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PubMed1980

Catechol oestrogens stimulate and direct prostaglandin synthesis.

We have tested the action of a catechol oestrogen -2,3,17 beta-trihydroxy oestra-1,3,5 (10)-triene (2-OH oestradiol) in stimulating prostaglandin (PG) production by an homogenate of rat uterus. Marked and dose dependent stimulation was observed in PGF2 alpha and PGE2 production using 20-250 microM concentrations of catechol oestrogen; a concentration of 250 microM 2-OH oestradiol resulted in a 23 fold increase in PGF2 alpha production with a 50% reduction in the synthesis of 6-keto PGF1 alpha. Tryptophan, catechol and glutathione were without effect on PGF2 alpha and PGE2 production whereas adrenalin stimulated the production of all PGs, although the increase was less than that seen with 2-OH oestradiol. Oestradiol had a slight stimulatory action on PGF2 alpha production which reached a maximum at around 40 microM but had a more marked stimulation of 6-keto PGF1 alpha formation. Stimulation of prostaglandin production by oestradiol and 2-OH oestradiol showed no variation at different stages of the rat oestrous cycle. The use of 5 to 100 mg of tissue/ml gave similar product distribution although the effect of catechol oestrogen both in terms of stimulation of E and F formation (expressed per mg of tissue) and in its action on product distribution was more marked at lower concentrations of tissue.

Animals↗
PubMed1997

Determination of the cytotoxic catechol metabolite of etoposide (3'O-demethyletoposide) in human plasma by high-performance liquid chromatography.

The anticancer drug etoposide undergoes O-demethylation in humans. The formed catechol metabolite exhibits significant cytotoxic activity. A simple, rapid, selective, and sensitive reversed-phase high-performance liquid chromatography assay was developed for the measurement of etoposide catechol in plasma of tumour patients. The metabolite was quantified using electrochemical detection. Ascorbic acid was added to each sample to prevent oxidation of etoposide catechol during sample preparation. Linear responses were obtained between 40 ng/ml and 1.25 microg/ml with correlation coefficients exceeding 0.991. The detection limit was 10 ng/ml. Recovery, within-day precision, between-day precision and accuracy were satisfactory. The method has been applied to characterize the concentration-time profile of etoposide catechol in plasma of tumour patients following administration of high-dose etoposide.

Antineoplastic Agents, Phytogenic↗
PubMed1998

A New Class of Complexes Possessing Cofacially-Oriented, Planar, Metal-Containing Subunits. Synthesis, Characterization, and Reactivity of [(MoO(2))(2)(&mgr;-O)](2+)-Linked, Catechol-Functionalized, Tetraazamacrocyclic and Salicylideneamine Complexes.

A new synthetic route to molecules that contain cofacially oriented, [Mo(2)O(5)](2+)-bridged bis(catecholate) dianions is described. This synthesis has been useful in the preparation of supermolecular molecules containing catechol-functionalized, metalated macrocyclic [M(II)(TAD(OH)(2))] (M = Co, Ni) and SALPHEN [M(II)(R(2)R'(2)SALPHEN(OH)(2))] (M = H(2), Mn, Fe, Co, Ni, Cu) ligands. Of the former, the (Bu(4)N)(2)[Mo(2)O(5)[Ni(TAD(O)(2))](2)] (7) complex has been structurally characterized. The complex crystallizes in the triclinic space group P&onemacr; with unit cell dimensions a = 12.324(3) Å, b = 17.740(4) Å, c = 20.920(4) Å, alpha = 108.79(3) degrees, beta = 98.20(3) degrees, and gamma = 103.12(3) degrees. The nearly-planar macrocyclic ligands are essentially parallel, with a dihedral angle of 6.5(2) degrees. The Ni(1)--Ni(2) separation in the anion is 3.938 Å. The structure of (Bu(4)N)(2)[Mo(2)O(5)[Cu(EtO(2)H(2)SALPHEN(O)(2))](2)] (19) has also been determined. This complex crystallizes in the monoclinic space group P2(1)/c, with unit cell dimensions a = 20.821(4) Å, b = 23.133(5) Å, c = 20.056(4) Å, and beta = 117.71(3) degrees. The Cu(1)--Cu(2) separation is 4.110 Å, and the dihedral angle between SALPHEN "planes" is approximately 9.7(1) degrees. Analytical and spectroscopic properties are provided. Reactions of these molecules with oxidants and strongly coordinating ligands are presented. The ability of the Fe(II) and Co(II) analogues of 19 to bind ligands such as O(2)(-) or S(2)(-) and O(2), respectively, in the "pocket" of the complex is described, and the products have been characterized. The synthesis and characterization of the unique "mixed catecholate" complexes (Bu(4)N)(2)[Mo(2)O(5)(D(t)()BC)(M(II)((t)()Bu(4)SALPHEN(O)(2)))] (M = H(2), Fe, Co, Ni, Cu) is described, and comparisons between these latter systems and the bis(M(II)SALPHEN-catecholate) complexes are provided.

