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Notes: Abstract: Spontaneous oxygen consumption by 5,6- and 5,7-DHT (dihydroxytryptamine), related indoleethylamines, and 6-hydroxydopamine and oxygen consumption by these compounds in the presence of rat liver mitochondria were measured by the polarographic oxygen electrode technique. 5,6- and 5,7-DHT react with oxygen at very different rates (2.7 nmol O2/min and 33.4 nmol O2/min, respectively) when incubated in buffer, pH 7.2, at a concentration of 1 mm and with different kínetic characteristics. While the oxidation of 5,7-DHT obeys a reaction of second-order type, the oxidation of 5,6-DHT is more complex and characterized by autocatalytic promotion. Coloured quinoidal oxidation products appeared during the degradation of both indoleamines. Glutathione, ascorbate, dithiothreitol, cysteine, albumin, and superoxide dismutase partially prevented 5,6- and 5,7-DHT from oxidative destruction. Catalase saved oxygen only in the case of 5,6-DHT by recycling of O2 released from near-stoichiometrically formed H2O2 during oxidation of 5,6-DHT: 5,7-DHT did not generate H2O2 in measurable amounts. Oxygen consumption rates of 5,6- and 5,7-DHT were enhanced after addition of rat liver mitochondria to the incubation medium; this resulted in an accelerated formation of quinoidal products. This stimulatory effect on the oxidation rates of both 5,6- and 5,7-DHT was blocked by cyanide, but not rotenone, and was abolished by boiling of the mitochondria fraction. The observed increase in oxygen consumption in the presence of mitochondria was found not to be influenced by monoamine oxidase-dependent deamination of 5,6- and 5,7-DHT. It is postulated that 5,6- and 5,7-DHT are capable of participating in the electron transfer of the mitochondrial respiration chain beyond complex III. Results obtained in determinations of ADP:0 ratios in respiratory control experiments exclude a possible interference of 5,6-DHT, 5,7-DHT, and 6-OH-DA with phosphorylating sites. During the activated state of respiration, no signs of electron transfer inhibition by 5,6- and 5,7-DHT were detectable. A comparison and evaluation of the autoxidation rates of various hydroxylated indoleethylamines, of their affinity to the 5-HT transport sites, and their neurotoxic potency in vivo reveals that interaction of these compounds with oxygen at restricted reaction velocity is a prerequisite for efficient toxicity in monoaminergic neurons following active accumulation in these neurons via the high-affinity uptake systems.

Notes: [14C]5,6-Dihydroxytryptamine ([14C] 5,6-DHT) and [14C]5,7-dihydroxytryptamine ([14C]5,7-DHT) were deaminated to toluene-isoamylalcohol extractable products when incubated with homogenates of rat hypothalamus or pons-medulla oblongata. [14C]5,6-Dihydroxyindole acetic acid ([14C]5.6-DHIAA) and [14C]5,7-dihydroxyindole acetic acid ([14C]5,7-DHIAA) were detected as MAO metabolites by TLC besides non-identified components. The conversion of [14C]5,6-DHT and [14C]5,7-DHT obeyed, at least initially, Michaelis-Menten kinetics (Km 5,7-DHT: 0.5 × 10−3M; Km 5,6-DHT: 1.25 × 10−3M). Inhibition of the reaction by the MAO A inhibitor, clorgyline, resulted in a typical double sigmoidal inhibition curve indicating that both amines are metabolized by both types of MAO (A and B). In deprenyl inhibition studies, however, 5,7- and 5,6-DHT seemed to be preferred substrates of MAO A.Incubation of rat brain homogenates with [14C]5,6-DHT and [14C]5,7-DHT or with the MAO metabolites [14C]5,6-DHIAA and [14C]5,7-DHIAA caused a time-dependent break-down of the dihydroxylated indole compounds with subsequent binding of radioactivity to perchloric acid insoluble tissue components.5,6-DHT inactivated MAO in rat brain homogenates parallel to its decomposition and extensive protein binding. The inactivation of MAO by 5,6-DHT and the extensive binding of radioactivity to protein were antagonized by dithiothreitol (DTT), glutathione (GSH) and L-ascorbic acid. Reduction of [O2] in the incubation medium slightly attenuated the inactivation of MAO by 5,6-DHT. Catalase or superoxide dismutase failed to prevent MAO from being inactivated by 5,6-DHT. The results suggest that oxidation products of 5,6-DHT, e.g. its corresponding o-quinone, are involved in the inactivation of MAO in vitro and mainly responsible for the binding of radioactivity to brain proteins in vitro. Similar mechanisms may also be operative in the in vivo neurotoxicity of 5,6-DHT.The lack of inactivation of MAO by 5,7-DHT in vitro correlated with a low degree of radioactivity binding (from [14C]5,7-DHT) to homogenate protein pellets; the binding to proteins was barely influenced by GSH, cysteine, DTT and l-ascorbic acid. These latter findings do not provide a plausible explanation for the mechanism(s) involved in the well known in vivo neurotoxicity of 5,7-DHT.

Notes: Recent work has shown that intracerebral injections of 5,6-dihydroxytryptamine (5,6-DHT) lead to a fairly selective and long lasting depletion of 5-HT in the rat CNS (BAUMGARTEN, BJORKLUND, LACHENMAYER, NOBIN and STENEVI, 1971; DALY, FUXE and JONSSON, 1973). This effect appears to result from a degeneration of the serotonin-containing neurons (BAUMGARTEN and LACHENMAYER, 1972a). 5,6-DHT does, however, to a lesser extent affect both NA and dopamine (DA) containing nerve terminals (BAUMGARTEN et al., 1971). In an attempt, therefore, to find compounds having a more specific toxic action we have investigated several other hydroxylated tryptamines. In order to obtain information about the differential affinities of these analogues for neuronal uptake sites we have examined their effects on the uptake of [3H]5-HT and (±)-[3H]NA into synaptosomes in homogenates of rat hypothalamus and of [3H]DA uptake into a similar preparation from the rat corpus striatum. It is known that the uptake of these putative transmitters in rat brain homogenates is predominantly into the synaptosome fraction (KANNENGIESSER, HUNT and RAYNAUD, 1973; COYLE and SNYDER, 1969).

Notes: In the absence of definitive legal precedents, family therapists must decide whether to warn sexual partners of HIV-positive clients when clients themselves refuse to do so. Deciding whether to break confidentiality reaises both legal and ethical issues. Legally, the Tarasoff ruling requires therapists to warn potential victims of illegal dangers posed by clients but does not require therapists to warn potential victims of dangers posed by their clients' legally permissible actions. unless the behavior of the seropositive client is proscribed by state law, warning the clients' partners does not fall within the scope of the Tarasoff ruling. Ethically, therapists must negotiate and adhere to a disclosure policy that balances considerations of respecting autonomy, maintaining integrity (avoiding fraud and betrayal), benefiting clients, and fostering responsibility. Some therapeutic and ethical aspects of these considerations are discussed.

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