Pigments mélaniques du pelage de quelques races bovines: le schéma possible de certaines actions géniques

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Non-enzymic oxidation of cysteinyldopa catalyzed by metallic ions

Under physiol. conditions, cysteinyldopa (I) behaves similarly to catecholamines, e.g. adrenaline, in forming reversible complexes with various metal cations. As a rule, these complexes are stable under anaerobic conditions, but readily autoxidize in the presence of O to give the 1,4-benzothiazine acid deriv. (II), corresponding to one of the postulated intermediates in the biosynthesis of pheomelanic pigments. Cu2+-catalyzed oxidn. of I proceeds differently to give the red-purple trichochrome F, presumably via decarboxylation and oxidative coupling of the same benzothiazine intermediate. The relevance of these in vitro expts. to the metab. of I is briefly discussed

New directions in Parkinson's research and treatment.

L-DOPA remains the mainstay of therapy for Parkinson's disease (PD). However, the side-effects assocd. with its chronic use have fuelled the search for novel strategies as an alternative to simply supplementing dopamine deficiency. In reviewing with 166 refs., the advances made over the last five years, focus has been given to dopamine agonists, as well as to new MAO inhibitors that appear more effective than the currently used compd., selegiline. A no. of new mols. acting at sites of the neuronal circuit distal from lesioned dopaminergic neurons have also been considered, including NMDA antagonists, adenosine antagonists and anticholinergic agents, this latter group representing the pioneering approach to PD treatment. In addn., new concepts of 'neuroprotection' have led to the exploitation of various agents, esp. anti-oxidants, directed toward slowing or halting disease progression. An entirely new perspective has been provided by methods that apply the techniques of mol. biol. to PD therapy and allow modified dopaminergic neurons capable of synthesizing specific neurotropic factors to be obtained by transfection. Parkinson's research has now progressed extensively, and further understanding of the etiol. of neuronal degeneration will disclose the key to the development of an effective therapy

Iron-Mediated Generation of the Neurotoxin 6-Hydroxydopamine Quinone by Reaction of Fatty Acid Hydroperoxides with Dopamine: A Possible Contributory Mechanism for Neuronal Degeneration in Parkinson's Disease.

Exposure of dopamine to an excess of linoleic acid 13-hydroperoxide (13-hydroperoxyoctadecadienoic acid) in the presence of ferrous ions in Tris buffer, pH 7.4, resulted in a relatively fast, oxygen-independent reaction exhibiting first-order kinetics with respect to both catecholamine and metal concentrations. Product analysis in the early stages revealed the presence of significant amounts of the quinone of the neurotoxin 6-hydroxydopamine, together with some aminochrome and ill-defined melanin-like material. Quinone formation required the presence of iron, either in the ferrous or ferric form, and was unaffected by peroxidase, catalase, and hydroxyl radical scavengers, e.g. mannitol, as well as biologically relevant antioxidants, like ascorbate and glutathione. Hydrogen peroxide proved as effective as linoleic acid hydroperoxide in inducing dopamine oxidation and conversion to 6-hydroxydopamine quinone. Metal chelators, including EDTA and bipyridyl, markedly suppressed quinone formation without, however, inhibiting dopamine oxidation. These and other results are consistent with a hydroxyl radical independent hydroxylation/oxidation mechanism basically different from the Fenton reaction, which involves direct interaction of the peroxide with a dopamine-Fe(III) chelate generated during the process

Activation of mammalian tyrosinase by ferrous ions

Mammalian tyrosinase from B16 mouse melanoma is significantly activated by Fe2+. Monitoring of tyrosine oxidn. by both dopachrome formation and O2 consumption showed that Fe2+ at micromolar concns. induce a marked enzymic activity with 0.01 U/mL of highly purified tyrosinase, whereas no detectable reaction occurs in the absence of metal over a sufficiently prolonged period of time. The extent of the activating effect, which is specific for the reduced form of Fe, is proportional to the concn. of the added metal with a typical satn. profile, no further effect being obsd. beyond a threshold value. Changing the buffer system from phosphate to Hepes or Tris results in a marked decrease of the Fe2+-induced activation. Scavengers of active O species, such as superoxide dismutase, catalase, formate, and mannitol have no detectable effect on the tyrosinase. These results are accounted for in terms of an activation mechanism involving redn. of the Cu2+ at the active site of the resting enzyme

Ironmediated generation of the neurotoxin 6-hydroxydopamine quinone by reaction of fatty acid hydroperoxides with dopamine: a possible contributory mechanism for neuronal degeneration in Parkinson’s disease

Exposure of dopamine to an excess of linoleic acid 13-hydroperoxide (13-hydroperoxyoctadecadienoic acid) in the presence of ferrous ions in Tris buffer, pH 7.4, resulted in a relatively fast, oxygen-independent reaction exhibiting first-order kinetics with respect to both catecholamine and metal concentrations. Product analysis in the early stages revealed the presence of significant amounts of the quinone of the neurotoxin 6-hydroxydopamine, together with some aminochrome and ill-defined melanin-like material. Quinone formation required the presence of iron, either in the ferrous or ferric form, and was unaffected by peroxidase, catalase, and hydroxyl radical scavengers, e.g. mannitol, as well as biologically relevant antioxidants, like ascorbate and glutathione. Hydrogen peroxide proved as effective as linoleic acid hydroperoxide in inducing dopamine oxidation and conversion to 6-hydroxydopamine quinone. Metal chelators, including EDTA and bipyridyl, markedly suppressed quinone formation without, however, inhibiting dopamine oxidation. These and other results are consistent with a hydroxyl radical independent hydroxylation/oxidation mechanism basically different from the Fenton reaction, which involves direct interaction of the peroxide with a dopamine-Fe(III) chelate generated during the process

Diffusible melanin-related metabolites are potent inhibitors of lipid peroxidation.

Although it has long been known that epidermal melanocytes produce and excrete a number of melanin-related metabolites, including 5,6-dihydroxyindole (DHI), 5,6-dihydroxyindole-2-carboxylic acid (DHICA), and 5-S-cysteinyldopa (CD), the possible functional significance of these compounds has been so far largely overlooked. We report now evidence that DHI, DHICA and CD exert potent inhibitory effects in different in vitro models of lipid peroxidation. The compounds, at 100 mu M concentration, substantially decreased malondialdehyde (MDA) formation by lipid peroxidation in rat brain cortex homogenates. At 1.2 mu M concentration, DHI proved as effective as alpha-tocopherol (alpha-T), one of the most potent endogenous antioxidants, in suppressing azo-induced peroxidation of linoleic acid in phosphate buffer (PH 7.4), containing 0.10 M SDS, whereas CD and DHICA at the same concentration were less active. DHI, CD and DHICA (all in the range 25 mu M-0.5 mM) were also found to inhibit Fe (II)/EDTA-induced oxidation of 0.5 mM arachidonic acid at pH 7.4, as well as MDA formation by iron-promoted degradation of 0.5 mM 15-hydroperoxy-5,8,11, 13-eicosatetraenoic acid (15-HPETE). In both cases the inhibitory effects were much greater than those of ascorbic acid and glutathione. These results point to melanin precursors as a novel class of biological antioxidants which may contribute to defense mechanisms against oxidative injury in human skin.