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PubMed1996

Innocuous hair deflection evokes a nociceptive-like activation of catechol oxidation in the rat locus coeruleus following intrathecal strychnine: a biochemical index of allodynia using in vivo voltammetry.

Blockade of spinal glycinergic inhibition with intrathecal (i.t.) strychnine induces a reversible allodynia-like state in both conscious and lightly-anaesthetized rats. Since the locus coeruleus (LC) is activated by noxious stimuli, we determined the effect of non-noxious hair deflection (HD) on noradrenergic neuronal activity in the LC of rats treated with i.t. strychnine. Differential normal pulse voltammetry was used to measure the catechol oxidation current (CA.OC), an index of LC activity. Rats were maintained in a light plane of anaesthesia with i.v. urethane and i.t. strychnine (40 micrograms) was injected near the L1-L2 segment. HD, applied to the caudal dermatomes affected by i.t. strychnine, evoked a significant increase (max. 141 +/- 7%, n = 5, P < 0.05) in CA.OC and mean arterial pressure as compared to baseline (no strychnine). In contrast, HD had no significant effect on CA.OC or mean arterial pressure in the saline-treated rats (n = 5). Pre-treatment with i.t. MK801 (30 micrograms) significantly blocked the increase in CA.OC and mean arterial pressure evoked by HD in strychnine-treated rats. The results of this study indicated that HD, in the presence of i.t. strychnine but not saline, can evoke noradrenergic activity in the LC of lightly anaesthetized rats. This effect on the LC is: (1) comparable to that observed with noxious stimulation without i.t. strychnine; (2) segmentally localized, corresponding to the spinal site of strychnine injection; and (3) mediated by spinal NMDA receptors, consistent with the role of excitatory amino acids in sensory transmission. These data provide the first neurochemical evidence that HD, in the presence of i.t. strychnine, is a nociceptive event, supporting the use of this preparation as an experimental model of allodynia.

Animals↗
PubMed1980

Detoxication disturbances and uncoupling effects in vitro of some chlorinated guaiacols, catechols and benzoquinones.

The effects of chlorinated guaiacols, catechols and benzoquinones - earlier identified in discharges from pulp and paper mills -- on oxidative phosphorylation in mitochondria and on detoxication mechanisms in microsomes have been investigated. The same biological systems have been used in testing outgoing water from a sulphite plant. Trichlorocatechol and tetrachlorocatechol and the corresponding guaiacols increase N oxygenation of N,N-dimethylaniline, while C-oxygenation decreases, indicating disturbances in microsomal detoxication. The substances tested have in general an uncoupling effect on mitochondrial oxidative phosphorylation. However, tetrachloroguaiacol seems to differ in having a specific effect on the succinate dehydrogenase part of the respiratory chain. Extracts from waste water from a sulphite plant have a considerable effect on the mitochondrial system such as to produce an increase in basal respiration and a loss of respiratory control. N- and C-oxygenation and phosphorylation have been extensively used in this and other laboratories for evaluating the toxicity of chemicals. The application on water extract described here is rapid and easily handled and thus provides a valuable complement to other water quality tests.

Animals↗
PubMed1978

Influence of endogenous S-adenosylmethionine on the determination of catechol O-methyltransferase activity in red blood cells.

A double isotope method for the simultaneous determination of S-adenosylmethionine (SAM) and catechol O-methyltransferase (COMT) activity in red blood cells was developed. Healthy persons contained 7.9 +/- 1.9 nmol SAM per ml red blood cells and 1.9 to 3.8 nmol per ml plasma. Epinephrine increases the SAM biosynthesis rate in red blood cells. The possible influence of endogenous SAM on previous methods to determine COMT activity in red blood cells is discussed. The statement of Briggs and Briggs (Briggs, M.H. and Briggs, M. (1973) Experientia 29, 278--281) that COMT activity in red blood cells is lower during the last 3 months of pregnancy could not be verified by us.

Catechol O-Methyltransferase↗
PubMed1995

Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans.

OBJECTIVES: To assess the tolerability, pharmacokinetics and pharmacodynamics of single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor tolcapone in healthy volunteers. METHODS: In this double-blind, placebo-controlled, ascending-single-dose study, doses of 5 to 800 mg tolcapone were administered orally to eight sequential groups of six young healthy male volunteers. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of tolcapone and its 3-O-methylmetabolite were determined. Pharmacodynamics were assessed by determination of COMT activity in erythrocytes. RESULTS: Tolcapone was well tolerated at all dose levels and did not exert a detectable influence on vital sign measurements. The drug was rapidly absorbed and showed dose-proportional pharmacokinetics. Its mean elimination half-life was 2.0 +/- 0.8 hours (n = 42). Plasma levels of the 3-O-methylmetabolite of tolcapone were not proportional to dose, and its formation was delayed at higher doses. Its elimination half-life was 32 +/- 7 hours (n = 29). Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes. At doses of 200 mg and higher, COMT activity was inhibited by more than 80%. The pharmacokinetic-pharmacodynamic relationship could be described by an inhibitory Emax model and suggested that metabolites of tolcapone did not substantially contribute to its inhibitory activity. CONCLUSIONS: The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.

