Page 47 - GPD-2-1

Gene & Protein in Disease

PERSPECTIVE ARTICLE
A hypothesis on the equilibrium between

dopamine toxicity and detoxification: The roles
of NQO2 and UDP-glucuronosyltransferases

Jean A. Boutin *, Gilles Ferry , and Karine Reybier 3
2
1,2
1 Laboratory of Neuroendocrine Endocrine and Germinal Differentiation and Communication
(NorDiC), Univ Rouen Normandie, Inserm, UMR 1239, Rouen, France
2 Institut de Recherches Servier, 125 chemin de Ronde, Croissy-sur-Seine, France
3 Pharma-Dev UMR 152, Université de Toulouse, IRD, UPS, Toulouse, France

Abstract
NQO2 and tyrosine hydroxylase are co-expressed in dopaminergic neurons.
These neurons produce dopamine, a diol, which, under aerobic conditions, can
spontaneously revert to the more stable form, the o-quinone. O-quinones are
preferred substrates of NQO2 over p-quinones. In ad hoc conditions, NQO2 reduces
o-quinones into the original diols, leading to a futile cycle, the endpoint of which is a
strong local production of reactive oxygen species that is deadly for the cells. This futile
cycle can be interrupted by the conjugation of dopamine with UDP-glucuronic acid,
leading to a glucuronide that cannot be part of the cycle because the glucuronide is
not a substrate of NQO2. In this paper, we confer whether this futile cycle could be
one of the causes of the specific death of dopaminergic neuronal population that is
the signature of some degenerative diseases.
*Corresponding author:
Jean A. Boutin
(ja.boutin.pro@gmail.com)
Keywords: Dopamine; Neurodegenerative diseases; Quinone reductase; Glucuronidation;
Citation: Boutin JA, Ferry G, Reactive oxygen species; Toxicity
Reybier K., 2023, A hypothesis
on the equilibrium between
dopamine toxicity and
detoxification: The roles of NQO2
and UDP-glucuronosyltransferases. 1. Drug metabolism and the case of dopamine
Gene Protein Dis, 2(1):277.
https://doi.org/10.36922/gpd.227 Reactive oxygen species (ROS) is a harmful chemical species, and the toxicity of
Received: October 14, 2022 which is well known for decades for its role in a range of pathologies and conditions
Accepted: January 18, 2023 from cancer to asbestos-induced toxicity . The constant production of ROS and
[1]
[2]
Published Online: February 1, 2023
its impact onto subcellular structures (DNA, proteins, and membranes) is associated
Copyright: © 2023 Author(s). with the process of aging at the cellular level . More generally, ROS causes harmful
[3]
This is an Open Access article lesions in organs in which they are massively generated. To overcome this, a series of
distributed under the terms of the
[4]
Creative Commons Attribution antioxidant mechanisms has been developed by evolution . Among other systems, ROS
License, permitting distribution, are generated via the redox cycling of quinones, such as menadione [5-7] . We have shown
and reproduction in any medium, that such a redox cycle occurs in the presence of NQO2, its co-substrate and a series
provided the original work is
[8]
properly cited. of quinones . We have also shown that the main source of ROS-generating quinone
reductase activity in the mouse brain was the activity of the enzyme NQO2 .
[9]
Publisher’s Note: AccScience
Publishing remains neutral with NQO2 is a quinone reductase (E.C. 1.10.5.1) expressed in many tissues of the body [10,11] .
regard to jurisdictional claims in
published maps and institutional Unlike NQO1, NQO2 does not recognize NAD(P)H as a co-substrate, making it a
affiliations. unique example in the literature of quinone reductases [12,13] . Its co-substrates are either
Volume 2 Issue 1 (2023) 1 https://doi.org/10.36922/gpd.227