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PubMed1985

Transmembrane calcium movement in 20,25-diazacholesterol myotonia.

An abnormality in myoplasmic Ca2+ regulation has frequently been proposed in 20,25-diazacholesterol (20,25-D) myotonia. We report here the results of several studies of transmembrane Ca2+ movement in this animal model. (i) Physiologic Ca2+ release by intact sarcoplasmic reticulum (SR) was examined in chemically skinned single muscle fibers preloaded in EGTA-buffered Ca2+ solutions (pCa2+7.0 to 6.4). Isometric tension development and Ca2+ release thresholds in response to Cl- or caffeine showed no differences between control and 20,25-D fibers at any pCa2+. (ii) The kinetics of energy-dependent Ca2+ accumulation in purified SR vesicles were followed spectrophotometrically using Ca2+-sensitive dyes. The apparent rate for ATP-dependent Ca2+ uptake and Ca2+ sequestering capacity were unchanged in SR from 20,25-D animals vs. controls. (iii) Surface membrane Ca2+ATPase activity was measured in red blood cell ghosts and sarcolemma. Enzyme Vmax was decreased by 25 to 50% in both membranes in the 20,25-D-treated animals with a compensatory increase in the number of Ca2+ATPase molecules. In general, the SR handling of Ca2+ appears normal in 20,25-D myotonia, although the activity of Ca2+ATPase in membranes with high sterol content may be altered in response to changes in the lipid environment in this model.

Adenosine Triphosphate↗
PubMed1993

Molecular changes in erythrocyte membranes induced by long-term administration of clofibrate.

It has been reported that an enantiomer ((S)-(-)-4) of clofibric acid, and the racemate, can block the chloride conductance of skeletal muscle membrane. It has also been reported that several analogs of clofibric acid inhibit the HCO3(-)-Cl- exchange of erythrocytes. Since the two effects are probably similar biophysical membrane phenomena, the possibility of a common molecular mechanism arises. We exposed Sprague-Dawley male rats to long-term administration of clofibrate and 20,25-diazacholesterol (20,25-D) for comparison, at equipotent doses. Clofibrate (but not 20,25-diazacholesterol) produced a significant increase in density of the 220,000 Da band (beta-spectrin) and a decrease, also significant, in density of bands 2.1, 2.2, 2.3, 2.6 (syndeins or ankyrins) and of bands 4.1 and 6. Thus, clofibrate exhibits a manifold effect on the protein profile of the erythrocyte membrane cytoskeleton which, due to the lack of effect of 20-25-D, does not seem to be produced by the hypolipidemic effect per se, and thus deserves further study.

Animals↗
PubMedDate not supplied

Antispermatogenic and antifertility effects of 20,25-diazacholesterol dihydrochloride in mice.

The effect of intraperitoneal administration for 28 days of 10, 20, and 30 mg/kg body weight per day of 20,25-diazacholesterol dihydrochloride (SC 12937), a hypocholesterolemic agent, on the testis of Parkes (P) strain mice was investigated. Histologically, testes in mice treated with 10 or 20 mg/kg body weight of SC 12937 showed non-uniform degenerative changes in the seminiferous tubules as both affected and normal tubules were observed in the same section; the affected tubules showed intraepithelial vacuolation, occurrence of giant cells, exfoliation of germ cells, and marginal condensation of chromatin in round spermatids. In both dosage groups, only 11-12% of the seminiferous tubules were affected, and no significant differences were found in the frequency of affected tubules between the two groups. By contrast, testes in mice treated with 30 mg/kg body weight of the drug exhibited a degenerated appearance of germ cells in all seminiferous tubules. The treatment also had adverse effects on motility, viability, morphology, and number of spermatozoa in the cauda epididymidis, and on fertility. Even 56 days after drug withdrawal, the above parameters remained markedly affected. Our results thus suggest that SC 12937 treatment causes antispermatogenic and antifertility effects in P mice and that the effects are not reversible up to 56 days after drug withdrawal. This compound may prove useful in the control of rodent populations.

Animals↗
PubMed2001

Structure-activity relationship of aza-steroids as PI-PLC inhibitors.

A number of aza-steroids were synthesized as potent phosphatidylinositol phospholipase C (PI-PLC) inhibitors. The epimeric mixtures 22,25-diazacholesterol (8a) and 3beta-hydroxy-22,25-diazacholestane (8b) were among the most active of these inhibitors, with IC(50) values of 7.4 and 7.5 microM, respectively. The 20alpha epimer, 8a2 (IC(50)=0.64 microM), whose stereochemistry at C-20 coincides with that of cholesterol, was found 50 times more potent than the 20beta epimer, 8a1 (IC(50)=32.2 microM). In diaza-estrone derivatives, the 3-methoxy group on the aromatic A-ring of 23 exhibited moderate PI-PLC inhibitory activity (IC(50)=19.7 microM), while compound with a free hydroxyl group (21) was inactive. However, in diaza-pregnane derivatives, epimers with a 3-hydroxyl group (8a, IC(50)=7.4 microM) exhibited more potent PI-PLC inhibitory activity than their counterparts with 3-methoxyl group on the non-aromatic A-ring (26, IC(50)=17.4 microM). We have illustrated in our previous publication that 3-hydroxyl-6-aza steroids are potent PI-PLC inhibitors.(3) However, simultaneous presence of the 6-aza and 22,25-diaza moieties in one molecule as in 13, led to loss of activity. Epimeric mixture 8a showed selective growth inhibition effects in the NCI in vitro tumor cell screen with a mean GI(50) value (MG-MID) of 5.75 microM for 54 tumors.

