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At least 847 records · Page 47Linked to original sources
PubMed1988

Inhibition of steroid-protein interactions by dicyclohexane derivatives.

Sixteen dicyclohexane derivatives including the parent compound d,1-3,4-bis (4-oxocyclohexyl)-hexane (PRDX) have been synthesized and studied for putative interference with androgen binding to transport proteins, metabolizing enzymes, and receptors from rat tissues. Several of these analogues inhibited competitively the binding of dihydrotestosterone to ABP, the epididymal androgen transport protein. One compound had an affinity for ABP as high as Kd = 70 nM. Some dicyclohexanes also inhibited the aromatase enzyme which catalyses conversion of androgens into estrogens, as well as the NADPH-dependent, particulate form of 3 alpha(beta)-hydroxysteroid dehydrogenase, the enzyme that converts dihydrotestosterone into 5 alpha-androstanediol. For both enzymes the inhibition potency Ki of PRDX was about equal to the Km of the substrate. All of these interactions were specific in that they were modulated by single substitutions on the dicyclohexane molecule and they did not occur with other steroid binding proteins such as 5 alpha-reductase and the intracellular androgen receptor. A conformational study showed that dicyclohexanes can assume a 'steroidoid' conformation that differs from the crystal structure and which could account for the specific interactions with the steroid binding sites described here.

Androgen Antagonists↗
PubMed1985

Diacylglycerol lipase and pituitary prolactin release in vitro: studies employing RHC 80267.

We studied the possible involvement of diacylglycerol lipase in the regulatory mechanisms governing the release of prolactin by primary cultures of anterior pituitary cells. This was accomplished by studying the effect of a selective inhibitor of diacylglycerol lipase activity, RHC 80267, on basal prolactin release and that stimulated by TRH and elevated potassium concentrations. RHC 80267 produced a concentration-dependent reduction in basal prolactin release and abolished its increase produced by TRH and potassium. These results are consistent with the hypothesis that the production of arachidonate from lipids via the diacylglycerol lipase pathway is an important event in the governance of prolactin release.

Animals↗
PubMed1987

Effects of RHC 80267, a diglyceride lipase inhibitor, on prolactin secretion and calcium uptake in GH3 pituitary cells.

The effect of the diglyceride lipase inhibitor RHC 80267 on the prolactin secretory process was examined in clonal anterior pituitary GH3 cells. This compound reduced basal prolactin secretion as well as secretion induced by TRH and phospholipase C but not that induced by phorbol myristate acetate. Although exogenous phospholipase C increased diglyceride, no increase in the products of diglyceride lipase was detected. Moreover, low doses of RHC 80267 were observed to effectively block potassium-stimulated 45calcium influx. It is unlikely that RHC 80267 inhibits prolactin release solely by inhibiting diglyceride lipase. These data suggest blockade of plasma membrane calcium channels as an alternate mechanism for the inhibitory actions of RHC 80267 on intact GH3 cells. These observations may have implications for RHC 80267 action in other cell types.

Animals↗
PubMed1989

Anti-hypoxic effect of glutathione depletors.

The effect of various reduced glutathione (GSH) depletors on the survival time under normobaric and hypobaric hypoxia was examined in mice. The survival time was markedly prolonged in mice treated with glutathione S-transferase substrate, 2-cyclohexene-1-one (50-100 mg/kg, ip) and phorone (100-250 mg/kg, ip). The anti-hypoxic effect lasted for at least 3 hr and the maximum effect was found 0.5 hr after injection. Further, both compounds significantly elevated blood glucose levels 0.5-1 hr after treatment. The extent of the elevated blood glucose was nearly comparable to that of the mice treated with glucose (1-2 g/kg, ip), which was found to possess an anti-hypoxic effect. However, a GSH synthesis inhibitor, buthionine sulfoximine, could cause neither a prolongation of survival time of hypoxic mice nor an elevation of blood glucose. Moreover, unlike the depletion of hepatic GSH, brain GSH was markedly decreased by 2-cyclohexene-1-one and phorone, but not by buthionine sulfoximine. These findings suggest that the elevated blood glucose may involve in one of the mechanisms of the anti-hypoxic effect of 2-cyclohexene-1-one and phorone. A relationship between the anti-hypoxic effect and the depletion of brain GSH was also discussed.

Animals↗
PubMed1989

Methods for depleting brain glutathione.

To search for a technique to deplete reduced glutathione (GSH) in brain, the influence of various types of compounds on brain GSH levels was investigated in mice. Of the compounds tested, cyclohexene-1-one, cycloheptene-1-one and diethyl maleate were shown to be potent GSH depletors in brain as well as in liver. The depletion of cerebral GSH ranged about 40-60% of control levels at 1 and 3 hr after intraperitoneal injection. Cyclohexene, cycloheptene, phorone, acetaminophen, and benzyl chloride caused mild depletion of cerebral GSH, but buthionine sulfoximine did not alter cerebral GSH levels. Further, intracerebroventricular injection of cyclohexene-1-one and cycloheptene-1-one caused depletion of brain GSH to about 60-80% of control levels at 1 hr after injection, and the effects persisted for at least 6 hr. Under these conditions, hepatic GSH was not altered. These results demonstrated that cyclohexene-1-one and cycloheptene-1-one can cause not only a marked depletion of brain GSH by systemic administration, but also depletion of cerebral GSH by intracerebroventricular injection by virtue of being water-soluble compounds. Thus, methods for depleting brain GSH employing both compounds are available for exploring possible functions of cerebral GSH in in vivo systems.

