts. J Agric Food Chem 54:1064–1074. doi:10.1021/jf051147i

    Article  CAS  Google Scholar 

  13. Understrup AG, Ravnskov S, Hansen HCB, Fomsgaard IS (2005) Biotransformation of 2-benzoxazolinone to 2-amino-(3H)-phenoxazin-3-one and 2-acetylamino-(3H)-phenoxazin-3-one in soil. J Chem Ecol 31:1205–1222. doi:10.1007/s10886-005-4257-x

    Article  CAS  Google Scholar 

  14. Etzerodt T, Mortensen AG, Fomsgaard IS (2008) Transformation kinetics of 6-methoxybenzoxazolin-2-one in soil. J Environ Sci Health B 43:1–7. doi:10.1080/03601230701734774

    Article  CAS  Google Scholar 

  15. Etzerodt T, Nielsen ST, Mortensen AG, Christophersen C, Fomsgaard IS (2006) Elucidating the transformation pattern of the cereal allelochemical 6-methoxy-2-benzoxazolinone (MBOA) and the trideuteriomethoxy analogue D-3-MBOA in soil. J Agric Food Chem 54:1075–1085. doi:10.1021/jf0509052

    Article  Google Scholar 

  16. Tanwir F, Fredholm M, Gregersen PL, Fomsgaard IS (2013) Comparison of the levels of bioactive benzoxazinoids in different wheat and rye fractions and the transformation of these compounds in homemade foods. Food Chem 141:444–450. doi:10.1016/j.foodchem.2013.02.109

    Article  CAS  Google Scholar 

  17. Fomsgaard IS, Mortensen AG, Carlsen SCK (2004) Microbial transformation products of benzoxazolinone and benzoxazinone allelochemicals—a review. Chemosphere 54:1025–1038. doi:10.1016/j.chemosphere.2003.09.004

    Article  CAS  Google Scholar 

  18. Adhikari KB, Lærke HN, Mortensen AG, Fomsgaard IS (2012) Plasma and urine concentrations of bioactive dietary benzoxazinoids and their glucuronidated conjugates in rats fed a rye bread-based diet. J Agric Food Chem 60:11518–11524. doi:10.1021/jf301737n

    Article  CAS  Google Scholar 

  19. Adhikari KB, Laursen BB, Gregersen PL, Schnoor HJ, Witten M, Poulsen LK, Jensen BM, Fomsgaard IS (2013) Absorption and metabolic fate of bioactive dietary benzoxazinoids in humans. Mol Nutr Food Res 57:1847–1858. doi:10.1002/mnfr.201300107

    CAS  Google Scholar 

  20. Adhikari KB, Laursen BB, Lærke HN, Fomsgaard IS (2012) Bioactive benzoxazinoids in rye bread are absorbed and metabolized in pigs. J Agric Food Chem 60:2497–2506. doi:10.1021/jf2048492

    Article  CAS  Google Scholar 

  21. Baba S, Osakabe N, Natsume M, Yasuda A, Muto Y, Hiyoshi T, Takano H, Yoshikawa T, Terao J (2005) Absorption, metabolism, degradation and urinary excretion of rosmarinic acid after intake of Perilla frutescens extract in humans. Eur J Nutr 44:1–9. doi:10.1007/s00394-004-0482-2

    Article  CAS  Google Scholar 

  22. Duda-Chodak A, Tarko T, Satora P, Sroka P (2015) Interaction of dietary compounds, especially polyphenols, with the intestinal microbiota: a review. Eur J Nutr 54:325–341. doi:10.1007/s00394-015-0852-y

    Article  CAS  Google Scholar 

  23. Epstein WW, Rowsemitt CN, Berger PJ, Negus NC (1986) Dynamics of 6-methoxybenzoxazolinone in winter wheat: effects of photoperiod and temperature. J Chem Ecol 12:2011–2020. doi:10.1007/BF01041950

    Article  CAS  Google Scholar 

  24. Søltoft M, Jørgensen LN, Svensmark B, Fomsgaard IS (2008) Benzoxazinoid concentrations show correlation with Fusarium Head Blight resistance in Danish wheat varieties. Biochem Syst Ecol 36:245–259. doi:10.1016/j.bse.2007.10.008

    Article  Google Scholar 

  25. Katina K, Liukkonen KH, Kaukovirta-Norja A, Adlercreutz H, Heinonen SM, Lampi AM, Pihlava JM, Poutanen K (2007) Fermentation-induced changes in the nutritional value of native or germinated rye. J Cereal Sci 46:348–355. doi:10.1016/j.jcs.2007.07.006

    Article  CAS  Google Scholar 

  26. Hanhineva K, Keski-Rahkonen P, Lappi J, Katina K, Pekkinen J, Savolainen O, Timonen O, Paananen J, Mykkanen H, Poutanen K (2014) The postprandial plasma rye fingerprint includes benzoxazinoid-derived phenylacetamide sulfates. J Nutr 144:1016–1022. doi:10.3945/jn.113.187237

    Article  CAS  Google Scholar 

  27. Macias FA, Oliveros-Bastidas A, Marin D, Castellano D, Simonet AM, Molinillo JMG (2005) Degradation studies on benzoxazinoids. Soil degradation dynamics of (2R)-2-O-β- d-glucopyranosyl-4-hydroxy-(2H)-1,4-benzoxazin-3(4H)-one (DIBOA-Glc) and its degradation products, phytotoxic allelochemicals from Gramineae. J Agric Food Chem 53:554–561. doi:10.1021/jf048702l