Azacosterol↗
PubMed2003

Desmosterol: a biomarker for the efficient development of 20,25-diazacholesterol as a contraceptive for pest wildlife.

20,25-Diazacholesterol is being evaluated as a contraceptive for the nonlethal control of avian and mammalian wildlife pests. The identification of an analyte in blood which was highly correlated with absorbed dose and efficacy is valuable for determining effective formulations and dosing variables. Such an analyte or biomarker is also valuable for determining the percentage of pest populations that consume an effective dose of the active ingredient in the field. HPLC analyses of blood collected from dosed animals failed to detect 20,25-diazacholesterol but indicated that levels of free cholesterol and related compounds were affected by 20,25-diazacholesterol absorption. The greatest percent change in chromatographic peak area associated with 20,25-diazacholesterol administration was observed for desmosterol, a cholesterol precursor. 20,25-Diazacholesterol appeared to block the conversion of desmosterol to cholesterol, resulting in an elevated concentration of the precursor. The elevation of blood desmosterol levels is being used as an indicator of 20,25-diazacholesterol absorption and to facilitate the development of a 20,25-diazacholesterol-based contraceptive for pest wildlife.

Animals↗
PubMed1985

3-Alkyl-3-hydroxyglutaric acids: a new class of hypocholesterolemic HMG CoA reductase inhibitors. 1.

Derivatives of 3-hydroxy-3-methylglutaric acid (HMG), a portion of the substrate for HMG CoA reductase, were prepared and tested for their inhibitory action against rat liver HMG CoA reductase and for their hypocholesterolemic activity. Structure-dependent competitive inhibition was observed. Optimal structures had a free dicarboxylic acid with an alkyl group of 13-16 carbons at position 3. 3-n-Pentadecyl-3-hydroxyglutaric acid (3j) (IC50 = 50 microM) reduced serum cholesterol in the Triton-treated rat and HMG CoA reductase activity in the 20,25-diazacholesterol-treated rat.

Animals↗
PubMed1990

Effect of chemical carcinogens on cholesterol biosynthetic pathways in the skin of mice.

The metabolism of zymosterol and mevalonic acid was studied in vitro using the skin homogenates of 3-methylcholanthrene (3MC), diazacholesterol-treated and untreated mice. In normal mouse skin only lathosterol was a major metabolite and the other metabolites, cholesta-5,7,24-trien-3 beta-ol, desmosterol, cholesterol and 7-dehydrocholesterol were much less abundant. However, in the skin homogenate of mice treated with 3MC lathosterol production was depressed, while the production of cholesta-5,7,24-trien-3 beta-ol and desmosterol was significantly increased, the cholesterol level being normal or a little higher. In contrast, in the skin homogenate of mice administered diazacholesterol the production of both lathosterol and cholesterol was almost completely blocked with the slightly increased production of cholesta-5,7,24-trien-3 beta-ol and desmosterol. The metabolism in vitro of [2-14C]-mevalonic acid was quite similar to that of zymosterol, and no additional product which might possibly have been produced by the Kandutsch-Russell pathway was observed. Two pathways for cholesterol biosynthesis, therefore, may exist in mouse skin; the first is lanosterol----zymosterol----5 alpha-cholesta-7,24-dien-3 beta-ol----lathosterol----7-dehydrocholesterol----cholesterol, and the second by Bloch: lanosterol----zymosterol----5 alpha-cholesta-7,24-dien-3 beta-ol----cholesta-5,7,24-trien-3 beta-ol----desmosterol----cholesterol. When mouse skin is treated with 3-MC the former pathway is virtually blocked and the latter is stimulated, keeping the level of cholesterol in the tissue constant or a little higher than normal, which seems to be a significant change in the early stage of chemical carcinogenesis.

Animals↗
PubMed2004

Effectiveness of twenty, twenty-five diazacholesterol, avian gonadotropin-releasing hormone, and chicken riboflavin carrier protein for inhibiting reproduction in Coturnix quail.

