Advertisement

Pharmaceutical Research

, 36:158 | Cite as

Metabolome Analysis Reveals Dermal Histamine Accumulation in Murine Dermatitis Provoked by Genetic Deletion of P-Glycoprotein and Breast Cancer Resistance Protein

  • Naoto Hashimoto
  • Noritaka Nakamichi
  • Hikari Nanmo
  • Kei-ichi Kimura
  • Yusuke Masuo
  • Yasuyuki Sakai
  • Alfred H. Schinkel
  • Shinichi Sato
  • Tomoyoshi Soga
  • Yukio KatoEmail author
Research Paper
  • 34 Downloads

Abstract

Purpose

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are xenobiotic transporters which pump out variety types of compounds, but information on their interaction with endogenous substrates in the skin is limited. The purpose of the present study was to clarify possible association of these transporters in dermal accumulation of inflammatory mediators.

Methods

Dermatitis model was constructed by repeated topical application of oxazolone in wild-type, and P-gp and BCRP gene triple knockout (Mdr1a/1b/Bcrp−/−) mice to observe difference in phenotype. Target metabolome analysis of 583 metabolites was performed using skin and plasma.

Results

Dermatitis and scratching behavior in dermatitis model of Mdr1a/1b/Bcrp−/− mice were more severe than wild-type mice, suggesting protective roles of these transporters. This hypothesis was supported by the metabolome analysis which revealed that concentration of histamine and other dermatitis-associated metabolites like urate and serotonin in the dermatitis skin, but not normal skin, of Mdr1a/1b/Bcrp−/− mice was higher than that of wild-type mice. Gene expression of P-gp and BCRP was reduced in oxazolone-treated skin and the skin of patients with atopic dermatitis or psoriasis.

Conclusions

These results suggest possible association of these efflux transporters with dermal inflammatory mediators, and such association could be observed in the dermatitis skin.

Key Words

breast cancer resistance protein dermatitis histamine metabolomics P-glycoprotein 

Abbreviations

36B4

Acidic ribosomal phosphoprotein P0

BCRP

Breast cancer resistance protein

CE-TOFMS

Capillary electrophoresis with time-of-flight mass spectrometry

ESI

Electrospray ionization

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

HBSS

Hanks’ balanced salt solution

HDC

Histidine decarboxylase

HNMT

Histamine N-methyltransferase

LC-MS/MS

High-performance liquid chromatography/tandem mass spectrometry

m/z

Mass-to-charge ratios

Mao

Monoamine oxidase

MDCK II

Madin-Darby canine kidney II

MDR1

Multidrug resistance 1

Oct

Organic cation transporter.

P-gp

P-glycoprotein

RT-PCR

Real-time polymerase chain reaction

Notes

Acknowledgments and Disclosures

We thank Mr. Kyosuke Shinoda (Laboratory of Molecular Pharmacotherapeutics, Kanazawa University, Japan) for performing transporter studies. This study was supported in part by Grant-in-Aids for Scientific Research to YK (25670011) and NN (No. 16 K08266) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and YK (S2601) from Japan Society for the Promotion of Science (JSPS).

Supplementary material

11095_2019_2695_MOESM1_ESM.docx (582 kb)
ESM 1 (DOCX 582 kb)

