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PubMed1982

Catechol O-methyltransferase. 10. 5-Substituted 3-hydroxy-4-methoxybenzoic acids (isovanillic acids) and 5-substituted 3-hydroxy-4-methoxybenzaldehydes (isovanillins) as potential inhibitors.

A series of 5-substituted 3-hydroxy-4-methoxybenzoic acids (isovanillic acids) and -benzaldehydes (isovanillins) have been synthesized and evaluated as inhibitors of rat liver catechol O-methyltransferase. The compounds exhibited either noncompetitive or competitive patterns of inhibition when 3,4-dihydroxybenzoic acid was the variable substrate. The benzaldehydes were significantly more potent inhibitors than the corresponding benzoic acids, and electron-withdrawing substituents in the 5 position greatly enhanced their inhibitory activity.

Animals↗
PubMed1995

Identification of 3-hydroxy-3-methylglutaric acid (HMG) as a hypoglycemic principle of Spanish moss (Tillandsia usneoides).

Bioactivity-directed fractionation, using brine shrimp lethality and murine hypoglycemia, of an ethanol extract prepared from Tillandsia usneoides, led to the isolation of four apparently bioactive compounds from the water-soluble fraction. The compounds were identified as citric acid, succinic acid, 3-hydroxy-3-methylglutaric acid (HMG), and 3,6,3',5'-tetramethoxy-5,7,4'-trihydroxyflavone-7-O-beta-D-g lucoside. The brine shrimp lethality of the acids was simply due to acidity; however, HMG elicited significant hypoglycemic responses in fasting normal mice. Ethyl and methyl esters of citric acid were prepared and tested in the murine hypoglycemic assay. Five of the predominant sugars were identified by tlc. Free thymidine was also isolated. Further evaluation of HMG and other potential inhibitors of HMG CoA lyase, in the treatment of symptoms of diabetes mellitus, is suggested.

Animals↗
PubMedDate not supplied

Radiation from ultraviolet phototherapy sources results in photodegradation of 12(R) and 12(S)-hydroxy-eicosatetraenoic acid: high-performance liquid chromatography and polymorph migration studies.

The effect of irradiation from Sylvania PUVA lamps (emitting predominantly in the ultraviolet (UVA) region) and broadband Philips TL-12 lamps (peaking in the UVB region) on two inflammatory mediators, 12(R)- and 12(S)-hydroxy-eicosatetraenoic acid (HETE) was studied. A high-performance liquid chromatography study showed significant photodegradation of both enantiomers at a concentration of 5 micrograms/ml in phosphate-buffered saline following irradiation with 10 J.cm-2 UVA or 0.375 J.cm-2 UVB. The in vitro chemokinetic microdroplet migration response of human peripheral polymorphonuclear leukocytes from normal and psoriatic subjects was significantly reduced following irradiation of 12(R)-HETE at a concentration of 1 micrograms/ml in medium with 40 J.cm-2 UVA and 1.5 J.cm-2 UVB respectively. No such effect was seen with 12(S)-HETE. The effect of ultraviolet on skin physiology, and in particular in the successful phototherapy of a range of inflammatory skin disorders, is not fully understood. The photodegradation of inflammatory mediators such as 12-HETE, as shown in this study, provides another factor of possible therapeutic significance.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2000

omega-Hydroxylation of epoxy- and hydroxy-fatty acids by CYP94A1: possible involvement in plant defence.

