Electron Transfer Factors in Psychosis and Dyskinesia This 40-year-old paper may contain the first suggestion that radicals are cellular messengers. later dubbed "redox-signaling" ), If anybody has anything earlier, please contact me at [email protected]. so I can give them proper credit. Other "lost" suggestions here are that homocysteine pathogenesis involves electron-transfer processes ( including oxidative stress ), that hyperuricemia involves oxidative stress, and that polyacetylenes such as melanin can be "doped" by charge-transfer agents (the proof of which won somebody else the 2000 Nobel Prize). Again, if this is wrong, please let me know. See Harman for a primary antecedent. For a later version of this review, go here. For more on homocysteine and redox signaling, go here. For more on homocysteine and altzheimers dementia go here, here and here . For more on doped polyacetylenes go here. Physiol Chem. & Physics 4 (1972) 349-360 ELECTRON-TRANSFER FACTORS IN PSYCHOSIS AND DYSKINESIA PETER PROCTOR Department of Physics, The University of Texas at Houston, M. D. Anderson Hospital and Tumor Institute, The University of Texas at Houston Graduate School of Biomedical Sciences, Houston Texas (Received May 17,1972) SUMMARY In man, chronic elevated systemic levels of compounds possessing electron-transfer properties are typically associated with one or more of a triad of characteristic. signs. These are psychosis, dyskinesia, and abnormalities in pigmentation. The possible in vivo interactions of such compounds are discussed. INTRODUCTION While there is strong indirect evidence for biological factors in the etiology of the heterogeneous group of psychiatric disorders known as "schizophrenia (1-3) and also in the etiology of various movement disorders such as parkinsonism (4) no single etiological factor has as yet been well defined in either class- of disease. A step in this direction is the work of Cotzias et al.(5) reiterated by Curzon(4), -who noted an intriging correlation between the chronic presence of substances having electron-transfer properties, e.g., in phenothiazine treatment or manganese poisoning, and the appearance of movement disorders (dyskinesias) in man. It has been noted (6) that disorders associated, with the chronic presence of electron-transfer agents are also typically characterized by either or both of two additional symptoms- schizophrenaia-like psychosis or pigment . abnormalities.: The occurrence, significance, and possible etiology of such coincident signs in relation to the common electronic property of the compounds involved in their production are discussed. ELECTRON-DONOR ASSOCIATED SYNDROMES An electron -donor may be described as a substance which shares an electron ( or rather a statistical part of one ) in a -charge-transfer complex with an electron acceptor. Complete electron~transfer results. in a reduction~oxidation reaction, the electron donor being-oxidized and the electron acceptor being reduced.(7). A single-electron transfer often results in unpaired electrons on both the electron donor and the electron acceptor, both of which become free radicals. A summary of pertinent data, concerning a number of syndromes associated with the presence of electron-transfer agents is given in Table 1. Column I lists the disorders, along with references to reviews of them. Column 2 lists the electron-transfer agent(s) involved, and the third column lists an electron-donor-ability-related, semiempirical quantity known as the energy of the highest occupied molecule orbital (HOMO) energy. Table 1: Syndromes Associated with Charge-transfer Agents Syndrome Compound HOMO energy Reduce PTA ? * Psychosis Dyskinesia Pigment Catalyzes Oxidation of .... ascorbate, (a) 0.49 yes (11) -- -- -- linoleic acid (41) tocopherol 0.58 ? -- -- -- -- Lesch-Nyhan Syndrome (b) Uric acid 0.18 Yes (11) yes (59) choreoathetosis (59) ? epinephrine (see figs 1&2) Dopa treatment Dopa 0.62 Yes yes (11) choreaoathetosis ? TMPD(29), autoxidizes (c) Phenothiazines chlorpromazine (e.g.) -0.11 ? see (67) parkinsonism, tardive dydkinesia (d) Yes Alcaptonuria (71) Homogentisic acid 0.63 yes (71) ? parksonsonism Yes (71) autoxidizes Homocystinuria (73) homocysteine thiolactone 0.07 yes (11) yes (73,74 ?, see comment e hypo ? (73) autoxidizes Hyperthyroidism e.g, thyroxine (f) 0.49 ? yes (75,76) choreoathetosis yes (75) glutathione Iodism iodide ref 29 -- yes (79) iodate (80) causes retinal hyperpigmentation TMPD (29), (c) Bromism (81) Bromide ref 29 -- yes (81) tremor & ataxia (81) yes (81) ? (29) Wilson's disease (g) copper ref (30) -- yes (52) yes (52) choreoathetosis yes many compounds (30) Manganese poisoning (h) manganese ores ref (5) -- yes (85) yes (84) ? e.g., epinephrine Hemochromatosis (87) iron (i) ref (30) -- occasionally (87) ? yes(87) many compounds (30) Acute intermittent porphyria (88) porphobilinogen 0.43 ? yes (88) choreoathetosis ? autoxidizes (88) * PTA = Phosphotungstic acid. Comments: a. Reducing