Posted by raybakes on October 21, 2004, at 5:04:44
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on October 17, 2004, at 14:34:12
Hi Lar,
found some more info on dopamine metabolism - find NADPH quinone oxidoreductase (NQO) of interest. From what I can make out, it seems that NQO reduces quinones to make them available for detoxification via sulphation or glucuronidation. One abstract talked about copper complexing with dopamine and inducing a neurotoxic reaction - NQO, inhibited this too.
On the mechanism of the Mn3(+)-induced neurotoxicity of dopamine:prevention of quinone-derived oxygen toxicity by DT diaphorase and superoxide dismutase.
Department of Biochemistry, University of Stockholm, Sweden.Dopamine (DA) is rapidly oxidized by Mn3(+)-pyrophosphate to its cyclized o-quinone (cDAoQ), a reaction which can be prevented by NADH, reduced glutathione (GSH) or ascorbic acid. The oxidation of DA by Mn3+, which appears to be irreversible, results in a decrease in the level of DA, but not in a formation of reactive oxygen species, since oxygen is neither consumed nor required in this reaction. The formation of cDAoQ can initiate the generation of superoxide radicals (O2-.) by reduction-oxidation cycling, i.e. one-electron reduction of the quinone by various NADH- or NADPH-dependent flavoproteins to the semiquinone (QH.), which is readily reoxidized by O2 with the concomitant formation of O2-.. This mechanism is believed to underly the cytotoxicity of many quinones. Two-electron reduction of cDAoQ to the hydroquinone can be catalyzed by the flavoprotein DT diaphorase (NAD(P)H:quinone oxidoreductase). This enzyme efficiently maintains DA quinone in its fully reduced state, although some reoxidation of the hydroquinone (QH2) is observed (QH2 + O2----QH. + O2-. + H+; QH. + O2----Q + O2-.). In the presence of Mn3+, generated from Mn2+ by O2-. (Mn2+ + 2H+ + O2-.----Mn3+ + H2O2) formed during the autoxidation of DA hydroquinone, the rate of autoxidation is increased dramatically as is the formation of H2O2. Furthermore, cDAoQ is no longer fully reduced and the steady-state ratio between the hydroquinone and the quinone is dependent on the amount of DT diaphorase present. The generation of Mn3+ is inhibited by superoxide dismutase (SOD), which catalyzes the disproportionation of O2-. to H2O2 and O2. It is noteworthy that addition of SOD does not only result in a decrease in the amount of H2O2 formed during the regeneration of Mn3+, but, in fact, prevents H2O2 formation. Furthermore, in the presence of this enzyme the consumption of O2 is low, as is the oxidation of NADH, due to autoxidation of the hydroquinone, and the cyclized DA o-quinone is found to be fully reduced. These observations can be explained by the newly-discovered role of SOD as a superoxide:semiquinone (QH.) oxidoreductase catalyzing the following reaction: O2-. + QH. + 2H+----QH2 + O2. Thus, the combination of DT diaphorase and SOD is an efficient system for maintaining cDAoQ in its fully reduced state, a prerequisite for detoxication of the quinone by conjugation with sulfate or glucuronic acid. In addition, only minute amounts of reactive oxygen species will be formed, i.e. by the generation of O2-., which through disproportionation to H2O2 and further reduction by ferrous ions can be converted to the hydroxyl radical (OH.). Absence or low levels of these enzymes may create an oxidative stress on the cell and thereby initiate events leading to cell death.
Drug treatment of Parkinson's disease. Time for phase II.
Department of Neurology, Research Institute Neurosciences, Vrije Universiteit, 1081 BT, Amsterdam, The Netherlands.Parkinson's disease (PD) is a neurodegenerative syndrome for which at present no cure is available; therapy consists mainly of amelioration of the symptoms with L-Dopa and/or dopamine (DA) agonists. Development of an effective causal therapy should be focussed on preventing or at least retarding the neurodegenerative process underlying the disease. At the cellular level, PD is characterized by degeneration of neuromelanin-containing dopaminergic neurons in the substantia nigra. Neuromelanin formation is the outcome of a process generally known as DA autooxidation, a chain of oxidation reactions in which highly neurotoxic DA-quinones are produced. The level of these DA-quinones, as estimated by the occurrence of their cysteinyl conjugates, is reported to be increased in the Parkinsonian substantia nigra. Hence, stimulation of pathways implicated in the detoxication of DA-quinones in the brain may provide neuroprotection in PD. Besides their inactivation through non-enzymatic antioxidants such as ascorbic acid and glutathione, DA-quinones are efficiently inactivated enzymatically by NAD(P)H:quinone oxidoreductase (NQO) and glutathione transferase(s), both of which are expressed in the human substantia nigra. The activity of these enzymes, which belong to the group of phase II biotransformation enzymes, can be up-regulated by a large variety of compounds. These compounds, including dithiolethiones, phenolic anti-oxidants, and isothiocyanates, have been shown to be active both in vitro and in vivo. Thus, considering the role of phase II biotransformation enzymes, in particular NQO and glutathione transferase(s), in the detoxication of DA-quinones, we propose that phase II enzyme inducers warrant evaluation on their neuroprotective potential in PD.
Ray
poster:raybakes
thread:404137
URL: http://www.dr-bob.org/babble/alter/20040928/msgs/405377.html