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Gene & Protein in Disease NQO2 and dopamine toxicity versus detoxification

that ROS production in CHO as well as in K562 or SH-SY5Y reacting with oxygen, it is very rapidly transformed in the
cells depends on the presence of NQO2. Exploring quinone form. This reaction generates superoxide anions,
neurons isolated from NQO2-knockout animals , the which decomposes into various ROS (Umek et al. and
[75]
[56]
ROS production was considerably decreased in similar references therein). The kinetic of this reaction is fairly
[9]
conditions . We concluded that the elevated expression rapid, depending on the pH of the milieu. This reaction
of NQO2 in brain cells in the presence of catechol occurs concomitantly with the formation of an indole-
quinones could lead to ROS-induced cell death via the based quinone for part of the produced oxidized species.
rapid conversion of superoxide radicals into peroxynitrite The quinone (dopamine quinone or dopaminechrome) is
by reaction with nitric oxide or into hydrogen peroxide, recognized and reduced by NQO2 back into the original
leading to the highly reactive hydroxyl radicals . Among quinol in the presence of its co-substrate. Then again, the
[9]
NQO2 substrates lay oxidized forms of catecholamines quinol (dopamine) is oxidized back almost immediately
such as adrenochrome. Catechols have been shown to into the quinone. As massive ROS bursts can cause cell
co-crystalize with NQO2, which has also been categorized death, the colocalization of both dopamine and NQO2
as a catecholamine reductase . in dopaminergic neurons could be responsible for
[57]
In the liver, the activity of oxidoreductase is mainly dopaminergic neuron death, leading to degenerative
catalyzed by NQO1, because this enzyme uses NADH as a situations. Thus, the metabolism of dopamine in those
neurons is central. Because dopamine glucuronides have
co-substrate [58,59] , which is massively present in liver tissue . been described in brain, and at least one UGT isoform is
[60]
NQO2, although expressed in liver, is not capable to reduce active in brain, it is clear that if conjugated to glucuronic
compounds due to the low availability of its co-substrate, acid, dopamine cannot enter into this futile cycle of
NRH, as well as the predominant role of NQO1.
oxidoreduction leading to ROS-mediated toxicity and
Finally, in the last years, the literature reported a possible neuron death.
relationship between NQO2 expression and memory [61-63] , UGT is a family of conjugated enzymes mainly expressed
before going deeper in a possible relationship between the in liver and kidneys where it detoxifies compounds from
enzyme regulation and neurogenerative diseases [61,64-67] the body. UGT is also expressed and active in the brain.
as well as schizophrenia . These association(s) need NQOs are two enzymes, expressed in many organs. In the
[68]
further validations, as they were dependent on the patient liver, the role of NQO1 is clearly to detoxify quinones and to
[69]
population tested . Mechanically speaking, an elegant facilitate conjugation, by UGT. Because NQO1 recognizes
study showed that if the promoter region of NQO2 gene NADH, which is massively present in the liver, its role is
[70]
contains a 29-bp insertion polymorphism, the NQO2 gene preponderant in this organ, while in the brain, the possible
expression is decreased. Mutation in this region would lead role of NQO2 is speculated in this context. NQO2 does not
to an enhanced expression of NQO2. Such mutation(s) recognize NAD(P)H as a co-substrate. The origin of NRH
was/were found in post-mortem brain studies of remains poorly explored. On the neuron side, the absence
neurodegenerative patients . A physiological hypothesis of conjugation leads to a futile cycle between quinone and
[68]
was also put forward as a possible role for NQO2 in the quinol that produces ROS, a toxic entity to the cells.
building of memory . Similarly, we showed that mice
[63]
devoid of NQO2 were apparently able to learn faster than In summary, as shown in Figure 2, in liver, the
their wild-type littermates [18,71] , linking again memory predominance of NQO1 and its co-substrate NADH
with NQO2 in a negative correlation way . Reduced as well as the large amount of UGT and UDPGa, its
[72]
NQO2 expression in inhibitory interneurons improves co-substrate, makes the metabolism of quinone quite
novel object memory. On the contrary, enhanced NQO2 safe, from reduction to diol followed by conjugation. In
activity would diminish memory after stress episodes . brain, though, the co-expression of NQO2 and tyrosine
[61]
This would form another link between dopaminergic hydroxylase (TH) might render the installment of this
neurons, NQO2 and memory, and following this tentative futile cycle very rapid, depending on NQO2 co-substrate
paradigm, a higher NQO2 expression/activity leads to a availability. The possible role of UGT in this organ is
lower memory formation [61,73] . On the pharmacological less clear, but the conjugation of diol might stop the
side, potent and specific NQO2 inhibitors, such as S29434 quinol/quinone futile cycle. Nevertheless, the presence of
[53]
and M11, have neuroprotective properties [18,74] . dopamine-glucuronides in cerebrospinal fluid indicates
the presence of at least one UGT isoform in the brain.
2. Hypothesis
An equilibrium between the conjugation of dopamine
A speculative but simple idea would be as follows: and its entrance in the quinone/quinol futile cycle would
dopamine is fairly unstable in aerobic conditions, and drive the overall possible toxicity of dopamine, under

Volume 2 Issue 1 (2023) 3 https://doi.org/10.36922/gpd.227