agents block O2-dependent inhibition of phenyalanine hydroxylase by epinephrine (97) b. Suggestion of some pigmentation in brain of Lesch-Nyhan patient (66) c. TMPD is tetramethylparaphenyenediamine d. Tardive dyskinesia resembles choreoathetosis e. " Hint of Parkinsonism " in father of ( homocystinuric) patient (74) f. Activity of thyroid hormones may be related to electorn-donor properties ( (29, 78 ) g. Wilson's (90) obesrvation that the symptoms of chronic lenticular degeneration are much like those of neonatal jaundice is significant in light of electron-transfer properties of the bile pigments (91). h. Unweathered (i.e., unoxidized ) manganese ores most toxic (86). Chronic mercury poiosoning is also associated with psychosis (92), dyskinesia (82, 92), and hyperpigmentation (93). i. Hallorvorden-Spatz disease associated with abnormal iron deposition. (4). 1) Phenothiazines inhibit the oxidation of reduced NAND by melanin (94). The HOMO energy values listed were calculated on an IBM 7094 computer using a program prepared by Novak and Furlong for the calculation of molecular orbital indices using the Huckle approximation. HOMO energy values range around 1.0 for most aromatic compounds. The electron-donor ability of a compound increases as the HOMO energy becomes more negative. While comparisons of HOMO energies of compounds not in the same homologous series are dangerous, a compound with a HOMO energy of 0.50 or less is generally considered to be a " good " electron donor. The HOMO energies of ascorbate and a-tocopherol, compounds whose physiological roles are generally considered to be related to their electron-donor, i.e., reducing, properties are included for comparison. Since HOMO energies can be calculated only for compounds having delocalized electrons (6) none are given for iodide, bromide, etc. The electron-transfer properties of these compounds are considered in the references given. Using these criteria, the compounds listed can be categorized as good to excellent electron donors. The negative value for chlorpromazine signifies an " antibonding orbital " and implies particlarly good- eletron-donor properties for this compound. . Column 4 provides an. empirical check on the electron-donor properties implied in column 3. The classical colorimetric method for the clinical determination of uric acid is based upon the unique ability of that compound to directly reduce phosphotungstic acid (11). The similar electron-donor properties of L-dopa and its metabolites account for the artifactual rise in serum uric acid levels found with L-dopa therapy (12). The next three columns of Table I summarize the main point of this paper; namely, that in man chronic elevated levels of substances having single-electron-transfer properties are typically associated with one or, more significantly, more than one of a triad of characteristic symptoms which include psychosis, dyskinesia, and pigmentary abnormalities. As the table shows, all three symptoms are reported in Wilson's disease and in thyrotoxicosis. In the Lesch-Nyhan syndrome and in L-dopa treatment, psychosis and dyskinesia are predominant. Likewise, chronic administration of the phenothiazines is accompanied by both dyskinesia and hyperpigmentation. Similarly, psychosis and hyperpigmentation are found in patients with bromism, while psychosis occurs independently in patients with homocystinuria. Because the compounds associated with the triad of psychosis, dyskinesia, and pigmentation abnormality have nothing in common but a rather unusual electronic property ( i.e., the ability to participate readily in electron-transfer processes ), the hypothesis seems tenable that there may be electron-transfer factors in the etiology of these disorders. For this reason, it is worthwhile to consider the possible common in vivo interactions of electron-transfer agents in order to clarify the nature of such factors. Particularly pertinent interactions are those involving melanin, the catalysis of nonenzymatic autoxidations, cofactor properties, general reducing properties, the activation of psychoactive (13-15) plasma protein components, and interactions with biological semiconductors. MELANIN As Table I shows, for example, abnormalities in pigmentation tend to be associated with the chronic presence of substances having charge-transfer properties. The question arises as to whether such pigmentary changes reflect, indirectly or not, analogous processes occurring in the brain. Are these pigmentary changes the indirect visible manifestation of some ongoing primary process such as altered monoamine metabolism or free radical or excited-state production, or do they reflect changes in brain melanin metabolism which directly produce the associated signs of psychosis and dyskinesia? Skin melanin presumably functions as a screen for UV fight. (16). However, the human brain has highly pigmented, nonilluminated areas, such as the substantia nigra and the locus coeruleus , (17) in