Journal Article↗
PubMed1999

Catechol-Pendant Terpyridine Complexes: Electrodeposition Studies and Electrocatalysis of NADH Oxidation.

The synthesis, spectroscopic characterization, and electrochemical characterization, including the electrodeposition onto glassy carbon (GC) and platinum (Pt) electrodes, of electroactive films of the homoleptic catechol-pendant terpyridine complexes [M(L(2))(2)](2+) (where M = Co, Cr, Fe, Ni, Ru, and Os, and L(2) = 4'-(3,4-dihydroxyphenyl)-2,2':6',2' '-terpyridine) are described. The potential dependence of the deposition was probed through electrochemical quartz crystal microbalance (EQCM) studies. Multilayer equivalent films were found to deposit at potentials less than that of the catechol oxidation process. Whereas the heteroleptic ruthenium(II) complex [Ru(tpy)(L(2))](2+) (tpy = 2,2':6',2' '-terpyridine) did not deposit onto electrode surfaces, the corresponding osmium(II) heteroleptic complex [Os(tpy)(L(2))](2+) deposited onto Pt and GC electrodes, suggesting that the metal center can play an important role in the deposition process. The heteroleptic cobalt(II) complex [Co(v-tpy)(L(2))](2+) (v-tpy = 4'-vinyl-2,2':6',2' '-terpyridine) was found to deposit onto Pt or GC electrodes through either a catechol-based deposition or a v-tpy-based electropolymerization, depending on the potential range over which a homogeneous solution of the complex was cycled. The electrochemical response of [Co(L(2))(2)](2+)-modified GC electrodes in aqueous solution was robust and pH-dependent over the pH range 1-11, suggesting that the catechol moieties retain their pH-dependent redox activity upon immobilization. The application of these complexes, in solution and as electrodeposited films, to the electrocatalytic oxidation of NADH was also probed. [Co(L(2))(2)](2+) in solution plus [Co(L(2))(2)](2+)- and [Co(v-tpy)(L(2))](2+)-modified GC electrodes were found to catalyze the oxidation of NADH in pH 7 phosphate buffer solution.

Journal Article↗
PubMed1998

Preparation and Structural Characterization of Nickel(II) Catecholates.

The early literature of catecholate complexes of Ni(II) is explained with regard to both high-spin octahedral and low-spin square-planar complexes. The former contain coordinated solvent, while the latter do not. The syntheses of the paramagnetic (S = 1; &mgr;(eff) = 2.93 &mgr;(B) at 300 K) octahedral Ni(II) complex Na(2)[trans-(H(2)O)(2)(cat)(2)Ni(II)].12H(2)O (1a) and the diamagnetic square-planar Ni(II) complex Na(2)[(cat)(2)Ni(II)].2DMF (2) are described. The physical and chemical properties of these Ni catecholates and their X-ray crystal structures are presented. In aqueous solution at low temperature the centrosymmetric octahedral complex is formed, which has average Ni-O distances of 2.044(3) Å (catecholate) and 2.162(3) Å (water). At higher temperature or under more weakly solvating conditions the square-planar complex is formed; the complex 2 is centrosymmetric with an average Ni-O(catecholate) distance of 1.863(3) Å. The crystals of 1a conform to space group C2/c, with unit cell dimensions a = 26.0287(8) Å, b= 9.0016(3) Å, c = 10.6992(3) Å, beta = 101.809(1) degrees, V = 2453.8(1) Å(3), and Z = 4. Those of 2 conform to space group P2(1)/m, with unit cell dimensions a = 6.0906(5) Å, b = 13.208(1) Å, c = 12.826(1) Å, beta = 95.711(1) degrees, V = 1026.7(1) Å(3), and Z = 2.

