Di(2-ethylhexyl)phthalate leached from medical PVC devices serves as a substrate and inhibitor for the P-glycoprotein

A di(2-ethylhexyl)phthalate (DEHP) was accidentally extracted from plastics in the process of purification of chemosensitizers reversing P-glycoprotein (Pgp)-inediated multidrug resistance (MDR). The purpose of this study was to investigate the Pgp-reversal activities of phthalates, which are endocrine-disrupting chemicals, by utilizing the Pgp-overexpressing leukemic cell line AML-2/D100. The phthalates includes DEHP, diethyl phthalate (DEP) and dibutyl phthalate (DBP). Of the tested phthalates, DEHP showed the highest Pup-reversal activity and DEP the most potent drug-accumulating activity. On the other hand, they did not show any chemosensitizing activity against multidrug resistance associated protein-mediated MDR. The complete inhibition of Pap by verapamil increased the cytotoxicity of DEHP, but neither DEP nor DBP had this effect, suggesting that DEHP alone may be a possible substrate for the Pap. DEHP showed higher hydrophobicity than the other phthalates when determined by reverse phase-HPLC. In addition, DEHP, but not the others increased the ATPase activity in a concentration-dependent manner. This is the first report that phthalates can reverse Pgp-mediated MDR by increasing drug accumulation. as well as serving as substrates for the Pap. It is thought that the hydrophobic characteristics of phthalates could play an important role in Pgp-inhibitory activity. Therefore, pharmaco- and toxicokinetic interactions between phthalates leached from medical PVC devices and substrates for the Pap should be kept in mind. (c) 2006 Elsevier B.V. All rights reserved.