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Gene & Protein in Disease NQO2 and dopamine toxicity versus detoxification

Box 1. State of the art and future trends Funding
(A) What is known None.
(i) Dopaminequinone is spontaneously generated in brain from
dopamine. Conflict of interest
(ii) Dopaminequinone is a substrate of NQO2 in the brain. The authors declare no conflict of interest.
(iii) NQO2 and TH are co-expressed in the dopaminergic neurons.
(iv) NQO2 catalytic activity indirectly leads to the production of ROS. Author contributions
(v) UGT1A6 produces glucuronide of dopamine. Conceptualization: Jean A. Boutin, Gilles Ferry, Karine
(vi) UGT is expressed in the brain and glucuronides are found in the Reybier
LCR. Writing – original draft: Jean A. Boutin, Gilles Ferry, Karine
(vii) UGT can be induced by phenobarbital in human. Reybier
(viii) Glucuronidation of dopamine interrupts the futile cycle catalyzed Writing – review & editing: Jean A. Boutin, Gilles Ferry,
by NQO2, resulting in the cessation of ROS production. Karine Reybier
(B) What remains to be demonstrated or reinforced Ethics approval and consent to participate
(i) The presence of UGT in the brain, and its subcellular localization,
including at the levels of the neurons as well as its possible Not applicable.
co-expression with NQO2.
(ii) The nature of the UGT isoform should be clarified (UGT1A6 or Consent for publication
UGT1A10) in the brain. Not applicable.
(iii) The availability of the NQO2 co-substrate (e.g., NRH or NMH).
(iv) The constant but low activity of NQO2 in dopaminergic neurons. Availability of data
(This would correspond to a continuous production of ROS at
low levels, and it could correspond to a long process of minimal Not applicable.
but repetitive accumulation of injuries in dopaminergic neurons).
(v) The regulations of both NQO2 and UGT expressions – at least References
the particular isoform in charge of dopamine conjugation. 1. Stich HF, Anders F, 1989, The involvement of reactive oxygen
(Particularly regarding their modulations by pollutant factors, species in oral cancers of betel quid/tobacco chewers. Mutat
in order to document the possible antagonistic effects of UGT Res, 214: 47–61.
dopamine conjugation onto NQO2-dependent toxicity).
(vi) At the cohort levels, could phenobarbital (as inducer of UGT) https://doi.org/10.1016/0027-5107(89)90197-8
delays the onset of neurodegenerative diseases? 2. Kamp DW, Graceffa P, Pryor WA, et al., 1992, The role of
(vii) Alternative conjugation pathways might play a similar free radicals in asbestos-induced diseases. Free Radic Biol
limiting role, such as sulfotransferase(s). (Further studies Med, 12: 293–315.
should complete the picture, in particular, the availability of
the co-substrate in the brain, and expression level variation https://doi.org/10.1016/0891-5849(92)90117-y
throughout life). 3. Hajam YA, Rani R, Ganie SY, et al., 2022, Oxidative stress
in human pathology and aging: Molecular mechanisms and
expression is an indication that in some of those perspectives. Cells, 11: 552.
pathological situations, NQO2 might have a causal role. https://doi.org/10.3390/cells11030552
Nevertheless, it is highly improbable that every type of 4. Lü JM, Lin PH, Yao Q, et al., 2010, Chemical and molecular
neurodegenerative situations is due to both NQO2 and mechanisms of antioxidants: Experimental approaches and
UGT dysregulations. The present commentary is based model systems. J Cell Mol Med, 14: 840–860.
on our thinking about the enzymes and the situations we https://doi.org/10.1111/j.1582-4934.2009.00897.x
encountered over the last 4 decades. To further explore
this hypothesis, Box 1 lists the simple questions to be 5. Nutter LM, Ngo EO, Fisher GR, et al., 1992, DNA strand
answered in this area. Since they do not seem to be in the scission and free radical production in menadione-
mainstreams of neurodegenerative disease research, they treated cells. Correlation with cytotoxicity and role of
may be understudied. Of course, more experiments are NADPH quinone acceptor oxidoreductase. J Biol Chem,
warranted to test this hypothesis. 267: 2474–2479.
https://doi.org/10.1016/S0021-9258(18)45903-0
Acknowledgments
6. Qiu XB, Cadenas E, 1997, The role of NAD(P)H: Quinone
None. oxidoreductase in quinone-mediated p21 induction in

Volume 2 Issue 1 (2023) 5 https://doi.org/10.36922/gpd.227