Journal Article↗
PubMed1991

trans-hexahydroindolo[4,3-ab]phenanthridines ("benzergolines"), the first structural class of potent and selective dopamine D1 receptor agonists lacking a catechol group.

In contrast to the many selective dopamine (DA) D2 receptor agonists known, only two prototypes of selective D1 receptor agonists have been described; both show preference for the periphery due to their catechol partial structures. Our search for non-catechol, selective D1 agonists was based on the hypothesis that D1 selectivity could be conferred upon ergolines by annulation with a phenyl ring. The target molecules, trans-4,6,6a,7,8,12b-hexahydroindolo-[4,3-ab]phenanthridi nes ("benzergolines"), were efficiently synthesized by using the Ninomiya enamide photocyclization reaction. These compounds were found to be as active as the most potent D1 agonists in the adenylate cyclase D1 receptor model, but showed no activity in the ACh release D2 receptor assay. The acquired subtype selectivity of the novel structures was accompanied by an enhanced potency and efficacy as compared to the corresponding ergolines. This points to a D1 affinity enhancing, D2 receptor discriminating role for the additional phenyl group and provides further support for the existence of a D1 receptor specific accessory aryl binding site. Thus the benzergolines represent the first structural class of potent and selective D1 agonists lacking a catechol group which should allow an efficient central nervous system penetration. On the basis of these results, the D1 agonist pharmacophore has to be revised in the sense that potent activity requires neither a catechol function nor an orthogonal conformation of the aromatic rings.

Acetylcholine↗
PubMed1984

The 3,4-catechol derivative of propranolol, a minor dihydroxylated metabolite.

The O,O-dibenzyl ether of the 3,4-catechol derivative of propranolol (11) was prepared to determine whether the catechol is a product of metabolic hydroxylation. 4-(Allyloxy)-1,2-naphthoquinone (5) was reduced with sodium dithionite and alkylated with benzyl chloride to produce ether 7. Osmium tetroxide oxidation of 7 afforded glycol 8. Subsequent monotosylation, oxirane formation with KOH, and opening with isopropylamine afforded benzyl ether 11. Although hydrogenolysis was successful, catechol 3 was rapidly oxidized to the corresponding o-quinone (12). Reduction of 12 with sodium bisulfite afforded 3, which was derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) to serve as a standard for the metabolic experiments. Gas chromatography-mass spectrometry of the Me3Si ethers of the products of metabolism of pseudoracemic propranolol (made up of equal molar (2R)-propranolol-d0/(2S)-propranolol-3',3'-d2) in the presence of the rat liver 9000g supernatant fraction showed four dihydroxylated metabolites, of which catechol 3 was in smallest amount, approximately 9% of the sum of dihydroxylated metabolites. Each of the four dihydroxylated propranolols arises stereoselectively from the 2R enantiomer of propranolol (by 1.15- to 2-fold), as determined by parent ion intensities at m/z 507 vs. 509. Quinone 12 was a nonselective competitive beta-adrenoceptor antagonist, being about 16-fold less potent than propranolol in both beta 1 and beta 2 assays.

Animals↗
PubMed1997

Assembling Organic Receptors around Transition Metal Templates: Functionalized Catechols and Dioxomolybdenum(VI) for the Recognition of Dicarboxylic Acids.