The C(18) fatty acid derivatives 9,10-epoxystearic acid and 9,10-dihydroxystearic acid were hydroxylated on the terminal methyl by microsomes of yeast expressing CYP94A1 cloned from Vicia sativa. The reactions did not occur in incubations of microsomes from yeast transformed with a void plasmid or in the absence of NADPH. After incubation of a synthetic racemic mixture of 9,10-epoxystearic acid, the chirality of the residual epoxide was shifted to 66:34 in favour of the 9S,10R enantiomer. Both the 9S,10R and 9R,10S enantiomers were incubated separately. We determined respective K(m) and V(max) values of 1.2+/-0.1 microM and 19.2+/-0.3 nmol/min per nmol of cytochrome P450 for the 9R,10S enantiomer and of 5.9+/-0.1 microM and 20.2+/-1.0 nmol/min per nmol of cytochrome P450 for the 9S,10R enantiomer. This demonstrated that CYP94A1 is enantioselective for the 9R,10S, which is preferentially formed in V. sativa microsomes. Cutin analysis of V. sativa seedlings revealed that it is mainly constituted of derivatives of palmitic acid, a C(16) fatty acid. Our results suggest that CYP94A1 might play a minor role in cutin synthesis and could be involved in plant defence. Indeed, 18-hydroxy-9,10-epoxystearic acid and 9,10,18-trihydroxystearic acid have been described as potential messengers in plant-pathogen interactions.

Cloning, Molecular↗
PubMed1988

High pressure liquid chromatography methods for separation of omega- and (omega-1)-hydroxy fatty acids: their applications to microsomal fatty acid omega-oxidation.

Fatty acids (C12-C18) and their omega- and (omega-1)-hydroxy derivatives, when converted to p-bromophenacyl (PBP) esters, can be completely separated from one another by high pressure liquid chromatography (HPLC) on a silicic acid column using 0.5% (v/v) isopropanol in n-hexane. In this system, fatty acid PBP esters are eluted at the solvent front, whereas the retention times of the omega- and (omega-1)-hydroxy derivatives are 14-20 and 24-29 min, respectively. The PBP esters can also be separated by reverse phase HPLC on a muBondapak C18 column, a method which has been developed by Fan et al. (Fan, L. L., Masters, B. S. S., and Prough, R. A. (1976) Anal. Biochem. 71, 265-272) for separation of methyl esters of fatty acids and their omega- and (omega-1)-hydroxy derivatives. In the latter method, however, the retention times of omega- and (omega-1)-hydroxy derivatives are only about 2 min apart and an increase in the solvent polarity is needed for elution of the esters of unmodified fatty acids. Fatty acid PBP esters, however, can be obtained as independent peaks which are not disturbed by the solvent front. An application of the former method to measure fatty acid omega oxidation by liver microsomes and by a reconstituted monooxygenase system containing purified cytochrome P-450 is described.

Animals↗
PubMed1984

Diabetogenic action of alloxan-like compounds: cytotoxic effects of 5-hydroxy-pseudouric acid and dehydrouramil hydrate hydrochloride on rat pancreatic beta cells.

The effects on islet morphology and blood glucose concentration of intravenous administration of alloxan to rats have been compared with those of two new diabetogenic agents, 5-hydroxy-pseudouric acid (5-HPUA) and dehydrouramil hydrate hydrochloride (DHU). Administration of alloxan (0.35 mmol/kg) caused a classical triphasic change in blood glucose characterised by initial hyperglycaemia, subsequent hypoglycaemia and a delayed persistent hyperglycaemia. In contrast, 5-HPUA and DHU elicited persistent hyperglycaemia as early as 30 min after administration. Morphological evidence for degranulation, pyknosis, necrosis and widening of pericapillary spaces was obtained with all three agents. However, both 5-HPUA and DHU elicit considerably more rapid and extensive changes than alloxan, with evidence for extensive pyknosis occurring as early as 15 min after administration of DHU and 5-HPUA compared with 24 h for alloxan. The more marked potency of DHU and 5-HPUA may be at least partially attributable to the greater stability of these agents compared with alloxan, since solutions of DHU or 5-HPUA kept for 15 min prior to administration retained full diabetogenic activity, whereas similar treatment of alloxan solution completely abolished its diabetogenic activity. Since both 5-HPUA and DHU are potential metabolites of uric acid, their marked diabetogenic potency raises the possibility of a role for uric acid metabolites in the pathogenesis of diabetes mellitus.

Alloxan↗
PubMed1988

Lipoxygenase catalyzed oxygenation of hydroxy fatty acids to lipoxins.