Administration, Oral↗
PubMed1982

Catechol estrogens and thrombosis: differential effect of 2-hydroxyestradiol and estradiol on prostacyclin release.

High estrogen burden states, such as that seen in women who ingest oral contraceptive preparations, are associated with increased thrombosis. In other instances, however, estrogens decrease thrombogenicity. Variations in conversion to active metabolites could explain this paradox. Thus, we examined the influence of estradiol and a major metabolite, 2-hydroxyestradiol (catechol estrogen), on prostacyclin release from cultured human umbilical venous endothelium. In micromolar concentrations, both compounds inhibited prostacyclin (PGI2) release from bradykinin-, arachidonic acid-, and ionophore-stimulated, as well as unstimulated monolayers. However, when thrombin was used to stimulate release, estradiol enhanced, while 2-hydroxyestradiol inhibited, PGI2 formation. These sex steroids probably exert their influence at micromolar concentrations through a non-specific interaction with the cell membrane, and may be of importance in the predisposition to thrombosis suffered by those who use oral contraceptives.

Cells, Cultured↗
PubMed1982

Inhibition of catechol-O-methyltransferase by gossypol: the effect of plasma proteins.

Catechol-O-methyltransferase (COMT) is a key enzyme in the metabolism of catecholamines. As gossypol, a recent male contraceptive, has been reported to inhibit some respiratory enzymes in vitro, we have studied its effect on rat liver COMT activity. Varying concentrations of gossypol acetic acid were incubated with 3H-methyl-S-adenosyl-methionine, COMT, a different concentrations of norepinephrine. It was found that addition of gossypol into the incubation medium greatly depressed COMT activity, with an I50 of 0.01 mM. A series of inhibitory curves constructed from using different concentrations of the substrate suggested that the inhibition was non-competitive. Addition of blood serum or BSA significantly reduced the inhibitory effect of gossypol. We concluded that gossypol may markedly decrease COMT activity through non-competitive inhibition. Since various organs of the rat have been shown to accumulate gossypol, ingestion of gossypol for the purpose of fertility control may have important effect on the metabolism of catecholamine.

Animals↗
PubMed1976

A kinetic analysis of a catechol-specific binding site in the microsomal fraction from the rabbit aorta.

(-)-3/-Norepinephrine (3H-NE) binding to the microsomal fraction of the rabbit aorta has been studied. Binding appears to increase linearly with time up to at least 30 min, shows no evidence of stereoselectivity and may be inhibited only by compounds possessing the catechol or 3-methoxy-4hydroxyphenyl moieties, with the latter being 100-fold less effective. 3H-NE binding is saturable with a Km of 8.5 X 10(-8) M and V max of 28 pmoles/mg protein. A Hill plot indicates that binding is noncooperative whereas a Scatchard plot suggests that two sites may be present. Binding does not appear to require physiological concentrations of Ca2+ or Mg2+ and is inhibited significantly by EDTA and sodium metabisulfite. In addition, binding is markedly enhanced by low and high pH values. This binding is also inhibited by sodium metabisulfite which suggests that an oxidized form of the catecholamine is the active binding species. Experiments with several group specific reagents indicate that binding may require a free sulfhydryl group but not a carboxyl function. The binding process requires an energy of activation of 14.8 kcal/mole whose magnitude may be partly explained, with the aid of optical rotatory dispersion spectra, by a non-stereoslective conformational change in protein structure induced by the amine. The characteristics of the 3H-NE binding sites observed in the microsomal fractional of the rabbit aorta appear to be different from those expected if binding were to the adrenoreceptors. A possible mechanism for catecholamine binding to free sulfhydryl groups on protein is presented.

Adrenergic beta-Antagonists↗
PubMed1981

In vivo electrochemical detection of catechols in several dopaminergic brain regions of anaesthetized rats.