The synthesis of two receptors for dicarboxylic acids [12](2)(-) and [13](2)(-), based on the self arrangement of two functionalized catechols 1 and 2 around a cis-[MoO(2)](2)(+) core, is described. Among the three pairs of enantiomers which may be produced during the complexation of two unsymmetrical catecholates around one molybdenum(VI) ion, only one is observed for each catechol derivative 1 or 2. Depending on the base used during the complexation of catechols to the molybdenum atom, the dianionic receptors obtained display different solubility properties. These molybdenum-based receptors are chromogenic and, in methylene chloride, the affinities of the assembled receptors for dicarboxylic acids ranging from C(4) to C(8) have been assessed by UV-visible titrations after determining the stoichiometry of the complex formation using Job's method. While receptor [12](2)(-) displays selectivity for C(4) and C(5) acids, the more flexible receptor [13](2)(-) exhibits selectivity for C(7) and C(8). The binding mode of the diacids to the molybdenum receptor has been determined based on (1)H NMR titration. Due to the intrinsic chirality of the receptors, their binding properties versus chiral dicarboxylic acid have been examined. The enantioselective binding of N-carbobenzyloxy protected L and D-glutamic acid due to additional pi-pi interactions of the protecting group with the receptor's framework is reported for [12](2)(-) in methylene chloride. For comparison, the association constants of receptor [12](2)(-) with a Boc protected L-glutamic acid and the racemic mixture of N-carbobenzyloxy protected glutamic acid have been determined.

Journal Article↗
PubMed1996

Bioactivation of estrone and its catechol metabolites to quinoid-glutathione conjugates in rat liver microsomes.

Although the carcinogenic effects of estrogens have been mainly attributed to hormonal properties, there is interest in estrogens acting as chemical carcinogens by binding to cellular macromolecules. In the present study, we explored factors which influence the rate of P450-catalyzed formation of the o-quinones (3,5-cyclohexadiene-1,2-diones) from 2-hydroxyestrone (2-OHE) and 4-hydroxyestrone (4-OHE) as well as from estrone in rat liver microsomes. The initially formed o-quinones were trapped as their GSH conjugates which were separated and characterized by HPLC with electrospray-MS detection. Two mono-GSH conjugates were observed from the 2-OHE-o-quinone as well as a conjugate where GSH had added twice to the molecule producing a di-GSH conjugate. 4-OHE-o-quinone gave only one mono-GSH adduct as well as a di-GSH adduct. Both 2-OHE and 4-OHE were excellent substrates for P450, generating o-quinone GSH adducts at 94 and 40 times, respectively, the rate of estrone. 2-OHE but not 4-OHE saturated P450 at unusually low concentrations (0.2 nmol of P450/mL) perhaps due to differences in the stability of the o-quinones formed in the active site of the enzyme. Preliminary data suggest that the o-quinones of both 2-OHE and 4-OHE could isomerize to quinone methides (4-alkyl-2,5-cyclohexadien-1-ones, QMs). The o-quinones of the catechol estrogens were incubated at 37 degrees C (pH 7.4) in the absence of GSH. Aliquots were removed at various times and combined with GSH. From the pseudo-first-order rate of disappearance of the o-quinone GSH adducts, the half-lives of the o-quinones were determined. The o-quinone from 2-OHE has a half-life of 42 +/- 3 s at 37 degrees C (pH 7.4), and the o-quinone from 4-OHE has a half-life of 12.2 +/- 0.4 min under identical conditions. The o-quinones of the AB ring analogs of the catechol estrogens (3,4-dihydroxy-5,6,7,8-tetrahydronaphthalene and 1,2-dihydroxy-5,6,7,8-tetrahydronaphthalene) isomerize to QMs, suggesting that a similar reaction pathway could occur with the o-quinones from catechol estrogens. In support of this, oxidation of 4-OHE and quenching with GSH after 70 min produced 9-dehydro-4-hydroxyestrone (3-hydroxy-1,3,5-(10),9(11)-estratetraen-17-one), a product which could result from either the QM hydrolysis product or the QM--glutathione conjugate, both of which could eliminate to give the conjugated alkene of 4-OHE. The implications of the o-quinone/QM pathway to the in vivo effects of catechol estrogens are not known; however, given the direct link between excessive exposure to endogenous estrogens and the enhanced risk of breast cancer, the potential for formation of additional reactive intermediates needs to be explored.

Animals↗
PubMed2005

Species differences in the tissue distribution of catechol and methylsulphonyl metabolites of 2,4,5,2',5'-penta- and 2,3,4,2',3',6'-hexachlorobiphenyls in rats, mice, hamsters and guinea pigs.