References

  1. 1.
    Wolking S, Schaeffeler E, Lerche H, Schwab M, Nies AT. Impact of genetic polymorphisms of ABCB1 (MDR1, P-glycoprotein) on drug disposition and potential clinical implications: update of the literature. Clin Pharmacokinet. 2015;54(7):709–35.PubMedCrossRefGoogle Scholar
  2. 2.
    Mao Q, Unadkat JD. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport--an update. AAPS J. 2015;17(1):65–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Skazik C, Wenzel J, Marquardt Y, Kim A, Merk HF, Bickers DR, et al. P-glycoprotein (ABCB1) expression in human skin is mainly restricted to dermal components. Exp Dermatol. 2011;20(5):450–2.PubMedCrossRefGoogle Scholar
  4. 4.
    Hashimoto N, Nakamichi N, Uwafuji S, Yoshida K, Sugiura T, Tsuji A, et al. ATP binding cassette transporters in two distinct compartments of the skin contribute to transdermal absorption of a typical substrate. J Control Release. 2013;165(1):54–61.PubMedCrossRefGoogle Scholar
  5. 5.
    Hashimoto N, Nakamichi N, Yamazaki E, Oikawa M, Masuo Y, Schinkel AH, et al. P-glycoprotein in skin contributes to transdermal absorption of topical corticosteroids. Int J Pharm. 2017;521(1–2):365–73.PubMedCrossRefGoogle Scholar
  6. 6.
    Fujita K, Masuo Y, Yamazaki E, Shibutani T, Kubota Y, Nakamichi N, et al. Involvement of the transporters P-gp and BCRP in dermal distribution of the multi-kinase inhibitor regorafenib and its active metabolites. J Pharm Sci. 2017;106(9):2632–41.PubMedCrossRefGoogle Scholar
  7. 7.
    Mizuno T, Terada T, Kamba T, Fukudo M, Katsura T, Nakamura E, et al. ABCG2 421C>a polymorphism and high exposure of sunitinib in a patient with renal cell carcinoma. Ann Oncol. 2010;21(6):1382–3.PubMedCrossRefGoogle Scholar
  8. 8.
    van Erp NP, Eechoute K, van der Veldt AA, Haanen JB, Reyners AK, Mathijssen RH, et al. Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol. 2009;27(26):4406–12.PubMedCrossRefGoogle Scholar
  9. 9.
    Olesen SP. An electrophysiological study of microvascular permeability and its modulation by chemical mediators. Acta Physiol Scand Suppl. 1989;579:1–28.PubMedGoogle Scholar
  10. 10.
    Reilly DM, Parslew R, Sharpe GR, Powell S, Green MR. Inflammatory mediators in normal, sensitive and diseased skin types. Acta Derm Venereol. 2000;80(3):171–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Potenzieri C, Undem BJ. Basic mechanisms of itch. Clin Exp Allergy. 2012;42(1):8–19.PubMedCrossRefGoogle Scholar
  12. 12.
    Sondergaard J, Glick D. Histidine decarboxylase activity in human allergic contact dermatitis. J Invest Dermatol. 1972;59(3):247–50.PubMedCrossRefGoogle Scholar
  13. 13.
    Francis D, Greaves MW, Yamamoto S. Enzymatic histamine degradation by human skin. Br J Pharmacol. 1977;60(4):583–7.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Heavey DJ, Ind PW, Miyatake A, Brown MJ, Macdermot J, Dollery CT. Histamine released locally after intradermal antigen challenge in man. Br J Clin Pharmacol. 1984;18(6):915–9.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Webb EF, Tzimas MN, Newsholme SJ, Griswold DE. Intralesional cytokines in chronic oxazolone-induced contact sensitivity suggest roles for tumor necrosis factor alpha and Interleukin-4. J Invest Dermatol. 1998;111(1):86–92.PubMedCrossRefGoogle Scholar
  16. 16.
    Soga T, Baran R, Suematsu M, Ueno Y, Ikeda S, Sakurakawa T, et al. Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption. J Biol Chem. 2006;281(24):16768–76.PubMedCrossRefGoogle Scholar
  17. 17.
    Soga T, Igarashi K, Ito C, Mizobuchi K, Zimmermann HP, Tomita M. Metabolomic profiling of anionic metabolites by capillary electrophoresis mass spectrometry. Anal Chem. 2009;81(15):6165–74.PubMedCrossRefGoogle Scholar
  18. 18.
    Akiyama Y, Takeuchi Y, Kikuchi K, Mishima E, Yamamoto Y, Suzuki C, et al. A metabolomic approach to clarifying the effect of AST-120 on 5/6 nephrectomized rats by capillary electrophoresis with mass spectrometry (CE-MS). Toxins (Basel). 2012;4(11):1309–22.CrossRefGoogle Scholar
  19. 19.
    Imamura S, Tachibana T, Taniguchi S. Impaired histamine metabolism in the Arthus reaction induced in Guinea-pig skin. Arch Dermatol Res. 1985;277(4):313–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin a. J Clin Invest. 1995;96(4):1698–705.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Shimizu T, Sugiura T, Wakayama T, Kijima A, Nakamichi N, Iseki S, et al. PDZK1 regulates breast cancer resistance protein in small intestine. Drug Metab Dispos. 2011;39(11):2148–54.PubMedCrossRefGoogle Scholar
  22. 22.
    Hamon M, Hanada S, Fujii T, Sakai Y. Direct oxygen supply with polydimethylsiloxane (PDMS) membranes induces a spontaneous organization of thick heterogeneous liver tissues from rat fetal liver cells in vitro. Cell Transplant. 2012;21(2–3):401–10.PubMedCrossRefGoogle Scholar
