title: Transport characteristics of tryptanthrin and its inhibitory effect on P-gp and MRP2 in Caco-2 cells.
abstract: PURPOSE. Tryptanthrin, an indole quinazoline alkaloid with multiple medical activities, has been recently under preclinical development as an anti-tuberculosis and anti-tumor drug. The aims of this study are to characterize the intestinal transport of tryptanthrin in Caco-2 cells, to determine whether P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) are involved in this issue, and to evaluate the potential influence of tryptanthrin on the function of P-gp and MRP2. METHODS. Transport assays of tryptanthrin were performed in Caco-2 monolayers with or without the supplement of P-gp and MRP2 inhibitors. Transport assays of P-gp and MRP2 substrates were also performed in the presence of tryptanthrin. The effect of tryptanthrin on the expression of P-gp and MRP2 was analyzed by reverse transcriptase-PCR. RESULTS. Both absorption and secretion of tryptanthrin were concentration-independent at a low concentration range of 0.8-20 µM. The apparent permeability (Papp) for the apical (AP) to basolateral (BL) was 6.138 ± 0.291 × 10-5. The ratio of Papp (BL→AP) to Papp (AP→BL) was 0.77, suggesting greater permeability in the absorptive direction. Both the P-gp inhibitor, verapamil, and the MRP2 inhibitor, glibenclamide, didn't affect the efflux transport of tryptanthrin. The efflux transport of the P-gp substrate, digoxin, and the MRP2 substrate, pravastatin sodium, decreased when tryptanthrin was present. However, tryptanthrin didn't change the expression of P-gp and MRP2. CONCLUSIONS. Tryptanthrin was well absorbed across the Caco-2 monolayers, and its transepithelial transports were dominated by passive diffusion. Tryptanthrin was not a substrate, but a potential inhibitor of P-gp and MRP2. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Xingang
authors.initials: X
authors.lastname: Zhu
authors.forename: Xuelian
authors.initials: X
authors.lastname: Zhang
authors.forename: Guo
authors.initials: G
authors.lastname: Ma
authors.forename: Junkai
authors.initials: J
authors.lastname: Yan
authors.forename: Honghai
authors.initials: H
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D004058:Diffusion; D004077:Digoxin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000995:Antitubercular Agents; D004077:Digoxin; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D005905:Glyburide; D007004:Hypoglycemic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011799:Quinazolines; C000715087:ABCC2 protein, human; C046243:tryptanthrine