Animals↗
PubMed1990

Effective depletion of glutathione in rat striatum and substantia nigra by L-buthionine sulfoximine in combination with 2-cyclohexene-1-one.

The effects of L-buthionine sulfoximine (L-BSO), 2-cyclohexene-1-one and diethylmaleate (DEM) on the concentration of rat brain glutathione (GSH) were investigated. Both DEM and 2-cyclohexene-1-one, administered subcutaneously, produced marked and rapid reduction of brain GSH, but 2-cyclohexene-1-one appeared less toxic than DEM. Six hours after 2-cyclohexene-1-one (100 microliters/kg) the striatal GSH concentration was 35% of control values, whereas the level was 55% of controls at 24 h and 80% of controls at 48 h. Similar results were obtained with DEM (800 microliters/kg). L-BSO (3.2 mg), administered intracerebroventricularly, produced a slower depletion of brain GSH. A 55% reduction of striatal GSH was obtained 24 h after the administration, and the level was approximately 50% of control at 48 h. Thus, the effect of 2-cyclohexene-1-one and DEM is rapid in onset but relatively short lasting, whereas the disappearance of brain GSH after L-BSO is slower but the effect is more long-lasting. By combining L-BSO with either 2-cyclohexene-1-one or DEM both a rapid and long-lasting GSH depletion was obtained that was more profound than after any of the drugs alone. The combination of L-BSO and 2-cyclohexene-1-one was well tolerated, but the combination of L-BSO and DEM led to death in half of the rats the second day after injection. The disappearance rate of GSH after L-BSO alone gives an estimate of the turn-over of GSH. We found the turn-over of GSH to be higher in the substantia nigra pars compacta than in the striatum. The present work suggest that L-BSO and 2-cyclohexene-1-one would be very useful for evaluation of the biological role of GSH in the central nervous system.

Animals↗
PubMed1994

Correlations between chemical reactivity and mutagenic activity against S. typhimurium TA100 for alpha-dicarbonyl compounds as a proof of the mutagenic mechanism.

The mutagenic activities in the Ames test against S. typhimurium TA100 for a series of alpha-dicarbonyl compounds are examined together with the formation constants of the adducts formed between such compounds and guanine and guanosine. Correlations between the equilibrium constants, the apparent reaction enthalpies, and the mutagenic activity are presented. These correlations imply that the mutagenic activity is related to the chemical reactivity of the dicarbonyl compounds with the puric bases.

Aldehydes↗
PubMed1992

Vomifoliol 9-O-beta-D-glucopyranosyl-4-O-beta-D-xylopyranosyl-6-O-beta-D- glucopyranoside: a trisaccharide glycoside from apple fruit.

From a methanolic extract of neutralized apple fruit pulp, a minor compound was isolated by adsorption chromatography on both XAD and PVPP resins followed by rotation locular countercurrent chromatography (RLCC). Clean-up for subsequent spectroscopic studies was performed by preparative HPLC on RP-18 and RP-select B phases. Data available from UV, NMR and mass spectroscopy together with the results obtained by enzymatic and acid hydrolyses revealed the structure of the polar glycoside as vomifoliol 9-O-beta-D-glucopyranosyl-4-O-beta-D-xylopyranosyl-6-O-beta-D-glucopyran oside.

Carbohydrate Sequence↗
PubMed1983

Isotope effects on the metabolism and pulmonary toxicity of butylated hydroxytoluene in mice by deuteration of the 4-methyl group.

A comparative test in mice for pulmonary toxicity between butylated hydroxytoluene (2,6-di-tert.-butyl-4-methylphenol, BHT) and 2,6-di-tert.-butyl-4-[alpha, alpha, alpha-2H3]methylphenol (BHT-d3) showed a significantly lower toxic potency of the latter. The rate of in vitro BHT metabolism to 2,6-di-tert.-butyl-4-methylene-2,5-cyclohexadienone (BHT-QM) was slowed by deuterating BHT in the 4-methyl group. On the other hand, the rate of in vitro metabolism to 2,6-di-tert.-butyl-4-hydroxy-4-methyl-2,5-cyclohexadienone (BHT-OH) was increased with the deuteration. A similar isotope effect of the deuterium substitution on the in vivo metabolic rates of BHT was observed. These observations support the concept that the lung damage caused by BHT is mediated by BHT-QM. The pulmonary toxicity of 2-tert.-butyl-4-ethylphenol (4-EP) and their deuterated analogs was also compared. 2-tert.-Butyl-4-[1,1-2H2]ethylphenol (4-EP-d2) showed a significantly lower toxic potency than 4-EP, whereas 2-tert.-butyl-4-[2,2,2-2H3]ethylphenol (4-EP-d3) showed a toxic potency comparable to that of 4-EP. This result is consistent with the hypothesis that a quinone methide metabolite is responsible for the onset of lung damage produced by 4-EP as well as BHT.