Polychlorinated biphenyls (PCBs) are metabolized to phenolic or methylsulphonyl PCBs (MeSO(2)-CBs) in animal species. The study determined the species differences in the tissue distribution of persistent PCB metabolites in rats, mice, hamsters and guinea pigs 4 days after exposure to 2,4,5,2('),5(')-pentachlorobiphenyl (CB101) or 2,3,4,2('),3('),6(')-hexachlorobiphenyl (CB132). For CB101 metabolism, the hydroxylation in rats, mice and hamsters occurred primarily at the 3(')-position in the 2('),5(')-dichlorinated phenyl ring, whereas the hydroxylation in guinea pigs occurred preferentially at the 3-position. Metabolite profiles in tissues of hamsters were dominated by 3('),4(')-catechol-CB101, whereas metabolite profiles in rats and mice were dominated by 3(')- or 4(')-MeSO(2)-CBs. For CB132 metabolism, rats and mice produced 4(')- and 5(')-MeSO(2)-CBs at similar concentration ratios, whereas guinea pigs produced MeSO(2)-CBs at higher levels and selectively retained 5(')-MeSO(2)-CB in liver. In contrast, hamsters preferentially produced 4('),5(')-catechol-CB132 that was retained in serum. Consequently, hamsters produced catechols, whereas guinea pigs produced meta-substituted MeSO(2)-CBs, preferentially from CB132. These findings indicate that PCBs with 2,3,6-chlorine substitution are preferred substrates for the formation of catechols or MeSO(2)-CBs and the differences in metabolite profiles are related to species-dependent metabolic capacities.

Animals↗
PubMed1989

Catechol Formation and Melanization by Na -Dependent Azotobacter chroococcum: a Protective Mechanism for Aeroadaptation?

Aeroadaptive microaerophilic Azotobacter chroococcum 184 produced a cell-associated black pigment when grown at high aeration rates under nitrogen-fixing conditions. This pigment was shown to be a catechol melanin. Polyphenol oxidase activity was detected in cell extracts of cells grown for 72 h. Melanin formation was optimal in the later stages of growth, and there was no correlation between nitrogenase activity and melanization. Nitrogenase activity in strain 184 was optimal at 10% O(2), and melanin formation was suppressed by O(2) limitation. In the presence of charcoal, an adsorbent of toxic oxygen intermediates, and benzoic acid, a scavenger of hydroxyl radicals, melanization was inhibited. However, in the presence of copper, the intensity of pigment color increased and melanization was accelerated. Copper also eliminated catalase and peroxidase activities of the organism but still permitted aerobic growth. In the presence of low levels of iron, melanization was accelerated under high aeration rates, and under low rates of aeration, melanization was observed only at higher levels of iron. Hydroxamate-siderophore production was detectable in the presence of soluble iron under high rates of aeration but was repressed by the same levels of iron under low aeration rates. Unlike melanization and hydroxamate formation, catechol formation was observed under both low and high rates of aeration under nitrogen-fixing conditions. Catechol formation and melanization were repressed by 14 mM NH(4), at which level nitrogenase activity was also repressed. Copper reversed the repressive effect of NH(4). A role for catechol formation and melanization in aeroadaptation is proposed.

Journal Article↗
PubMed1994

Two Genomic Regions Involved in Catechol Siderophore Production by Erwinia carotovora.

Two regions involved in catechol biosynthesis (cbs) of Erwinia carotovora W3C105 were cloned by functional complementation of Escherichia coli mutants that were deficient in the biosynthesis of the catechol siderophore enterobactin (ent). A 4.3-kb region of genomic DNA of E. carotovora complemented the entB402 mutation of E. coli. A second genomic region of 12.8 kb complemented entD, entC147, entE405, and entA403 mutations of E. coli. Although functions encoded by catechol biosynthesis genes (cbsA, cbsB, cbsC, cbsD, and cbsE) of E. carotovora were interchangeable with those encoded by corresponding enterobactin biosynthesis genes (entA, entB, entC, entD, and entE), only cbsE hybridized to its functional counterpart (entE) in E. coli. The cbsEA region of E. carotovora W3C105 hybridized to genomic DNA of 21 diverse strains of E. carotovora but did not hybridize to that of a chrysobactin-producing strain of Erwinia chrysanthemi. Strains of E. carotovora fell into nine groups on the basis of sizes of restriction fragments that hybridized to the cbsEA region, indicating that catechol biosynthesis genes were highly polymorphic among strains of E. carotovora.

