Glutathione and multidrug resistance protein transporter mediate a self-propelled disposal of bismuth in human cells.
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.
Department of Chemistry and Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China.
Yifan
Y
Hong
Department of Chemistry and.
Yau-Tsz
YT
Lai
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China.
Godfrey Chi-Fung
GC
Chan
Department of Chemistry and hsun@hku.hk.
Hongzhe
H
Sun
D001729:Bismuth / Q000378:metabolism* / Q000494:pharmacology; D002451:Cell Compartmentation / Q000187:drug effects; D002460:Cell Line; D003102:Colloids / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology; D040901:Proteomics; D013223:Statistics as Topic; D013997:Time Factors
D001729:Bismuth; D003102:Colloids; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009942:Organometallic Compounds; C002791:bismuth tripotassium dicitrate; C421109:multidrug resistance-associated protein 1
MRP; bismuth; drug selectivity; glutathione; positive feedback