Evasion of the Toxic Effects of Oxygen

Hazell, Stuart L.; Harris, Andrew G.; Trend, Mark A.

doi:10.1128/9781555818005.ch15

Cited by 10 publications

(2 citation statements)

References 85 publications

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“…112 | no. 11 | 3215 CHEMISTRY PHARMACOLOGY many anaerobic or microaerobic bacteria and protozoans, in which cysteine is the major thiol (42)(43)(44)(45), as when oxygen is absent, cysteine is a steady source of thiol (45). Human gastrointestinal tract is microaerobic/anaerobic, a perfect habitat for these organisms.…”

Section: Hong Et Almentioning

confidence: 99%

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

Hong

Lai²,

Chan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.bismuth | drug selectivity | glutathione | MRP | positive feedback

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Section: Hong Et Almentioning

confidence: 99%

“…Human gastrointestinal tract is microaerobic/anaerobic, a perfect habitat for these organisms. Many GIT microbes are lack of glutathione, such as H. pylori and G. lamblia (43,45). It would be of interest to further investigate how glutathione affects the efficacy of bismuth drugs in microbes.…”

Section: Hong Et Almentioning

confidence: 99%

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

Hong

Lai²,

Chan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Helicobacter

Owen¹

2010

Topley &Amp; Wilson's Microbiology and Microbial Infections

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The role of iron in Campylobacter gene regulation, metabolism and oxidative stress defense

Vliet

Ketley

Park

et al. 2002

FEMS Microbiology Reviews

102

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Enteric Campylobacter species cause gastrointestinal diseases in humans. Like almost all organisms, campylobacters have an absolute requirement for iron, but are faced with variable availability of iron in the environment and host tissues. Campylobacters have developed mechanisms to scavenge sufficient iron for metabolism and growth. However, iron also participates in the formation of reactive oxygen species, and this forces pathogens to maintain intracellular iron homeostasis and to cope with oxidative stresses. The presence of two separate, but possibly overlapping iron-responsive regulatory systems, which regulate iron acquisition and oxidative stress defense, and the presence of genes encoding multiple iron acquisition and detoxification systems in Campylobacter indicate the central role that iron plays in Campylobacter gene regulation and virulence.

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Evasion of the Toxic Effects of Oxygen

Cited by 10 publications

References 85 publications

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

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

Helicobacter

The role of iron in Campylobacter gene regulation, metabolism and oxidative stress defense

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