Identification of the synthetic surfactant nonylphenol ethoxylate: a P-glycoprotein substrate in human urine.
P-glycoprotein (Mdr1p) is an ATP-dependent drug efflux pump that is overexpressed in multidrug-resistant cells and some cancers. Mdr1p is also expressed in normal tissues like the kidney, where it can mediate transepithelial drug transport. A human urinary compound that reverses multidrug resistance and blocks [3H]azidopine photolabeling of P-glycoprotein was purified to homogeneity and identified by 1H-NMR and mass spectrometry as the synthetic surfactant nonylphenol ethoxylate (NPE). Multidrug-resistant Chinese hamster ovary (CHO) C5 cells accumulated less [3H]NPE than parental drug-sensitive Aux-B1 cells, and Mdr1p substrates, verapamil and cyclosporin A, increased this surfactant's accumulation in C5 cells. NPE blocked the net transepithelial transport (basolateral to apical) of [3H]cyclosporin A in epithelia formed by Madin-Darby canine kidney (MDCK) cells. Net transepithelial transport (basal to apical) of [3H]NPE was demonstrated in MDCK cells and was inhibited by cyclosporin A. These findings show NPE is a Mdr1p substrate excreted into urine by kidney P-glycoprotein. NPE is a widely used surfactant and a known hormone disrupter that is readily absorbed orally or topically. The current findings indicate the function of kidney Mdr1p may be to eliminate exogenous compounds from the body.
Charuk
M H
MH
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Grey
A A
AA
Reithmeier
R A
RA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000345:Affinity Labels; D000818:Animals; D001386:Azides / Q000037:antagonists & inhibitors; D016466:CHO Cells / Q000378:metabolism; D002463:Cell Membrane Permeability; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D016572:Cyclosporine / Q000378:metabolism; D004095:Dihydropyridines / Q000037:antagonists & inhibitors; D004285:Dogs; D018432:Drug Resistance, Multiple; D005026:Ethylene Glycols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000652:urine*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D001386:Azides; D004095:Dihydropyridines; D005026:Ethylene Glycols; C021754:terics; C041130:azidopine; D016572:Cyclosporine