Animals↗
PubMed1989

Modification of arginine in sea anemone toxin RTX-III from Radianthus macrodactylus.

Chemical modifications of the polypeptide neurotoxin RTX-III have allowed us to study the functional role of Arg residues. The effect of chemical modification has been estimated by measuring toxicity in mice. 2,4-Pentanedione did not react with Arg residues of RTX-III even after 100 hr incubation. Malonic aldehyde reacted readily with RTX-III, yielding an unusual derivative; a Schiff's base obtained by condensation of one of two aldehyde groups of malonic aldehyde with the guanidine group. The derivative was one-fourth as toxic as the native toxin. Modification of the guanidine side chain of Arg-13 with both 1,2-cyclohexanedione and phenylglyoxal decreased the toxicity of RTX-III by a factor of five. We conclude that Arg-13 is not fully responsible for toxicity. The toxin-receptor attachment might be multipoint, involving several structural elements of the protein molecule, with Arg-13, probably being one of them. The guanidine side chain of Arg-45 is buried in the sequence and apparently functionally nonessential.

Aldehydes↗
PubMed1995

Chemical modification of cationic groups in the polypeptide cardiac stimulant anthopleurin-A.

Chemical modification studies have been carried out on the sea anemone polypeptide anthopleurin-A in order to clarify the role of Arg-14 in its cardiac stimulatory activity. Reaction with 1,2-cyclohexanedione at 37 degrees C produced a range of protein products, including some with amino group modifications. These side-reactions were eliminated by prior citraconylation of the amino groups, which, following reaction with cyclohexanedione, could be reversed under conditions which preserved the cyclohexanedione adduct. Citraconylation of the three amino groups, one from the N-terminus and two from Lys-37 and Lys-48, destroyed the cardiac stimulatory activity of the molecule, but this was fully recoverable upon reversal of this reaction. It appears that one or more of the amino groups is essential for activity. Anthopleurin-A contains only one arginine residue, and this was confirmed as the site of modification by cyclohexanedione by showing that the product was refractory to proteolysis by trypsin, which normally cleaves the molecule at this residue. The positive inotropic activity of the cyclohexanedione adduct on isolated guinea-pig atria was identical to that of unmodified anthopleurin-A, indicating that the side-chain of Arg-14 is not required for cardiotonic activity.

Amino Acid Sequence↗
PubMed1984

Diglyceryl lipase activity in mouse platelets.

These studies reveal for the first time that mouse platelets have substantial diglyceryl lipase (DGL) activity (138 +/- 29 nmols/hr/10(9) platelets) compared with human 37 +/- 56 nmols/hr/10(9) platelets) or rat platelets (25 +/- 11 nmols/hr/10(9) platelets). Our demonstration of the enzyme in rat platelets contrasts with the scant activity of DGL in that species as reported by others. The activity of DGL in mouse platelets was inhibited by RHC80267, an agent previously described as an inhibitor of DGL in dog and rat platelets.

Animals↗
PubMed1986

Receptor-independent low-density lipoprotein catabolism.

Cultured cells, animal models, and man all possess mechanisms for LDL degradation that do not require the agency of the high-affinity receptor. In healthy individuals their functional significance can be determined using LDL which has been modified by specific chemical reactions designed to inhibit it receptor binding. Although the precise nature of the pathways has not been defined, there is evidence to implicate the monocyte-macrophage system in the process.

Animals↗
PubMed1984

RHC 80267 inhibits thyrotropin-stimulated prostaglandin release from rat thyroid lobes.

In the present report, we studied the effect of the diglyceride (DG) lipase inhibitor, RHC 80267 on basal and thyrotropin (TSH)-stimulated prostaglandin (PG) release from rat thyroid lobes Further, we tested the effect of RHC 80267 on phosphatidylinositol phospholipase C (PIPLC), DG lipase, and arachidonate cyclo-oxygenase activities in rat thyroid cytosol, plasma membrane, and whole homogenate preparations, respectively. Whereas RHC 80267 inhibited DG lipase activity in a dose-related manner from 0.5-10 microns (17-80% inhibition), it failed to inhibit either PIPLC or arachidonate cyclo-oxygenase activities by more than 9% when tested at 5 and 10 microns (n = 3). RHC 80267 reduced TSH-stimulated 6-keto-PGF1alpha and PGF2alpha release by 100 +/- 14% and 57 +/- 12%, respectively (means + S.E.; p less than 0.01 for both; n = 10-12); the diglyceride lipase inhibitor did not reduce basal release of either PG. These data provide additional evidence which implicate a PIPLC-DG lipase pathway in TSH-stimulated PG synthesis in thyroid.

Animals↗