The pure lipoxygenases from rabbit reticulocytes and soybeans convert a variety of substrates (arachidonic acid, 15-HPETE, 15-HETE, 5-HETE, various DiHETE isomers) to trihydroxy eicosanoids containing a conjugated tetraene system (lipoxins). In general, the methyl esters are better substrates for lipoxin formation than are the free acids. Lipoxygenase inhibitors (5,8,11,14-eicosatetraynoic acid, nordihydroguaiaretic acid) strongly inhibit the lipoxin formation. The complete stereochemistry of the lipoxin B formed from 15S-HETE methyl ester has been established by co-chromatography with authentic standards on various types of HPLC columns, by GC/MS analysis, by gas liquid chromatography of the ozonolysis fragments of the menthoxy carbonyl derivatives and 1H-NMR studies. The molar absorption coefficient of the conjugated tetraenes was measured as epsilon 301 = 53,000. The lipoxins formed from 15-HETE and various DiHETE isomers are formed exclusively via the oxygenation pathway as shown by experiments under an 17O2 atmosphere and/or by anaerobic incubations. Our results indicate that lipoxins can be synthesized via lipoxygenase-catalyzed sequential oxygenation of polyenoic fatty acids and their hydro(pero)xy derivatives.

Animals↗
PubMed2000

Determining double-bond positions in monoenoic 2-hydroxy fatty acids of glucosylceramides by gas chromatography-mass spectrometry.

We applied a gas chromatography-mass spectrometry (GC-MS) method using dimethyl disulfide (DMDS) adducts and were able to determine the double-bond positions in monounsaturated 2-hydroxy fatty acids (2-HFA). 2-HFA methyl esters, prepared from the hydrolysate of Arabidopsis thaliana leaf glucosylceramides, were acetylated and methylthiolated. GC-MS analysis of the resulting DMDS adducts showed simple mass spectra with recognizable molecular ions and a series of key fragment ions indicating the original double-bond positions in the aliphatic chain. Based on this GC-MS elucidation, we confirmed that Arabidopsis leaf glucosylceramides have C22, C23, C24, C25, and C26 chain length 2-HFA with monounsaturation, and all their double bonds are placed at the n-9 position. This procedure is simple, time efficient, and highly sensitive.

Arabidopsis↗
PubMed1999

Use of quadrupole GC-MS and ion trap GC-MS-MS for determining 3-hydroxy fatty acids in settled house dust: relation to endotoxin activity.

Gas chromatography-mass spectrometry (GC-MS) using a quadrupole instrument and GC-tandem MS (GC-MS-MS) using an ion trap instrument were applied to determine 3-hydroxy fatty acids (3-OH FAs) with 10-18 carbon chain lengths, specific components of the endotoxin (lipopolysaccharide, LPS) of Gram-negative bacteria, in 30 house dust samples. The two methods provided similar detection sensitivity for methyl ester/trimethylsilyl derivatives of the 3-OH FAs and allowed these acids to be distinguished from co-eluting 2-OH FA derivatives. The correlation coefficients between endotoxin activity (Limulus test) and the combined amounts of 3-OH C10, 3-OH C12, and 3-OH C14 were 0.60 and 0.61 when using GC-MS and GC-MS-MS, respectively. The superior selectivity of GC-MS-MS was illustrated in analyses of sub-milligram amounts of dust, where the chromatograms achieved by GC-MS were difficult to interpret due to a high background and several closely eluting compounds. GC-MS-MS is therefore preferable to GC-MS for determining 3-OH FAs in minute (sub-milligram) amounts of dust.

Air Pollution, Indoor↗
PubMed1999

Formation of 9-hydroxy linoleic acid as a product of phospholipid peroxidation in diabetic erythrocyte membranes.

