Abstract
Oxidative stress may arise from a variety of pathologies and results in the formation of toxic and reactive chemical species. Extensive research has been done to establish mechanisms of formation and cytotoxic effects of a number of different products of oxidation stress including peroxynitrite (PN) and 4-hydroxynonenal (4HNE). However, relatively few studies have investigated their effects on ATP-binding cassette (ABC) transporters. The objective of this investigation was to determine the effects of PN and 4HNE on BCRP/ABCG2. To eliminate the effect of metabolic enzymes, the experiments were carried out with inside-out Sf9 membrane vesicles overexpressing BCRP/ABCG2 using riboflavin as a substrate. The experiments revealed that PN produced IC50 of about 31.2 ± 2.7 μM, based upon initial concentrations. The IC50 for 4HNE was estimated to be 92 ± 1.4 μM. Preincubation of membrane vesicles with either PN or 4HNE caused the maximal rate of transport (Vmax) to drop drastically, up to 19 times, with no or much smaller effect on Km. Thus, PN and 4NE can inhibit BCRP transport activity.
Highlights
Oxidative stress is a frequent complication of various disease conditions such as Alzheimer and Parkinson’s diseases [1, 2], atherosclerosis [3], HIV [4], preeclampsia [5], rheumatoid arthritis [6], and diabetes [7] including gestational diabetes [8]
The purpose of this study was to demonstrate if 4HNE and PN can inhibit the transport of riboflavin mediated by Breast cancer resistance protein/ABCG2 OSP (BCRP)/ABCG2 and identify half maximal inhibitory concentration (IC50) for both PN and 4HNE
In this work we investigated ATP-dependent uptake of riboflavin into inside-out Sf membrane vesicles overexpressing BCRP/ABCG2
Summary
Oxidative stress is a frequent complication of various disease conditions such as Alzheimer and Parkinson’s diseases [1, 2], atherosclerosis [3], HIV [4], preeclampsia [5], rheumatoid arthritis [6], and diabetes [7] including gestational diabetes [8]. Different molecules associated with oxidative stress are involved in the development of pathogenesis; peroxynitrite (PN) and 4-hydroxynonenal (4HNE) are the most studied. The former is a reaction product of superoxide and nitric oxide, while 4HNE is a product of lipid peroxidation of polyunsaturated fatty acids [9]. Both of them are implicated in damage, adduction, or inhibition of synthesis of DNA or RNA, cell apoptosis or necrosis, mitochondrial dysfunction, and lipid peroxidation [10, 11]. The effect of PN and 4HNE on ATP-binding cassette (ABC) transporters has not been thoroughly investigated
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