    Article  CAS  Google Scholar 

  28. Zikmundova M, Drandarov K, Hesse M, Werner C (2002) Hydroxylated 2-amino-3H-phenoxazin-3-one derivatives as products of 2-hydroxy-1,4-benzoxazin-3-one (HBOA) biotransformation by Chaetosphaeria sp., an endophytic fungus from Aphelandra tetragona. Z Naturforsch C 57:660–665

    Article  CAS  Google Scholar 

  29. Bondia-Pons I, Barri T, Hanhineva K, Juntunen K, Dragsted LO, Mykkanen H, Poutanen K (2013) UPLC-QTOF/MS metabolic profiling unveils urinary changes in humans after a whole grain rye versus refined wheat bread intervention. Mol Nutr Food Res 57:412–422. doi:10.1002/mnfr.201200571

    Article  CAS  Google Scholar 

  30. Beckmann M, Lloyd AJ, Haldar S, Seal C, Brandt K, Draper J (2013) Hydroxylated phenylacetamides derived from bioactive benzoxazinoids are bioavailable in humans after habitual consumption of whole grain sourdough rye bread. Mol Nutr Food Res 57:1859–1873. doi:10.1002/mnfr.201200777

    CAS  Google Scholar 

  31. Rosenfeld MJ, Forsberg SR (2009) Compounds for use in weight loss and appetite suppression in humans. US 7,507,731 B2, March 24

Download references

Acknowledgments

We gratefully acknowledge the financial support from the Danish Strategic Research Council for the project “Exploiting newly discovered multiple-effect bioactive compounds for the development of immunoregulatory and appetite-controlling bread and breakfast products” (BREAD AND BREAKFAST) (contract no. 10-093543). Furthermore, the authors would like to thank Lantmännen Unibake, Denmark, for providing all the bread products.

Author information

Authors and Affiliations

  1. Allergy Clinic, Gentofte Hospital, Copenhagen University Hospital, dept. 22, 1. Floor, Hellerup, 2900, Gentofte, Denmark

    Bettina M. Jensen, Heidi J. Schnoor, Nanna Juel-Berg & Lars K. Poulsen

  2. Department of Agroecology, Aarhus University, Slagelse, Denmark

    Khem B. Adhikari & Inge S. Fomsgaard

Authors
  1. Bettina M. Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Khem B. Adhikari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heidi J. Schnoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nanna Juel-Berg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Inge S. Fomsgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lars K. Poulsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bettina M. Jensen.

Ethics declarations

Conflict of interest

Inge S. Fomsgaard is listed as co-inventor on a patent application, PA 84245 “Use of benzoxazinoids-containing cereal grain products for health-improving purposes”. The remaining authors do not have any conflicts of interest. Lantmännen, Unibake, Denmark, provided all bread products used in the study.

Additional information

Bettina M. Jensen and Khem B. Adhikari are joint first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplement 1

Chemical structures of benzoxazinoids found in mature wholegrain rye and bakery products. BOA, benzoxazolin-2-one; MBOA, 6-methoxy-benzoxazolin-2-one; HBOA, 2-hydroxy-1,4-benzoxazin-3-one; HMBOA, 2-hydroxy-7-methoxy-1,4-benzoxazin-3-one; HBOA-Glc, 2-β- d-glucopyranosyloxy-1,4-benzoxazin-3-one; HMBOA-Glc, 2-β- d-glucopyranosyloxy-7-methoxy-1,4-benzoxazin-3-one; HBOA-Glc-Hex, dihexose derivative of HBOA (structure not fully elucidated); DIBOA, 2,4-dihydroxy-1,4-benzoxazin-3-one; DIMBOA, 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one; DIBOA-Glc; 2-β- d-glucopyranosyloxy-4-hydroxy-1,4-benzoxazin-3-one, DIMBOA-Glc; 2-β- d-glucopyranosyloxy-4-hydroxy-7-methoxy-1,4-benzoxazin-3-one; DIBOA-Glc-Hex, dihexose derivative of DIBOA (structure not fully elucidated) (PDF 88 kb)

Supplement 2

Chemical structures of phenoxazinone derivatives of benzoxazinoids. APO (top left), AMPO (top right), AAPO (bottom left), and AAMPO (bottom right). APO, 2-amino-3H-phenoxazin-3-one; AMPO, 2-amino-7-methoxy-3H-phenoxazin-3-one; AAPO, 2-actylamino-3H-phenoxazin-3-one; AAMPO, 2-acetylamino-7-methoxy-3H-phenoxazin-3-one (PDF 83 kb)

Supplement 3

Ingredients of bread and cereal in HIGH and LOW BX diets (PDF 11 kb)

Supplement 4

The level of DIBOA-Glc, HBOA, HMBOA-Glc in plasma during 1-5 hours after the HIGH breakfast diet. Each line represents a participant (participant code in grey indicates undetectable BX level) (PDF 300 kb)

Supplement 5

BX level in urine before and after breakfast. Grey lines indicate the median (PDF 55 kb)

Supplement 6

BX intake and HBOA-Glc plasma level at 3 hours. The HBOA-Glc level was correlated to the total BX intake (PDF 90 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jensen, B.M., Adhikari, K.B., Schnoor, H.J. et al. Quantitative analysis of absorption, metabolism, and excretion of benzoxazinoids in humans after the consumption of high- and low-benzoxazinoid diets with similar contents of cereal dietary fibres: a crossover study. Eur J Nutr 56, 387–397 (2017). https://doi.org/10.1007/s00394-015-1088-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-015-1088-6

Keywords

Search

Navigation