The increased production of oxygen-derived free radicals (OFR) and lipid peroxidation may contribute to vascular complications in diabetes. Some lipid peroxidation products have already been reported to be formed via glucose-induced oxidative stress. We have identified 9-hydroxy linoleic acid (9-OH-C18:2) in the red cell membrane phospholipid of diabetic subjects. We hypothesized that 9-OH-C18:2 would be formed in hydroxyl radical reactions to linoleic acid (C18:2) during glucose-induced oxidative stress, and confirmed that the formation of 9-OH-C18:2 was induced by ultraviolet (UV)-C irradiation to the synthetic C18:2. UV-C light generates highly reactive hydroxy radicals. C18:2 is confirmed to be the precursor of 9-OH-C18:2. To estimate the degree of oxidative damage to red cell membrane phospholipids, we developed a selective ion monitoring gas chromatography-mass spectrometric measurement for C18:2 and 9-OH-C18:2, following methanolysis of red cell membrane phospholipids. The relative peak height ratio of C18:2 to 9-OH-C18:2 (9-OH-C18:2/C18:2) was measured in phospholipid extracts of red cell membranes from healthy (n=29, 3.1+/-1.9%) and diabetic (n=27, 20. 9+/-16.1%) subjects. It was confirmed that 9-OH-C18:2/C18:2 is significantly (P<0.001) elevated in patients with diabetes. The measurement of 9-OH-C18:2/C18:2 in red cell membranes should be useful for assessing oxidative damage to membrane phospholipids in diabetes.

Biomarkers↗
PubMed1996

Site-directed mutagenesis of the human A1 adenosine receptor: influences of acidic and hydroxy residues in the first four transmembrane domains on ligand binding.

To provide new insights into ligand/A1 adenosine receptor (A1 AR) interactions, site-directed mutagenesis was used to test the role of several residues in the first four transmembrane (TM) domains of the human A1 AR. Based on multiple sequence analysis of all known ARs, both acidic (glutamic acid and aspartic acid) and polar hydroxy (serine and threonine) amino acids were identified that could potentially play a role in binding adenosine. Glu16 (TM1), Asp55 (TM2), Ser93 and Ser94 (TM3), Ser135 (TM4), and Thr 141 (TM4) were identified in all ARs, and Ser6 and Ser23 (TM1) were identified in all A1 ARs. To test the role of these residues, each was individually mutated to alanine. When Ala6, Ala23, Ala50, Ala93, Ala135, and Ala141 constructs were tested, affinities for [3H]2-chloro-N6-cyclopentyladenosine (CCPA) and [3H]1,3-dipropyl-8-cyclopentylxanthine (DPCPX) were similar to those seen for the wild-type receptor. After conversion of Glu16 to Ala16, the affinity for [3H]CCPA and other agonists fell 10-100-fold, whereas the affinity for [3H]DPCPX and other antagonists was not affected. After conversion of Asp55 to Ala55, the affinity for [3H]CCPA and other agonists increased < or = 100-fold, whereas the affinity for [3H]DPCPX and other antagonists was not affected. Studies of the Ala55 construct also revealed that Asp55 is responsible for allosteric regulation of binding by sodium because the affinity for [3H]CCPA did not change over broad ranges of sodium concentrations. When Ser94 was converted to Ala94, A1 AR immunoreactivity was present on stable cell lines; however, functional binding sites could not be detected. When Ser94 was converted to Thr94, the affinity for some xanthine antagonists fell. These data show that Glu16 in TM1 and Asp55 in TM2 play important roles in agonist/A1 AR interactions and show that Asp55 is responsible for allosteric regulation of ligand/A1 AR binding by sodium. We also identify Ser94 as an important site for ligand binding.

Allosteric Regulation↗
PubMed1988

In vitro inhibition of leukotriene B4 formation by exogeneous 5-lipoxygenase inhibitors is associated with enhanced generation of 15-hydroxy-eicosatetraenoic acid (15-HETE) by human neutrophils.