which melanin must have some other function, e.g., a sink for free radicals,(18) a redox buffer,(9) or a biological device for dissipating the energy of the excited states of biological molecules (20). Melanin is also a good electron acceptor, (14), has semiconductor properties, (14) and might be expected to form charge-transfer complexes with compounds having electron-transfer properties. Cotzias et al (5) noted that both naturally occurring and drug-induced dyskinesias occurred only in species which possessed visible melanin in the substantia nigra . These authors explained the paradoxical ability of such free radical-forming agents as the phenothiazines to induce and to relieve dyskinetic symptoms by suggesting that there is an optimum level of melanin free radicals in the brain, and that increasing or decreasing this level can result in dyskinetic symptoms. Such phenomena also might be related to the process of changing melanin alternately from a conductor to an insulator by progressively filling conduction bands by electron transfer (21). Dr P sez: Speaking of "doping" of melanin. In 1974, we reported that melanin can act as a semiconductor " bistable switch ". That is, melanin is an " active device ", i.e., one whose electrical conductivity can be modulated by an electric field, such as in a transitor. Your computor is just an array of bistable switches. Three years later others reported that another polyacetylene can be chemically-modified to a similar high conductivity state by iodine. Note that " iodism " is listed in this review. They received the 2000 Noble Prize in Chemistry for this discovery. There is no evidence that the prize committee was aware of our earlier, more advanced work, though it was published in a major journal, Science. For more on this, go here. As noted, we also found that melanin can be doped chemically. Though clearly the Nobel committee differs, we considered this trivial. It was eight years before anyone else reported anything similar ( a field-effect transistor ) using a conductive organic polymer. Our "gadget" is now in the electrical collection of the Smithsonian as the putative first organic electronic device. Similarly, electron donors are known to play several different roles in the synthesis of melanin. For example, catechols such as L-dopa are presumably the substrates from which melanin is synthesized and, as we shall see, electron donors may act as cofactors for melanin synthesizing Systems (22,23). For example, the similarity between the symptoms of the Lesch-Nyhan syndrome and., the. side effects of L -dopa therapy (24) might be explained by examining either the affinity of the purines and the catechols for brain melanin. or the possible action of the purines as cofactors - in the peroxidase-catalyzed (22,23) synthesis of L-dopa and, ultimately, melanin. ( For other ways in which alterations in the metabolism of melanin or its precursors might affect CNS function see references 25-28.) CATALYSIS OF AUTOXIDATIONS Another property of electron-transfer agents is their general ability to catalyze non-enzymatic autoxidations by participating in a charge-transfer complex with molecular oxygen, which becomes " activated " by accepting an odd electron (29--31). Cooperative oxidations also occur in which an organic electron donor serves to maintain a catalytic transition-series metal in the active reduced state (30). Since the substrate-independent initial step in catalysis-that is, the formation of such a complex-is the critical one, the catalysis of the oxidation of one compound should imply the ability to catalyze the oxidation of others. Column 8 of Table I notes oxidations catalyzed by the various compounds listed. (An example of such a reaction-- the uric acid-catalyzed autoxidation of epinephrine-- is given in Figures I and 2.) The common catalytic ability of thyroxine, bromide, and iodide may be relevant to their common pharmacologic properties (32,33). Further, such oxidations involve single-electron transfers and would thus give rise to free radicals. In this case, the work of Polis et al (34) on the psychoactivity of the free radical derivatives of several biological molecules is relevant, as is the possible role of melanin as a sink for free radicals(8), and the role of free radicals in initiating melanin synthesis (35). Figure 1. Spectrophotometric assay of catalysis of epinephrine oxidation by uric acid. Procedure: Increase m optical density at 485 nrn followed using a Gilford model 240 spectrophotometer with a Heath model EUW 20-A servorecorder, 0.00 to 0.10 O.D. full-scale. Control: 1.0 x 10-4 ML-epinephrine in 0.012 M phosphate buffer (pH 7.4). Uric acid: control + 3.5 x 10-4 M uric acid (5.9 mg% urate). Standard errors are given. Figure 2. Radiometric assay of catalysis of epinephrine autoxidation by uric acid. Procedure: (Modification of the method of Axelrod.38) Control: 1.0 ml of 0.1 M phosphate buffer (pH 7.4) + .18 Mg MgS04 + 0.1 mg phenylisopropylhydrazine + 0.3 gCi DL-epinephrine-4-3H (0.96 mCi/gM). Urate: control + 3.4 x 10-4 uric acid (equivalent to 5.7 mg % urate, a physiological concentration). Samples are incubated for 10 min at 370C, at which time is added LO ml of 1.0 M borate (pH 10. 