Identification of the synthetic surfactant nonylphenol ethoxylate,
a p-glycoprotein substrate in human urine.
Charuk, Jeffrey H. M., Arthur A. Grey, and Reinhart A. F. Reithmeier.
Medical Research Council Group in Membrane Biology, Department of
Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8.
Molecular Medicine Research Centre, Department of Medical Genetics
and Microbiology, University of Toronto, Toronto, Ontario, Canada,
M5S 1A8
APStracts 5:0055F, 1998.
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 photolabelling
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.
Received 28 October 1997; accepted in final form 19 February
1998.
APS Manuscript Number F341-7.
Article publication pending Am. J. Physiol. (Renal Physiology).
ISSN 1080-4757 Copyright 1998 The American Physiological Society.
Published in APStracts on 9 March 1998