An in vitro and in silico study on the flavonoid mediated modulation of the transport of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) through Caco-2 monolayers

M.E. Schutte, A.P. Freidig, J.J.M. van de Sandt, G.M. Alink, I.M.C.M. Rietjens, J.P. Groten

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19 Citations (Scopus)

Abstract

The present study describes the effect of different flavonoids on the absorption of the pro-carcinogen PhIP through Caco-2 monolayers and the development of an in silico model describing this process taking into account passive diffusion and active transport of PhIP. Various flavonoids stimulated the apical to basolateral PhIP transport. Using the in silico model for flavone, kaempferol and chrysoeriol, the apparent Ki value for inhibition of the active transport to the apical side was estimated to be below 53 muM and for morin, robinetin and taxifolin between 164 and 268 microM. For myricetin, luteolin, naringenin and quercetin, the apparent Ki values were determined more accurately and amounted to 37.3, 12.2, 11.7 and 5.6 microM respectively. Additional experiments revealed that the apical to basolateral PhIP transport was also increased in the presence of a typical BCRP or MRP inhibitor with apparent Ki values in the same range as those of the flavonoids. This observation together with the fact that flavonoids are known to be inhibitors of MRPs and BCRP, corroborates that inhibition of these apical membrane transporters is involved in the flavonoid-mediated increased apical to basolateral PhIP transport. Based on the apparent Ki values obtained, it is concluded that the flavonols, at the levels present in the regular Western diet, are capable of stimulating the transport of PhIP through Caco-2 monolayers from the apical to the basolateral compartment. This points to flavonoid-mediated stimulation of the bioavailability of PhIP and, thus, a possible adverse effect of these supposed beneficial food ingredients.
Original languageEnglish
Pages (from-to)204-215
JournalToxicology and Applied Pharmacology
Volume217
Issue number2
DOIs
Publication statusPublished - 2006

Fingerprint

Flavonoids
Computer Simulation
Monolayers
Modulation
flavone
Active Biological Transport
Luteolin
Flavonols
Membrane Transport Proteins
Quercetin
Nutrition
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
In Vitro Techniques
Carcinogens
Biological Availability
Food
Experiments

Keywords

  • cancer resistance protein
  • multidrug-resistance
  • p-glycoprotein
  • cell-lines
  • biochanin-a
  • absorption
  • carcinogen
  • expression
  • quercetin
  • efflux

Cite this

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title = "An in vitro and in silico study on the flavonoid mediated modulation of the transport of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) through Caco-2 monolayers",
abstract = "The present study describes the effect of different flavonoids on the absorption of the pro-carcinogen PhIP through Caco-2 monolayers and the development of an in silico model describing this process taking into account passive diffusion and active transport of PhIP. Various flavonoids stimulated the apical to basolateral PhIP transport. Using the in silico model for flavone, kaempferol and chrysoeriol, the apparent Ki value for inhibition of the active transport to the apical side was estimated to be below 53 muM and for morin, robinetin and taxifolin between 164 and 268 microM. For myricetin, luteolin, naringenin and quercetin, the apparent Ki values were determined more accurately and amounted to 37.3, 12.2, 11.7 and 5.6 microM respectively. Additional experiments revealed that the apical to basolateral PhIP transport was also increased in the presence of a typical BCRP or MRP inhibitor with apparent Ki values in the same range as those of the flavonoids. This observation together with the fact that flavonoids are known to be inhibitors of MRPs and BCRP, corroborates that inhibition of these apical membrane transporters is involved in the flavonoid-mediated increased apical to basolateral PhIP transport. Based on the apparent Ki values obtained, it is concluded that the flavonols, at the levels present in the regular Western diet, are capable of stimulating the transport of PhIP through Caco-2 monolayers from the apical to the basolateral compartment. This points to flavonoid-mediated stimulation of the bioavailability of PhIP and, thus, a possible adverse effect of these supposed beneficial food ingredients.",
keywords = "cancer resistance protein, multidrug-resistance, p-glycoprotein, cell-lines, biochanin-a, absorption, carcinogen, expression, quercetin, efflux",
author = "M.E. Schutte and A.P. Freidig and {van de Sandt}, J.J.M. and G.M. Alink and I.M.C.M. Rietjens and J.P. Groten",
year = "2006",
doi = "10.1016/j.taap.2006.08.005",
language = "English",
volume = "217",
pages = "204--215",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Elsevier",
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An in vitro and in silico study on the flavonoid mediated modulation of the transport of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) through Caco-2 monolayers. / Schutte, M.E.; Freidig, A.P.; van de Sandt, J.J.M.; Alink, G.M.; Rietjens, I.M.C.M.; Groten, J.P.

