Selective regulation of multidrug resistance protein in vascular smooth muscle cells by the isoquinoline alkaloid coptisine.
When the biological activites of hydrophobic drugs or xenobiotics are studied, it is important to clarify their effects on expression and function of multidrug resistance (MDR) protein. We therefore evaluated the effects of coptisine on MDR in comparison with the structurally related isoquinoline alkaloids berberine and palmatine. To achieve this, we investigated the effects of the three alkaloids on the expression and function of P-glycoprotein/MDR1, MDR1 gene products, in vascular smooth muscle cells (VSMCs). In A10 cells (a rat VSMC line), coptisine upregulated the mRNAs of Mdr1a and Mdr1b, rodent homologues of human MDR1, and these effects were completely abrogated by actinomycin D. Coptisine also induced Mdr1a/1b protein expression and enhanced the efflux of rhodamine 123 from A10 cells. In contrast, berberine and palmatine slightly upregulated the mRNAs of Mdr1a and Mdr1b, but failed to induce Mdr1a/1b protein expression or stimulate rhodamine 123 efflux. To clarify whether these effects occurred in other cells, the effects of the three alkaloids on Mdr1a/1b function were examined in 3Y1, dRLh-84 and B16 cells. Coptisine and berberine enhanced rhodamine 123 efflux in all three cell types, while palmatine inhibited it, based on the finding that palmatine efficiently activated the Mdr1a ATPase activity as a good substrate for Mdr1a. Therefore, the three isoquinoline alkaloids regulated MDR differently in cell type-specific manners. In particular, only coptisine induced Mdr1a/1b in A10 cells and stimulated rhodamine 123 efflux. Taken together, coptisine appears to exert VSMC-selective effects on Mdr1a/1b induction in contrast to berberine and palmatine.
Suzuki
Hiroka
H
Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, Japan.
Tanabe
Hiroki
H
Mizukami
Hajime
H
Inoue
Makoto
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001600:Berberine Alkaloids / Q000737:chemistry / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D039323:Coptis / Q000737:chemistry*; D003609:Dactinomycin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D005786:Gene Expression Regulation; D019450:Genes, MDR; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012235:Rhodamines / Q000378:metabolism; D015854:Up-Regulation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001600:Berberine Alkaloids; D002317:Cardiovascular Agents; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D012235:Rhodamines; C034384:coptisine; D001599:Berberine; D003609:Dactinomycin; C005413:palmatine