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Peroxynitrite and 4-Hydroxynonenal Inactivate Breast Cancer Resistance Protein/ABCG2

Svetlana Verenich1, Phillip M Gerk1

  • 1Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, P.O. Box 980533, Richmond, VA 23298-0533, USA.

Biomed Research International
|February 26, 2019
PubMed

Insights

Oxidative stress products, peroxynitrite (PN) and 4-hydroxynonenal (4HNE), significantly inhibit BCRP/ABCG2 transporter activity. These compounds drastically reduce transport rates, impacting cellular function.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Toxicology

Background:

  • Oxidative stress generates reactive species like peroxynitrite (PN) and 4-hydroxynonenal (4HNE).
  • These compounds have known cytotoxic effects, but their impact on ATP-binding cassette (ABC) transporters is less understood.
  • BCRP/ABCG2 is a crucial ABC transporter involved in effluxing various substrates.

Purpose of the Study:

  • To investigate the inhibitory effects of PN and 4-hydroxynonenal (4HNE) on the BCRP/ABCG2 transporter.
  • To quantify the potency of PN and 4HNE as inhibitors of BCRP/ABCG2-mediated transport.

Main Methods:

  • Experiments utilized inside-out Sf9 membrane vesicles overexpressing BCRP/ABCG2.
  • Riboflavin was employed as a substrate to measure BCRP/ABCG2 transport activity.
  • Inhibition kinetics were determined by measuring IC50 values and effects on Vmax and Km.

Main Results:

  • Peroxynitrite (PN) exhibited an IC50 of approximately 31.2 ± 2.7 μM.
  • 4-hydroxynonenal (4HNE) showed an IC50 of approximately 92 ± 1.4 μM.
  • Preincubation with PN or 4HNE drastically reduced the maximal transport rate (Vmax) by up to 19-fold, with minimal impact on the Michaelis constant (Km).

Conclusions:

  • Both PN and 4HNE act as potent inhibitors of BCRP/ABCG2 transporter activity.
  • The inhibition mechanism primarily affects the transporter's catalytic rate (Vmax) rather than substrate affinity (Km).
  • These findings highlight a potential mechanism by which oxidative stress can impair cellular efflux functions mediated by BCRP/ABCG2.

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