Journal Article↗
PubMed2026

Identification and functional analysis of 2,3-dihydroxybenzoic acid and catechol catabolic pathway genes in Aspergillus niger.

Microorganisms catabolize many plant-derived aromatic compounds through the β-ketoadipate pathway. This pathway has two branches, beginning with protocatechuic acid and catechol, which converge on β-ketoadipate before further catalysis to produce tricarboxylic acid cycle intermediates. The protocatechuic acid branch of the pathway has been characterized in fungi.Here, we characterized the genes of the catechol branch of the β-ketoadipate pathway in the filamentous fungus Aspergillus niger. We predicted the genes involved using comparative transcriptomics and homology to characterized genes. We tested the predictions by constructing knockout mutants lacking candidate genes to observe the growth phenotype on 2,3dihydroxybenzoic acid (2,3-DHB), which is catabolized through the catechol branch, and by detection of metabolites accumulated in knockout mutants using mass spectrometry. Using these approaches to reconstruct the pathway, we confirmed the reported assignments of dhbA, crcA, kstA, and kctA as encoding 2,3-dihydroxybenzoate decarboxylase, catechol 1,2dioxygenase, β-ketoadipate:succinyl-CoA transferase, and β-ketoadipyl-CoA thiolase, respectively. We further assigned mciA, mliA, and kelA as encoding muconate cycloisomerase, muconolactone isomerase, and β-ketoadipate enol-lactonase, respectively. Additionally, we identified a transcription regulator involved with the β-ketoadipate pathway in fungi for the first time. This gene, pcaR, is upregulated on 2,3-DHB and deletion of the gene impaired growth on 2,3-DHB.

Journal Article↗
PubMed1993

Cephalosporins having a heterocyclic catechol in the C3 side chain. I. Enhancement of efficacy against gram-negative bacteria.

Two groups of cephalosporins substituted with a variety of heterocyclic catechols in the C3 side chain were synthesized. One is a group of 3-(heterocyclic catechol-substituted methyl)cephalosporins and another is 3-[(E)-3-heterocyclic catechol-substituted 1-propen-1-yl]cephalosporins. Cephalosporins in the latter group showed higher in vivo efficacies than those in the former group having the same heterocyclic catechol, especially against Pseudomonas aeruginosa A9843A, although there was no significant difference between their in vitro activity. Among the latter group, the 5,6-dihydroxybenzimidazole derivative (6e) and the 2,6-dihydro-7-hydroxy-6-oxo- isoquinoline derivative (6b) showed much higher activity than ceftazidime (CAZ) and imipenem (IPM) against P. aeruginosa A9843A both in in vitro and in vivo studies.

Animals↗
PubMed1997

Acetates and benzoates of alkyl catechols and evaluation of their antibacterial activity.

Potential biologically active alkyl catechol esters were prepared and their antibacterial activity was determined against 12 Gram-positive and 16 Gram-negative bacteria. Esterification (acetylation and benzoylation) of mono-, di- and tetra- substituted alkyl catechols afforded the di-acetyl and di-benzoyl derivatives in each case. In the primary screening it was observed that the substitution of hydroxyl group in alkyl catechol with an acyl group generally resulted in a decrease of antibacterial activity. A number of acetyl and benzoyl derivatives inhibited the growth of Salmonella typhi. In case of Gram-positive bacteria only di-O-benzoyl-3,5,6,-tetra-(3-hexyl) catechol (26) showed a significant activity.

Journal Article↗
PubMed2000

Structure-based design, synthesis, and in vitro evaluation of bisubstrate inhibitors for catechol O-methyltransferase (COMT).

The enzyme catechol O-methyltransferase (COMT) catalyzes the Me group transfer from the cofactor S-adenosylmethionine (SAM) to the hydroxy group of catechol substrates. Potential bisubstrate inhibitors of COMT were developed by structure-based design and synthesized. The compounds were tested for in vitro inhibitory activity against COMT obtained from rat liver, and the inhibition kinetics were examined with regard to the binding sites of cofactor and substrate. One of the designed molecules was found to be a bisubstrate inhibitor of COMT with an IC50 = 2 microM. It exhibits competitive kinetics for the SAM and noncompetitive kinetics for the catechol binding site. Useful structure-activity relationships were established which provide important guidelines for the design of future generations of bisubstrate inhibitors of COMT.

