@article{fdi:010081510,
  title = {{A}ssociation of {NQO}2 with {UDP}-glucuronosyltransferases reduces menadione toxicity in neuroblastoma cells},
  author = {{C}hhour, {M}. and {P}erio, {P}ierre and {G}ayon, {R}. and {T}ernet-{F}ontebasso, {H}. and {F}erry, {G}. and {N}epveu, {F}. and {B}outin, {J}. {A}. and {S}udor, {J}. and {R}eybier, {K}.},
  editor = {},
  language = {{ENG}},
  abstract = {{T}he balance between detoxification and toxicity is linked to enzymes of the drug metabolism {P}hase {I} (cytochrome {P}450 or oxidoreductases) and phase {II} conjugating enzymes (such as the {UGT}s). {A}fter the reduction of quinones, the product of the reaction, the quinols-if not conjugated-re-oxidizes spontaneously to form the substrate quinone with the concomitant production of the toxic reactive oxygen species ({ROS}). {H}erein, we documented the modulation of the toxicity of the quinone menadione on a genetically modified neuroblastoma model cell line that expresses both the quinone oxidoreductase 2 ({NQO}2, {E}.{C}. 1.10.5.1) alone or together with the conjugation enzyme {UDP}-glucuronosyltransferase ({UGT}1{A}6, {E}.{C}. 2.4.1.17), one of the two {UGT} isoenzymes capable to conjugate menadione. {A}s previously shown, {NQO}2 enzymatic activity is concomitant to massive {ROS} production, as previously shown. {T}he quantification of {ROS} produced by the menadione metabolism was probed by electron-paramagnetic resonance ({EPR}) on cell homogenates, while the production of superoxide was measured by liquid chromatography coupled to mass spectrometry ({LC}-{MS}) on intact cells. {I}n addition, the dysregulation of the redox homeostasis upon the cell exposure to menadione was studied by fluorescence measurements. {B}oth {EPR} and {LCMS} studies confirmed a significant increase in the {ROS} production in the {NQO}2 overexpressing cells due to the fast reduction of quinone into quinol that can re-oxidize to form superoxide radicals. {H}owever, the effect of {NQO}2 inhibition was drastically different between cells overexpressing only {NQO}2 vs. both {NQO}2 and {UGT}. {W}hereas {NQO}2 inhibition decreases the amount of superoxide in the first case by decreasing the amount of quinol formed, it increased the toxicity of menadione in the cells co-expressing both enzymes. {M}oreover, for the cells co-expressing {QR}2 and {UGT} the homeostasis dysregulation was lower in presence of menadione than for the its counterpart expressing only {QR}2. {T}hose results confirmed that the cooperation of the two enzymes plays a fundamental role during the cells' detoxification process. {T}he fluorescence measurements of the variation of redox homeostasis of each cell line and the detection of a glucuronide form of menadiol in the cells co-expressing {NQO}2 and {UGT}1{A}6 enzymes further confirmed our findings.},
  keywords = {{NQO}2 ; conjugation ; glucuronide ; menadiol ; cellular toxicity},
  booktitle = {},
  journal = {{F}rontiers in {P}harmacology},
  volume = {12},
  numero = {},
  pages = {660641 [11 p.]},
  ISSN = {1663-9812},
  year = {2021},
  DOI = {10.3389/fphar.2021.660641},
  URL = {https://www.documentation.ird.fr/hor/fdi:010081510},
}