  23. 23.
    O'Mahony L, Akdis M, Akdis CA. Regulation of the immune response and inflammation by histamine and histamine receptors. J Allergy Clin Immunol. 2011;128(6):1153–62.PubMedCrossRefGoogle Scholar
  24. 24.
    Kim K. Neuroimmunological mechanism of pruritus in atopic dermatitis focused on the role of serotonin. Biomol Ther (Seoul). 2012;20(6):506–12.CrossRefGoogle Scholar
  25. 25.
    Uratsuji H, Tada Y, Kawashima T, Kamata M, Hau CS. Asano, et al. P2Y6 receptor signaling pathway mediates inflammatory responses induced by monosodium urate crystals. J Immunol. 2012;188(1):436–44.PubMedCrossRefGoogle Scholar
  26. 26.
    Eisen AZ, Seegmiller JE. Uric acid metabolism in psoriasis. J Clin Invest. 1961;40:1486–94.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Thorslund K, El-Nour H, Nordlind K. The serotonin transporter protein is expressed in psoriasis, where it may play a role in regulating apoptosis. Arch Dermatol Res. 2009;301(6):449–57.PubMedCrossRefGoogle Scholar
  28. 28.
    Haddock RC, Mack P, Fogerty FJ, Baenziger NL. Role of receptors in metabolic interaction of histamine with human vascular endothelial cells and skin fibroblasts. An ordered sequence of enzyme action. J Biol Chem. 1987;262(21):10220–8.PubMedGoogle Scholar
  29. 29.
    Ind PW, Brown MJ, Lhoste FJ, Macquin I, Dollery CT. Concentration effect relationships of infused histamine in normal volunteers. Agents Actions. 1982;12(1–2):12–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Gao J, Murase O, Schowen RL, Aubé J, Borchardt RT. A functional assay for quantitation of the apparent affinities of ligands of P-glycoprotein in Caco-2 cells. Pharm Res. 2001;18(2):171–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Suzuki M, Suzuki H, Sugimoto Y, Sugiyama Y. ABCG2 transports sulfated conjugates of steroids and xenobiotics. J Biol Chem. 2003;278(25):22644–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Solimando DA Jr, Wilson JP. Doxorubicin-induced hypersensitivity reactions. Drug Intell Clin Pharm. 1984;18(10):808–11.PubMedCrossRefGoogle Scholar
  33. 33.
    Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E, et al. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res. 2004;64(7):2333–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Ozvegy-Laczka C, Hegedus T, Várady G, Ujhelly O, Schuetz JD, Váradi A, et al. High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol. 2004;65(6):1485–95.PubMedCrossRefGoogle Scholar
  35. 35.
    Belum VR, Washington C, Pratilas CA, Sibaud V, Boralevi F, Lacouture ME. Dermatologic adverse events in pediatric patients receiving targeted anticancer therapies: a pooled analysis. Pediatr Blood Cancer. 2015;62(5):798–806.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Burotto M, Manasanch EE, Wilkerson J, Fojo T. Gefitinib and erlotinib in metastatic non-small cell lung cancer: a meta-analysis of toxicity and efficacy of randomized clinical trials. Oncologist. 2015;20(4):400–10.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009;79(2):135–40.PubMedGoogle Scholar
  38. 38.
    Iqbal M, Baello S, Javam M, Audette MC, Gibb W, Matthews SG. Regulation of multidrug resistance P-glycoprotein in the developing blood-brain barrier: interplay between glucocorticoids and cytokines. J Neuroendocrinol. 2016;28(3):12360.PubMedCrossRefGoogle Scholar
  39. 39.
    Black AK, Keahey TM, Eady RA, Greaves MW. Dissociation of histamine release and clinical improvement following treatment of acquired cold urticaria by prednisone. Br J Clin Pharmacol. 1981;12(3):327–31.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Owen A, Goldring C, Morgan P, Park BK, Pirmohamed M. Induction of P-glycoprotein in lymphocytes by carbamazepine and rifampicin: the role of nuclear hormone response elements. Br J Clin Pharmacol. 2006;62(2):237–42.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Naoto Hashimoto
    • 1
    • 2
  • Noritaka Nakamichi
    • 1
  • Hikari Nanmo
    • 1
  • Kei-ichi Kimura
    • 3
  • Yusuke Masuo
    • 1
  • Yasuyuki Sakai
    • 4
  • Alfred H. Schinkel
    • 5
  • Shinichi Sato
    • 6
  • Tomoyoshi Soga
    • 7
  • Yukio Kato
    • 1
    Email author
  1. 1.Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
  2. 2.Drug Development Research Laboratories, Drug Metabolism and Pharmacokinetic Research DivisionMaruho Company Ltd.KyotoJapan
  3. 3.Department of Bioengineering, Graduate School of EngineeringUniversity of TokyoTokyoJapan
  4. 4.Department of Chemical System Engineering, Graduate School of EngineeringUniversity of TokyoTokyoJapan
  5. 5.The Netherlands Cancer InstituteAmsterdamThe Netherlands
  6. 6.Department of Dermatology, Graduate School of MedicineUniversity of TokyoTokyoJapan
  7. 7.Institute for Advanced BiosciencesKeio UniversityTsuruokaJapan

Personalised recommendations