The one-electron reduction potential of several substrates can be related to their reduction rates by cytochrome P-450 reductase

Butler, J. A. V.; Hoey, Brigid M.

doi:10.1016/0167-4838(93)90198-z

Cited by 77 publications

(43 citation statements)

References 16 publications

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“…4, panel B, and data not shown). The most active redox cycling quinone based on k cat /K m was 1,2-naphthoquinone followed by 9,10-phenanthrenequinone, 1,4-naphthoquinone, menadione, and 2,3-dimethoxy-1,4-naphthoquinone (Table 2), which is generally consistent with previous reports on the redox potentials of these compounds (32)(33)(34). In contrast, two related quinones, p-benzoquinone (1,4-benzoquinone) and phenylquinone (2-phenyl-1,4-benzoquinone), did not redox cycle with sepiapterin reductase (Fig.…”

Section: Identification Of Sepiapterin Reductase As a Mediator Of Redsupporting

confidence: 81%

Sepiapterin Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells

Yang¹,

Jan

Gray

et al. 2013

Journal of Biological Chemistry

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Background: Enzymes mediating chemical redox cycling in the lung are poorly defined. Results: Sepiapterin reductase was identified as a key mediator of redox cycling and was analyzed using inhibitors and sitedirected mutagenesis. Conclusion: Sepiapterin reductase generates reactive oxygen species during redox cycling in a mechanism distinct from sepiapterin reduction. Significance: This is the first report demonstrating that sepiapterin reductase mediates chemical redox cycling.

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Section: Identification Of Sepiapterin Reductase As a Mediator Of Redsupporting

confidence: 81%

Sepiapterin Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells

Yang¹,

Jan

Gray

et al. 2013

Journal of Biological Chemistry

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“…The relatively negative redox potential of anthracyclines (-348 mV) compared with other, less substituted quinone compounds may explain the delayed onset of thiol oxidation in our system (Butler and Hoey, 1993). It is generally accepted that most RyR thiol residues have a pKa of ∼8, where they are relatively inert.…”

Section: Discussionmentioning

confidence: 89%

Adverse Effects of Doxorubicin and Its Metabolic Product on Cardiac RyR2 and SERCA2A

Hanna

Lam

Tham

et al. 2014

Molecular Pharmacology

129

101

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The use of anthracycline chemotherapeutic drugs is restricted owing to potentially fatal cardiotoxic side effects. It has been hypothesized that anthracycline metabolites have a primary role in this cardiac dysfunction; however, information on the molecular interactions of these compounds in the heart is scarce. Here we provide novel evidence that doxorubicin and its metabolite, doxorubicinol, bind to the cardiac ryanodine receptor (RyR2) and to the sarco/endoplasmic reticulum Ca 21 ATPase (SERCA2A) and deleteriously alter their activity. Both drugs (0.01 mM-2.5 mM) activated single RyR2 channels, and this was reversed by drug washout. Both drugs caused a secondary inhibition of RyR2 activity that was not reversed by drug washout. Preincubation with the reducing agent dithiothreitol (DTT, 1 mM) prevented drug-induced inhibition of channel activity. Doxorubicin and doxorubicinol reduced the abundance of thiol groups on RyR2, further indicating that oxidation reactions may be involved in the actions of the compounds. Ca 21 uptake into sarcoplasmic reticulum vesicles by SERCA2A was inhibited by doxorubicinol, but not doxorubicin. Unexpectedly, in the presence of DTT, doxorubicinol enhanced the rate of Ca 21 uptake by SERCA2A. Together the evidence provided here shows that doxorubicin and doxorubicinol interact with RyR2 and SERCA2A in similar ways, but that the metabolite acts with greater efficacy than the parent compound. Both compounds modify RyR2 and SERCA2A activity by binding to the proteins and also act via thiol oxidation to disrupt SR Ca 21 handling. These actions would have severe consequences on cardiomyocyte function and contribute to clinical symptoms of acute anthracycline cardiotoxicity.

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“…Other cellular organelles like endoplasmic reticulum consist of cytochrome P 450 in mammalian cells (Butler 1993). Cytochrome P 450 is responsible for the detoxification of toxic compounds carried out by oxidation of foreign/toxic compounds with the aid of enzyme monooxygenase.…”

Section: Sources and Formation Of Free Radicalsmentioning

confidence: 99%

“…Cytochrome P 450 is responsible for the detoxification of toxic compounds carried out by oxidation of foreign/toxic compounds with the aid of enzyme monooxygenase. This process of detoxification is also responsible for the leakage of molecular oxygen to eventually form superoxide radical (Butler 1993). This reaction also occurs in the mitochondria (Thannikal and Fanburg 2000).…”

Section: Sources and Formation Of Free Radicalsmentioning

confidence: 99%