Animals↗
PubMed1986

Characterization of the O-methylation of catechol oestrogens by intact rabbit thoracic aorta and subcellular fractions thereof.

In the present study we investigated the O-methylation of catechol oestrogens by intact rabbit thoracic aorta and subcellular fractions thereof. The O-methylation of 2-hydroxyoestradiol (2OHE2) and 2-hydroxyoestriol (2OHE3) displayed saturation kinetics in the intact tissue. The apparent Km and Vmax values for the O-methylation of 2OHE2 were determined to be 0.91 mumol/l and 104 pmol g-1 min-1, respectively, when 2OHE2 was used as substrate; and 1.14 mumol/l and 188 pmol g-1 min-1 when 2OHE3 was used as substrate. The inhibitors of the extraneuronal uptake process (viz; phenoxybenzamine 33 mumol/l; normetanephrine, 46 mumol/l; and deoxycorticosterone acetate 27 mumol/l) failed to inhibit the O-methylation of either 2OHE2 (3.4 mumol/l) or 2OHE3 (3.4 mumol/l) in intact segments of the rabbit thoracic aorta. (-)-Isoprenaline (40 mumol/l) abolished the O-methylation of 2OHE2 (3.4 mumol/l) and markedly reduced that of 2OHE3 (3.4 mumol/l). Pretreatment of tissues with phenoxybenzamine (33 mumol/l) partially restored the O-methylation of 2OHE2 and 2OHE3 in the presence of (-)-isoprenaline (40 mumol/l). The O-methylation of 2OHE2 (5 mumol/l) was significantly reduced in segments of aorta in which the endothelium was removed. The latter reduction could not be attributed to damage to components of the vessel media. The O-methylation of 2OHE2 and (-)-isoprenaline by subcellular fractions of the rabbit aorta also was examined. Both the microsomal and cytosolic fractions were shown to O-methylate 2OHE2 and (-)-isoprenaline, providing evidence for the existence of membrane-bound and soluble forms of COMT in the rabbit aorta. The O-methylation of 2OHE2 by cytosolic and microsomal fractions of the aorta was determined and compared to that of (-)-isoprenaline. The kinetic constants for the O-methylation of 2OHE2 by cytosolic (Km: 0.27 mumol/l; V max: 112 pmol g-1 min-1) and microsomal (Km: 0.15 mumol/l; Vmax: 161 pmol g-1 min-1) fractions were similar. In contrast, the kinetic constants for the O-methylation of isoprenaline by cytosolic (Km: 121 mumol/l; Vmax: 174 pmol g-1 min-1) and membranal (Km: 0.91 mumol/l; Vmax: 105 pmol g-1 min-1) fractions were very different. It is concluded that catechol oestrogens are excellent substrates for catechol-O-methyltransferase (COMT) in the rabbit aorta. Their O-methylation can occur in endothelial structures as well as in the smooth muscle-containing medial sections of the vessel.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Catechol-O-methyltransferase as a target for melanoma destruction?

Catechols may interfere in melanogenesis by causing increased levels of toxic quinones. Several catechols and known inhibitors of the enzyme catechol-O-methyltransferase (COMT) were therefore tested for their toxicity towards a pigmented melanoma cell line, UCLA-SO-(M14). The inhibition of thymidine incorporation as a result of exposure to the compounds was measured. All agents were compared to 4-hydroxyanisole (4HA), a depigmenting agent extensively studied as an antimelanoma drug. The compounds were also tested on the epithelial cell line, CNCM-I-(221) in the presence and absence of tyrosinase. All the compounds were more effective than 4HA towards the M14-cells at either 10(-4) M or 10(-5) M. The toxicity of 4HA towards the 221-cells was shown to be completely dependent on the presence of tyrosinase. Effects of the test agents on the 221-cells were also observed in the absence of tyrosinase. Although some of them were shown to be good substrates for tyrosinase only small changes in toxicity were observed as a result of the presence of the enzyme in comparison with 4HA. No direct correlation of the toxicity of the agents and COMT inhibition was observed. The possible mode of action of the compounds through inhibition of COMT and interference in melanogenesis is discussed together with other possibilities and factors involved.

Anisoles↗