Leukotrienes, products of the 5-lipoxygenase pathway of arachidonic acid metabolism, have been suggested to play a pathogenic role in psoriasis, because of their ability to induce skin inflammation and to stimulate epidermal proliferation. The 15-lipoxygenase product 15-hydroxy-eicosatetraenoic acid (15-HETE) has no proinflammatory capacity. In contrast, it can inhibit the activity of the 5-lipoxygenase. The purpose of the present study was to study the effect of 5-lipoxygenase inhibitors on the formation of 15-HETE by human neutrophils in vitro. Purified neutrophils were incubated with A 23187 (5 microM) and arachidonic acid (25 microM) with and without different inhibitors of 5-lipoxygenase activity (RS 43179, benoxaprofen, NDGA, and CP 66248). Methods for identifying eicosanoids included RP-HPLC and radioimmunoassay. Formation of leukotriene B4 was inhibited in a dose-dependent way, which was strongly correlated with a concomitant increase in the formation of 15-HETE (r = 0.97, p less than 0.01). The cyclooxygenase inhibitor indomethacin did not change 15-HETE formation. The stimulation of 15-HETE formation was not associated with cell damage as assessed by LDH release. Furthermore, identical incubations of T lymphocytes, characterized by a low 5-lipoxygenase activity, did not result in increased 15-HETE formation. These results show that inhibition of 5-lipoxygenase activity can lead to increased formation of 15-HETE. Because 15-HETE inhibits formation of 5-LO products, it may amplify the effect of 5-lipoxygenase inhibitors.

Arachidonate Lipoxygenases↗
PubMed1976

Properties of the testicular lactate dehydrogenase isoenzyme.

1. Studies were carried out with pure lactate dehydrogenase isoenzymes C4 (LDH isoenzyme X), B4, (LDH isoenzyme 1) and A4 (LDH isoenzyme 5) isolated from mouse testis, heart and muscle tissue respectively; with LDH isoenzyme X purified from pigeon testes and with crude lysates of spermatozoa from man, bull and rabbit. 2. LDH isoenzyme X from all species showed greater ability than the other isoenzymes to catalyse the NAD+-linked interconversions of 2-oxobutanoate into 2-hydroxybutanoate and of 2-oxopentanoate into 2-hydroxypentanoate. 3. Mouse LDH isoenzyme X presented the broadest spectrum of substrate specificity. It exhibited very similar Km values for a variety of 2-oxo acids: 2-oxopropanoate (pyruvate), 2-oxobutanoate, 2-oxo-3-methylbutanoate, 2-oxopentanoate, 2-oxo-3-methylpentanoate, 2-oxo-4-methylpentanoate, 2-oxohexanoate and 2-oxo-3-phenylpropanoate (phenylpyruvate). The corresponding 2-hydroxy acids were also readily utilized in the reverse reaction. A strong inhibition by substrate and product was demonstrated for the direct reaction. 4. Intracellular distribution of LDH isoenzyme X was investigated in mouse testes. LDH isoenzyme X activity was located in the fraction of "heavy mitochondria" and in the soluble phase. 5. A possible functional role for LDH isoenzyme X is proposed: the redox couple-2-oxo acid-2-hydroxy acid could integrate a shuttle system transferring reducing equivalents from cytoplasm to mitochondria.

Animals↗
PubMedDate not supplied

Toward non-toxic antifouling: synthesis of hydroxy-, cinnamic acid-, sulfate-, and zosteric acid-labeled poly[3-hydroxyalkanoates].

The side-chain double bonds of bacterial poly[3-hydroxyalkanoate-co-3-hydroxyalkenoate] (PHAE, 1) were transformed into thioether bonds (derivative 2) via the radical addition reaction of 11-mercapto-1-undecanol. The terminal hydroxy functionalities of derivative 2 were subsequently esterified with cinnamic acid (derivative 3), sulfatized with ClSO(3)H (derivative 4), or coupled with tert-butyldimethylsilyl-protected coumaric acid, to give, after deprotection with tetrabutylammonium fluoride (derivative 5) followed by sulfatization, p-(sulfooxy) cinnamic acid- (zosteric acid) labeled PHAE (derivative 6). The reactions proceeded with good yields and little side reactions, which was confirmed with (1)H NMR and GPC experiments. These functionalized polyesters are currently investigated as environmentally friendly coatings to protect surfaces from biofouling.

Acids↗
PubMed1980

Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.

Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolini and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was shown to be 1,2,6,7,8,8a-hexahydro-beta, delta-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-hepatanoic acid delta-lactone. Mevinolin in the hydroxy-acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 microgram/kg). Furthermore, it was shown that mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 weeks with mevinolin at 8 mg/kg per day resulted in a 29.3 +/- 2.5% lowering of plasma cholesterol.

Animals↗