Differential pulse voltammetry (DPV) was used in conjunction with electrochemically treated carbon fibre microelectrodes to monitor in vivo the catechols (CA) levels in the substantia nigra (SN), ventral mesencephalic tegmentum (VMT) and nucleus accumbens of anaesthetized rats. The current corresponding to CA oxidation was always closely related to the anatomical localisation of the dopaminergic neurons e.g. it was maximal in tht pars compacta of the SN. In addition, the current was selectively suppressed in all regions after 6-OHDA-induced degeneration of the dopaminergic neurons and after pargyline treatment. These findings together with our previous results suggest that 3,4-dihydroxyphenylacetic acid (DOPAC) is the main contributor to the CA oxidation current measured in these areas. Haloperidol induced a significant increase of the CA signal in the nucleus accumbens (+70%) but not in the SN or VMT. The DOPAC concentrations declined exponentially after pargyline administration. The fractional rate constant of DOPAC, computed from these results appears to be similar in all regions studied except for n. accumbens where the low rate of disappearance might be responsible for the high DOPAC concentration measured in this area. In conclusion, DPV with electrochemically treated carbon fibre electrodes is a useful means of monitoring extracellular DOPAC levels in dopaminergic brain regions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Cholinergic control of catechol metabolism in the rat locus coeruleus as studied by in vivo voltammetry.

Differential pulse voltammetry with treated carbon fibre electrodes was used to study the effect of cholinergic drugs on the metabolism of locus coeruleus (LC) noradrenergic cells in vivo. A catechol peak corresponding to DOPAC synthesized by noradrenergic cells and reflecting their metabolic activity, was recorded every two minutes in the LC of freely moving rats. Cholinergic agonists like eserine (0.5 mg/kg s.c.) and oxotremorine (0.1 and 0.4 mg/kg s.c.) increased the DOPAC peak. This effect seemed to be mediated by muscarinic receptors since it was antagonized by scopolamine (5 mg/kg i.p.). Oxotremorine in high doses (1.5 mg/kg s.c. for 3 days) induced 'delayed activation' of tyrosine hydroxylase (+273%). In these conditions LC cells were no longer responsive to a challenge dose of oxotremorine though they maintained normal responsiveness to noradrenergic drugs. The results show that cholinergic drugs can greatly influence the metabolism of LC noradrenergic neurons.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Possible role of excitatory amino acids in the convulsant action of catechol.

The effects of several excitatory amino acid receptor antagonists on sensory-evoked electromyographic activity induced by catechol have been studied in urethane-anaesthetised rats. 2-Amino-5-phosphono-valearic acid (1.2 mumol/kg i.c.), cis-2,3-piperidine dicarboxylic acid (1.4 mumol/kg i.c.), gamma-D-glutamyl-glycine (2.0 mumol/kg i.c.), 2-amino-7-phosphono-heptanoic acid (230 mumol/kg i.v.) and MK-801 (5 mg/kg i.p.) all significantly decreased the frequency of occurrence of those components of the sensory evoked EMG dependent on supraspinal structures, but were without effect on the spinal component.

2-Amino-5-phosphonovalerate↗
PubMed1989

Effects of a peripherally acting alpha 2-adrenoceptor antagonist (L-659,066) on hemodynamics and plasma levels of catechols in conscious rats.

L-659,066 is a new alpha 2-adrenoceptor antagonist which does not enter the central nervous system after systemic administration and therefore can be used to examine effects of blockade of peripheral alpha 2-receptors on hemodynamics and plasma levels of catechols. After i.v. administration to conscious rats, L-659,066 produced dose-related, small decreases in mean arterial pressure (MAP) and large increases in heart rate (HR), arterial plasma levels of norepinephrine (NE), and levels of the intraneuronal NE metabolite, dihydroxyphenylglycol (DHPG). After administration of L-659,066, HR, but not MAP, was strongly correlated with NE levels (r = 0.93, P less than 0.001). Levels of DHPG and dihydroxyphenylalanine (DOPA) also were strongly correlated with NE levels (r = 098 and r = 0.71). After comparison with responses during hypotension induced by the vasodilator, nitroprusside, the results indicated that L-659,066 increases sympathetically mediated NE release and catecholamine turnover due to inhibition of presynaptic alpha 2-receptors as well as due to reflexive sympathetic activation related to blockade of alpha 2-receptors on arterial smooth muscle cells.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Effects of tolcapone, a novel catechol-O-methyltransferase inhibitor, on striatal metabolism of L-dopa and dopamine in rats.

In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-dopa bioavailability through peripheral and central inhibition of L-dopa O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Purification and partial characterization of rat liver soluble catechol-O-methyltransferase.

The rat liver soluble catechol-O-methyltransferase (EC 2.1.1.6.) has been purified utilizing a combination of conventional chromatography and HPLC. The purified enzyme has a molecular mass of 25 kDa, a pI of 5.1, and exists in two forms which differ in the nature of their intramolecular disulfide bonds. This difference causes these two protein forms to behave differently in reversed phase chromatography.

Amino Acid Sequence↗
PubMed1994

Aliphatic and aromatic inhibitors binding to the active site of catechol 2,3-dioxygenase from Pseudomonas putida mt-2.