Contraception may provide a useful nonlethal management tool when it is desirable to reduce populations of birds. We tested the efficacy of 20,25 diazacholesterol, and immunization with avian gonadotropin-releasing hormone (AGnRH-I) and chicken riboflavin carrier protein (cRCP) as contraceptives and investigated their modes of action in Coturnix quail (Coturnix coturnix japonica). Females that were paired with males treated with 20,25 diazacholesterol produced lower percentages of eggs that were fertile and hatched. Females treated with 20,25 diazacholesterol and paired with control males laid fewer eggs, and lower percentages of their eggs were fertile and hatched. Treatment with 20,25 diazacholesterol reduced testosterone levels in males and progesterone levels in females. Nonesterified cholesterol levels were reduced, whereas desmosterol levels increased in birds treated with 20,25 diazacholesterol. Treatment with AGnRH-I and cRCP immunocontraceptive vaccines did not decrease average egg production and hatchability or hormone levels, but this failure might have been due to the vaccination protocol. If registered, wildlife managers may be able to use 20,25 diazacholesterol when other methods, such as lethal control, are undesirable for reducing damage caused by specific breeding behaviors such as the building of nests.

Animals↗
PubMed1984

Cholesterol synthesis and nerve regeneration.

In this report, we examine the requirement of cholesterol biosynthesis and its axonal transport for goldfish optic nerve regeneration. Cholesterol, labeled by intraocular injection of [3H]mevalonolactone, exhibited a delayed appearance in the optic tectum. Squalene and other minor components were labeled but not transported. Following optic nerve crush, the amount of labeled cholesterol transport was elevated, while retinal labeling was not altered relative to control fish. A requirement for cholesterol biosynthesis is inferred from the inhibition of neurite outgrowth in retinal explants caused by the cholesterol synthesis inhibitor, 20,25-diazacholesterol. The inhibition of growth could be overcome by addition of mevalonolactone, but not cholesterol, to the medium. Intraperitoneal administration of 200 nmol of diazacholesterol resulted in 92-98% inhibition of retinal cholesterol synthesis and accumulation of labeled desmosterol and other lipids in fish retina and brain which persisted for 2 weeks. Diazacholesterol-treated fish showed no reduction in the amount of lipid-soluble radioactivity transported following intraocular injection of [3H]mevalonolactone, but there were alterations in the chromatographic pattern of the transported labeled lipids. In contrast to its effects on neurite outgrowth in vitro, diazacholesterol did not inhibit optic nerve regeneration in vivo, as measured both by arrival of labeled rapidly transported protein at the tectum and by time required for the return of visual function.

Animals↗
PubMed1978

Metabolic interconversion of free sterols and steryl esters in Saccharomyces cerevisiae.

The interconversion of free and esterified sterols was followed radioisotopically with [U-14C]acetate and [methyl-14C]methionine. In pulse-chase experiments, radioactivity first appeared mainly in unesterified sterols in exponential-phase cells. Within one generation time, the label equilibrated between the free and esterified sterol pools and subsequently accumulated in steryl esters in stationary-phase cells. When the sterol pools were prelabeled by growing cells aerobically to the stationary phase and the cells were diluted into unlabeled medium, the prelabeled steryl esters returned to the free sterol form under several conditions. (i) During aerobic growth, the prelabeled sterols decreased from 80% to 45% esters in the early exponential phase and then returned to 80% esters as the culture reached the stationary phase. (ii) Under anaerobic conditions, the percentage of prelabeled steryl esters declined continuously. When growth stopped, only 15% of the sterols remained esterified. (iii) In the presence of an inhibitor of sterol biosynthesis, which causes accumulation of a precursor to ergosterol, prelabeled sterols decreased to 40% steryl esters while the precursor was found preferentially in the esterified form. These results indicate that the bulk of the free sterol and steryl ester pools are freely interconvertible, with the steryl esters serving as a supply of free sterols. Furthermore, there is an active cellular control over what types of sterol are found in the free and esterified sterol pools.

Aerobiosis↗
PubMed1981

Dependence of membrane potential on extracellular ionic concentrations in myotonic goats and rats.

Intracellular potassium concentration([K]i) and the resting sodium-to-potassium permeability ratio (alpha = PNa/PK) were determined by recording resting potentials at 25 degrees C in six solutions with variable potassium concentrations, constant [K+] + [Na+], and constant [K+] X [Cl-] product and fitting the results by nonlinear least squares to the Goldman-Hodgkin-Katz equation. Fits to models including chloride permeability terms suggest that chloride is in Donnan equilibrium in the muscles studied. External intercostal muscle was biopsied from anesthetized normal goats and goats with hereditary myotonia. In normal goat muscle, alpha was 0.012 +/- 0.001 (mean +/- SE, n = 11), and [K]i was 133 +/- 6 mM (n = 9); myotonic goat muscle did not differ from this. Extensor digitorum longus (EDL) muscle was removed from anesthetized male Wistar rats and from like rats pretreated with a single large dose of 20,25-diazacholesterol (DAC). In normal rat EDL, alpha was 0.019 +/- 0.002 (n = 12), and [K]i was 142 +/- 4 mM (n = 12). In the 16-day DAC-treated rats, alpha was significantly reduced (P < 0.002) to 0.010 +/- 0.002 (n = 8), and [K]i was slightly reduced by DAC. It is concluded that DAC reduced PNa in rat fibers. Tetrodotoxin at 5 microM did not affect either parameter in the rats.

Animals↗