Drug Metabolism Letters

Zhiyang Zhao
Amgen
Cambridge, MA
USA

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Study of Oxidized Lipids as Endogenous Substrates of P-gp (ABCB1)

Author(s): Masatoshi Masuda, Emi Nakai, Takaharu Mizutani.

Abstract:

We studied endogenous substrates for P-glycoprotein (P-gp) in an oxidative reaction mixture of ceramides, phospholipids, sphingolipids, or GM1-gangliosides (GM1-G). Extracts from the reaction mixture of galactocerebrosides (GalCer), sphingomyelin (SM) , lactocerebrosides (LactoCer), and asolectine (AS) with 0.3% hydrogen peroxide exhibited significant ATPase activity of P-gp of 7.6, 7.8, 5.3, and 4.7 nmol/min/mg protein, respectively, at a concentration of 10 μg equivalent/ml, but not GalCer, SM, LactoCer, and AS themselves. Meanwhile, both GM1-G and its oxidized product showed ATPase activity of 3.7 nmol/min/mg protein at a concentration of 0.75 μM. Phosphatidylcholine, phosphatidylethanolamine, phophatidylserine, triglyceride, and cholesterol did not show P-gp activity. When reactive oxygen species, such as hydrogen peroxide, exceed the ability of antioxidant defense systems to remove it from living cells, SM, GalCer, LactoCer, and AS could react with it; therefore, it is possible for these oxidized lipids to play as substrates for Pgp in living cells. This finding should be a milestone to search a new physiological P-gp function.

Keywords: MDR1, P-glycoprotein, ABCB1, Sphingolipid, GM1-ganglioside, ROS

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Article Details

VOLUME: 2
ISSUE: 4
Year: 2008
Page: [238 - 244]
Pages: 7
DOI: 10.2174/187231208786734139
Price: $58