The interaction of different classes of inhibitors with the extradiol cleaving catechol 2,3-dioxygenase from Pseudomonas putida mt-2 was monitored by longitudinal and transverse proton relaxation measurements as well as by kinetic activity studies in order to characterize the type of interaction of such inhibitors with the active site of the enzyme. The average distances of the inhibitors from the catalytic iron(II) ion have been estimated from the 1H longitudinal relaxation rates. Phenols and aliphatic ketones appear to be coordinated to the iron(II) ion in the active site.

Alcohols↗
PubMed1985

Aromatase, estrogen 2-hydroxylase, and catechol-O-methyltransferase activity in isolated, cultured gonadotropic cells of mature African catfish, Clarias gariepinus (Burchell).

Isolated gonadotropic cells were able to convert androstenedione into estrone. Subsequently, estrone could be metabolized via catecholestrone into 2-methoxyestrone. From these results it can be concluded that the gonadotropes of mature catfish contain the enzymes aromatase, estrogen 2-hydroxylase, and catechol-O-methyltransferase. The possible function of these enzymes in the steroid negative feedback regulation of gonadotropic hormone release is discussed.

Aging↗
PubMed1983

Kinetics of rat brain soluble catechol-O-methyltransferase and its inhibition by substrate analogues.

1. The initial rates and inhibition of rat brain catechol-O-methyltransferase were studied. Double reciprocal plots of initial rates versus either S-adenosyl-L-methionine or 3,4-dihydroxybenzoic acid, in the absence of product, gave a series of lines intersecting to the left of the ordinate. 2. Inhibition in the presence of S-adenosyl-L-homocysteine was competitive but in the presence of vanillic acid was non-competitive if S-adenosyl-L-methionine was the varied substrate. 3. When 3,4-dihydroxybenzoic acid was the varied substrate, both S-adenosyl-L-homocysteine and vanillic acid gave rise to a non-competitive inhibition. 4. The initial rate and product inhibition patterns were consistent with an ordered BiBi mechanism with S-adenosyl-L-methionine being the first substrate and 3,4-dihydroxybenzoic acid the second substrate to combine with the enzyme. 5. In addition, these results suggest that vanillic acid is the first product and S-adenosyl-L-homocysteine the second product to dissociate from the enzyme. 6. The substrate analogues salsolinol and 3-carboxysalsolinol were competitive inhibitors with respect to 3,4-dihydroxybenzoic acid but were non-competitive with respect to S-adenosyl-L-methionine. For enzymes with an ordered mechanism an uncompetitive inhibition would be expected. 7. A possible explanation is that both substrate analogues can combine with either free enzyme with lower affinity or with an intermediary enzyme form with much greater affinity. 8. A scheme which is consistent with the data is presented.

Animals↗
PubMed1983

Protection of catechol oestrogen from oxidation during enzymic hydrolysis of biliary conjugates.

2-Hydroxyethynyloestradiol (2-OHEE2), a major biliary metabolite of 17 alpha-ethynyloestradiol in female rats, is conjugated largely with glucuronic acid. Accurate quantitation of [3H]2-OHEE2 deconjugated by enzymic hydrolysis depends upon co-incubation with ascorbate (5-10 mM). In the absence of ascorbate, the proportion of [3H]2-OHEE2 declines by 30 +/- 7% (x +/- SD, n = 4) during a 3 h incubation of bile with arylsulphohydrolase and beta-glucuronidase. Over 16 h, decomposition of the catechol leads to a decrease in ether-extractable 3H labelled components.

Animals↗
PubMed1986

Androgens inhibit the formation of catechol estrogens by estrogen 2-hydroxylase present in rat liver microsomal preparations.

The inhibition of estrogen 2-hydroxylase by androgens was demonstrated in screening assays and has been further investigated under initial velocity conditions. The ability of testosterone, 5 alpha-dihydrotestosterone, and dehydroepiandrosterone to block the conversion of estradiol to 2-hydroxyestradiol by male rat liver microsomal preparations was determined using two radiotracer methods--the conversion of [4-14C]estradiol to [4-14C]2-hydroxyestradiol and the release of 3H2O from [2-3H]estradiol. The apparent Ki's for the androgens ranged from 12.0 to 14.0 microM, with the apparent Km for the substrate estradiol in these assays of 2.08 microM. Multiple inhibition studies with the androgens and 2-bromoestradiol, an effective estrogen inhibitor, in male rat liver microsomes resulted in Dixon plots consisting of a series of nonparallel, intersecting lines. Thus, the androgens and 2-bromoestradiol are non-exclusive inhibitors, i.e. the binding of one compound to the enzyme does not interfere with the binding of the other. These interactions of androgens suggest that the steroid hormonal environment be considered in the examination of the physiological role(s) of the estrogen 2-hydroxylase and the catechol estrogen products.

Androgens↗