TY - JOUR
T1 - Effect of bioflavonoids on vincristine transport across blood-brain barrier
AU - Mitsunaga, Yoshiharu
AU - Takanaga, Hitomi
AU - Matsuo, Hirotami
AU - Naito, Mikihiko
AU - Tsuruo, Takashi
AU - Ohtani, Hisakazu
AU - Sawada, Yasufumi
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan.
PY - 2000/5/3
Y1 - 2000/5/3
N2 - Several grapefruit juice bioflavonoids, including quercetin, are reported to stimulate P-glycoprotein-mediated drug efflux from cultured tumor cells. To see whether these bioflavonoids alter the permeation of vincristine across the blood-brain barrier, we conducted experiments with cultured mouse brain capillary endothelial cells (MBEC4 cells) in vitro and ddY mice in vivo. The steady-state uptake of [3H]vincristine by MBEC4 cells was decreased by 10 μM quercetin, but increased by 50 μM quercetin. Similarly, the in vivo brain-to-plasma concentration ratio of [3H]vincristine in ddY mice was decreased by coadministration of 0.1 mg/kg quercetin, but increased by 1.0 mg/kg quercetin. Kaempferol had a similar biphasic effect on the in vitro uptake of [3H]vincristine. Other aglycones tested (chrysin, flavon, hesperetin, naringenin) increased [3H]vincristine uptake in the 10-50 μM range, and glycosides (hesperidin, naringin, rutin) were without effect. We then addressed the mechanism of the concentration-dependent biphasic action of quercetin. Verapamil, a P-glycoprotein inhibitor, inhibited the efflux of [3H]vincristine from MBEC4 cells, while 10 μM quercetin significantly stimulated it. The uptake of [3H]vincristine by MBEC4 cells was increased by inhibitors of protein kinase C, but decreased by phorbol 12-myristate-13- acetate (PMA), as well as by 10 μM quercetin. The phosphorylation level of P-glycoprotein was increased in the presence of 5 μM quercetin or 100 nM PMA, but decreased by the protein kinase C inhibitor H7 (1-(5- isoquinolinesulfonyl)-2-methylpiperazine, 30 μM). We conclude that low concentrations of quercetin indirectly activate the transport of [3H]vincristine by enhancing the phosphorylation (and hence activity) of P- glycoprotein, whereas high concentrations of quercetin inhibit P- glycoprotein. Our results indicate that patients taking drugs which are P- glycoprotein substrates may need to restrict their intake of bioflavonoid- containing foods and beverages, such as grapefruit juice. (C) 2000 Elsevier Science B.V.
AB - Several grapefruit juice bioflavonoids, including quercetin, are reported to stimulate P-glycoprotein-mediated drug efflux from cultured tumor cells. To see whether these bioflavonoids alter the permeation of vincristine across the blood-brain barrier, we conducted experiments with cultured mouse brain capillary endothelial cells (MBEC4 cells) in vitro and ddY mice in vivo. The steady-state uptake of [3H]vincristine by MBEC4 cells was decreased by 10 μM quercetin, but increased by 50 μM quercetin. Similarly, the in vivo brain-to-plasma concentration ratio of [3H]vincristine in ddY mice was decreased by coadministration of 0.1 mg/kg quercetin, but increased by 1.0 mg/kg quercetin. Kaempferol had a similar biphasic effect on the in vitro uptake of [3H]vincristine. Other aglycones tested (chrysin, flavon, hesperetin, naringenin) increased [3H]vincristine uptake in the 10-50 μM range, and glycosides (hesperidin, naringin, rutin) were without effect. We then addressed the mechanism of the concentration-dependent biphasic action of quercetin. Verapamil, a P-glycoprotein inhibitor, inhibited the efflux of [3H]vincristine from MBEC4 cells, while 10 μM quercetin significantly stimulated it. The uptake of [3H]vincristine by MBEC4 cells was increased by inhibitors of protein kinase C, but decreased by phorbol 12-myristate-13- acetate (PMA), as well as by 10 μM quercetin. The phosphorylation level of P-glycoprotein was increased in the presence of 5 μM quercetin or 100 nM PMA, but decreased by the protein kinase C inhibitor H7 (1-(5- isoquinolinesulfonyl)-2-methylpiperazine, 30 μM). We conclude that low concentrations of quercetin indirectly activate the transport of [3H]vincristine by enhancing the phosphorylation (and hence activity) of P- glycoprotein, whereas high concentrations of quercetin inhibit P- glycoprotein. Our results indicate that patients taking drugs which are P- glycoprotein substrates may need to restrict their intake of bioflavonoid- containing foods and beverages, such as grapefruit juice. (C) 2000 Elsevier Science B.V.
KW - Bioflavonoid
KW - Blood-brain barrier
KW - P-Glycoprotein
KW - Protein kinase C
KW - Vincristine
UR - http://www.scopus.com/inward/record.url?scp=0034600237&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034600237&partnerID=8YFLogxK
U2 - 10.1016/S0014-2999(00)00180-1
DO - 10.1016/S0014-2999(00)00180-1
M3 - Article
C2 - 10812049
AN - SCOPUS:0034600237
VL - 395
SP - 193
EP - 201
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 3
ER -