0) and 5.0 ml cold toluene: isoamyl alcohol (3:2, v/v). Mixture is shaken for five min and then centrifuged for 10 min at 900 x g. Three ml of the organic phase is then counted in a suitable liquid scintillation medium (" Diatol "). Axelrod (38) has found that most of the radioactivity in the organic phase after such a procedure is in the form of the 0-phenylisopropylhydrazine derivative of adrenochrome. Standard errors are given. The blank represents the amount of radioactivity extracted without incubation. Dr P note : Uric acid levels are correlated with risk of dying from heart attack . " Free radicals " have been postulated as a possible mechanism. Also, Heikkila and Cohen (36) have shown that the damage to noradrenergic nerve terminals produced by 6-hydroxydopamine-- an autoxidation product of dopamine which Stein and Weise (37) relate to the etiology of schizophrenia-- is in fact caused by peroxide, a product of the autoxidation of the former compound. COFACTOR PROPERTIES Another common property of strong electron donors is their ability to act as cofactors for certain oxidative enzymes, either by maintaining a transition-series metal in the reduced state at an active site or by providing activated oxygen as an' electron acceptor (29). For example, L-dopa acts as a cofactor in the peroxidase-catalyzed oxidation of tyrosine to L-dopa; in addition, through its autoxidation, it serves as a possible, source of peroxide (22). (Peroxidase, in addition to possibly initiating some brain melanin synthesis, may also play a role in brain catecholamine production.(22,23) ). Likewise, chlorpromazine, monophenols (38) and uric acid (39) all stimulate parotid adrenaline oxidase, while epinephrine and serotonin may have similar cofactor roles in the oxidative synthesis of the prostaglandins (40). REDUCING PROPERTIES Strong electron donors can also inhibit oxidation by either reducing oxidized species, terminating free radical chain reactions, or by competing with an oxidizable substrate, e.g., sulfhydryl groups, for activated -oxygen. Thus, Haase (41) found that ascorbate could catalyze the autoxidation of linoleic acid at low concentrations while inhibiting it at higher ones. Presumably, whether electron-transfer agents catalyze or inhibit oxidations is dependent upon the amount of oxygen dissolved in solution. ACTIVATION OF PSYCHOACTIVE PLASMA PROTEIN FACTORS Bergen (42) reported that Plasma Globulin- Precipitate ( PGP ), a psychoactive plasma protein from schizophrenics, is greatly activated in vitro in the presence of moderate levels of reducing substances such as mercaptoethanol or ascorbate. The fact that PGP is a lipoprotein and that higher concentrations of electron donor tend to suppress its activity suggests that the electron donor may be catalyzing an oxidation, for example, to a lipid free radical. SEMICONDUCTOR INTERACTIONS The interaction of electron-transfer agents with biologically important semiconductors has been noted in relation to melanin. However, as Szent-Gyorgyi (13) and Cope (43) point out, many other biologic materials, such as proteins, bimolecular lipid membranes, and DNA, have quite appreciable semiconductor properties which may be relevant to their functions. Electron-transfer agents might alter the electronic properties of such materials by inserting electrons into a conduction band, as in the case of N-type semiconductor, or into holes, as in the case of a P-type semiconductor. For example, Pant and Rosenberg showed that the magnitude of the photocurrent through the Fe+++ -complexed-oxidized cholesterol bimolecular membrane--- a P-type semiconductor-is greatly diminished in the presence of reducing agents. Similar results were -found with a mixture of chlorpromazine (45)and melanin. As -has been considered, a combination of these effects ( i.e., filling of a conduction.band to produce an insulator followed by the insertion of carrier electrons into the next highest empty band to restore conductivity ) might be relevant to the ability of certain electron donors, e.g., phenothiazines' or bromides (4) to induce the very symptoms they are-effective against (20,21). MISCELLANEOUS INTERACTIONS Other interactions are also possible. Brillouin (51) has proposed that band splitting resulting from the interaction of degenerate (equal energy) orbitals on two electron donors, such as a protein and an aromatic amine, might elevate the highest occupied orbital to such a degree an electron transfer to a suitable electron acceptor could occur. The importance of charge-transfer phenomena in enzyme action has been considered in refs. 14, 47-49. Furthermore, transition-series metals such as selenium may also faci… truncated (15,218 more characters in archive)