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Glutathione and multidrug resistance protein transporter mediate a self-propelled disposal of bismuth in human cells.

Proceedings of the National Academy of Sciences of the United States of America (2015-03-05)
Yifan Hong, Yau-Tsz Lai, Godfrey Chi-Fung Chan, Hongzhe Sun
ABSTRACT

Glutathione and multidrug resistance protein (MRP) play an important role on the metabolism of a variety of drugs. Bismuth drugs have been used to treat gastrointestinal disorder and Helicobacter pylori infection for decades without exerting acute toxicity. They were found to interact with a wide variety of biomolecules, but the major metabolic pathway remains unknown. For the first time (to our knowledge), we systematically and quantitatively studied the metabolism of bismuth in human cells. Our data demonstrated that over 90% of bismuth was passively absorbed, conjugated to glutathione, and transported into vesicles by MRP transporter. Mathematical modeling of the system reveals an interesting phenomenon. Passively absorbed bismuth consumes intracellular glutathione, which therefore activates de novo biosynthesis of glutathione. Reciprocally, sequestration by glutathione facilitates the passive uptake of bismuth and thus completes a self-sustaining positive feedback circle. This mechanism robustly removes bismuth from both intra- and extracellular space, protecting critical systems of human body from acute toxicity. It elucidates the selectivity of bismuth drugs between human and pathogens that lack of glutathione, such as Helicobacter pylori, opening new horizons for further drug development.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
L-Glutathione reduced, ≥98.0%
Sigma-Aldrich
L-Glutathione reduced, suitable for cell culture, BioReagent, ≥98.0%, powder
Supelco
Glutathione, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
L-Glutathione reduced, BioXtra, ≥98.0%
Glutathione, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Bismuth, powder, −100 mesh, 99% trace metals basis
Sigma-Aldrich
Bismuth, granular, ≥99.99% trace metals basis
Sigma-Aldrich
Bismuth, pieces, 1-12 mm, 99.999% trace metals basis
Sigma-Aldrich
Bismuth, powder, −100 mesh, ≥99.99% trace metals basis
Sigma-Aldrich
Bismuth, shot, 4-30 mesh, 99.9% trace metals basis
Bismuth, foil, 25x25mm, thickness 0.25mm, 100%
Bismuth, foil, 25x25mm, thickness 1.0mm, 99.97%
Bismuth, foil, 25x25mm, thickness 0.5mm, 100%
Bismuth, foil, 25x25mm, thickness 1.0mm, 100%
Bismuth, foil, 25x25mm, thickness 2.0mm, 100%
Bismuth, foil, 50x50mm, thickness 0.25mm, 100%
Bismuth, foil, 50x50mm, thickness 0.5mm, 100%
Bismuth, foil, 50x50mm, thickness 1.0mm, 100%
Bismuth, foil, 50x50mm, thickness 1.0mm, 99.97%
Bismuth, foil, 50x50mm, thickness 2.0mm, 100%
Bismuth, foil, light tested, 25x25mm, thickness 0.01mm, permanent polyester support, 99.97%
Bismuth, foil, light tested, 25x25mm, thickness 0.025mm, permanent polyester support, 99.97%
Bismuth, foil, light tested, 25x25mm, thickness 0.02mm, permanent polyester support, 99.97%
Bismuth, foil, light tested, 25x25mm, thickness 0.05mm, permanent polyester support, 99.97%
Bismuth, foil, light tested, 50x50mm, thickness 0.015mm, permanent polyester support, 99.97%
Bismuth, foil, light tested, 50x50mm, thickness 0.01mm, permanent polyester support, 99.97%
Bismuth, foil, light tested, 50x50mm, thickness 0.025mm, permanent polyester support, 99.97%
Bismuth, foil, light tested, 50x50mm, thickness 0.02mm, permanent polyester support, 99.97%
Bismuth, foil, light tested, 50x50mm, thickness 0.05mm, permanent polyester support, 99.97%
Bismuth, foil, not light tested, 100x100mm, thickness 0.015mm, permanent polyester support, 99.97%