In: Toxicology and Applied Pharmacology, Vol. 217, No. 2, 2006, p. 204-215.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - An in vitro and in silico study on the flavonoid mediated modulation of the transport of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) through Caco-2 monolayers

AU - Schutte, M.E.

AU - Freidig, A.P.

AU - van de Sandt, J.J.M.

AU - Alink, G.M.

AU - Rietjens, I.M.C.M.

AU - Groten, J.P.

PY - 2006

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N2 - The present study describes the effect of different flavonoids on the absorption of the pro-carcinogen PhIP through Caco-2 monolayers and the development of an in silico model describing this process taking into account passive diffusion and active transport of PhIP. Various flavonoids stimulated the apical to basolateral PhIP transport. Using the in silico model for flavone, kaempferol and chrysoeriol, the apparent Ki value for inhibition of the active transport to the apical side was estimated to be below 53 muM and for morin, robinetin and taxifolin between 164 and 268 microM. For myricetin, luteolin, naringenin and quercetin, the apparent Ki values were determined more accurately and amounted to 37.3, 12.2, 11.7 and 5.6 microM respectively. Additional experiments revealed that the apical to basolateral PhIP transport was also increased in the presence of a typical BCRP or MRP inhibitor with apparent Ki values in the same range as those of the flavonoids. This observation together with the fact that flavonoids are known to be inhibitors of MRPs and BCRP, corroborates that inhibition of these apical membrane transporters is involved in the flavonoid-mediated increased apical to basolateral PhIP transport. Based on the apparent Ki values obtained, it is concluded that the flavonols, at the levels present in the regular Western diet, are capable of stimulating the transport of PhIP through Caco-2 monolayers from the apical to the basolateral compartment. This points to flavonoid-mediated stimulation of the bioavailability of PhIP and, thus, a possible adverse effect of these supposed beneficial food ingredients.

AB - The present study describes the effect of different flavonoids on the absorption of the pro-carcinogen PhIP through Caco-2 monolayers and the development of an in silico model describing this process taking into account passive diffusion and active transport of PhIP. Various flavonoids stimulated the apical to basolateral PhIP transport. Using the in silico model for flavone, kaempferol and chrysoeriol, the apparent Ki value for inhibition of the active transport to the apical side was estimated to be below 53 muM and for morin, robinetin and taxifolin between 164 and 268 microM. For myricetin, luteolin, naringenin and quercetin, the apparent Ki values were determined more accurately and amounted to 37.3, 12.2, 11.7 and 5.6 microM respectively. Additional experiments revealed that the apical to basolateral PhIP transport was also increased in the presence of a typical BCRP or MRP inhibitor with apparent Ki values in the same range as those of the flavonoids. This observation together with the fact that flavonoids are known to be inhibitors of MRPs and BCRP, corroborates that inhibition of these apical membrane transporters is involved in the flavonoid-mediated increased apical to basolateral PhIP transport. Based on the apparent Ki values obtained, it is concluded that the flavonols, at the levels present in the regular Western diet, are capable of stimulating the transport of PhIP through Caco-2 monolayers from the apical to the basolateral compartment. This points to flavonoid-mediated stimulation of the bioavailability of PhIP and, thus, a possible adverse effect of these supposed beneficial food ingredients.

KW - cancer resistance protein

KW - multidrug-resistance

KW - p-glycoprotein

KW - cell-lines

KW - biochanin-a

KW - absorption

KW - carcinogen

KW - expression

KW - quercetin

KW - efflux

U2 - 10.1016/j.taap.2006.08.005

DO - 10.1016/j.taap.2006.08.005

M3 - Article

VL - 217

SP - 204

EP - 215

JO - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

SN - 0041-008X

IS - 2

ER -