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Cancer Research May 1988When polycyclic aromatic hydrocarbons were applied solely or together with a tumor promoter (12-O-tetradecanoylphorbol-13-acetate) to the skin of mice, a marked decrease...
When polycyclic aromatic hydrocarbons were applied solely or together with a tumor promoter (12-O-tetradecanoylphorbol-13-acetate) to the skin of mice, a marked decrease in the level of lathosterol was observed, reflecting a significant change in the metabolism of sterols. Yet the total amount of cholesterol was not changed. When diazacholesterol (a metabolic inhibitor) was administered to mice, both desmosterol and 5 alpha-cholesta-7,24-dien-3 beta-ol accumulated in the skin, whereas the level of lathosterol decreased. These results seem to suggest that a significant portion of lathosterol is formed via 5 alpha-cholesta-7,24-dien-3 beta-ol in addition to the pathway through methostenol. When polycyclic aromatic hydrocarbon was applied to the skin of the mouse treated with diazacholesterol, a significant increase of desmosterol and a marked drop of the level of 5 alpha-cholesta-7,24-dien-3 beta-ol were observed. These results strongly suggest that polycyclic aromatic hydrocarbons perturb the metabolism of sterol in the skin of mice while keeping the total amount of cholesterol unchanged. A similar metabolism also seems to be operating in tumor tissue itself.
Topics: Animals; Azacosterol; Carcinogens; Cholesterol; Male; Mass Spectrometry; Methylcholanthrene; Mice; Polycyclic Compounds; Skin; Skin Neoplasms; Sterols; Tetradecanoylphorbol Acetate
PubMed: 3356016
DOI: No ID Found -
Pflugers Archiv : European Journal of... Mar 1986Experimental myotonia was induced by feeding rats with 20,25-diazacholesterol for up to 8 months. Histochemical analysis of myotonic extensor digitorum longus (EDL)...
Experimental myotonia was induced by feeding rats with 20,25-diazacholesterol for up to 8 months. Histochemical analysis of myotonic extensor digitorum longus (EDL) muscle showed a progressive decrease of type IIB fibres and a concomitant increase of type IIA and type I fibres. A transient hypertrophy of type IIA fibres was observed 6 months after beginning the treatment. Analysis of the pattern of myosin light chains of single fibres from EDL showed that myotonia caused a progressive decrease of fibres showing a pure fast myosin light chain pattern and an increase of fibres showing coexistence of fast and slow myosin light chains (intermediate fibres). Only a small percentage of intermediate fibres showed coexistence of fast and slow myosin heavy chains. Myotonic fibres presented an increased sensitivity to caffeine which approached that of normal soleus fibres. Furthermore, sarcoplasmic reticulum (SR) vesicles isolated from hind limb fast muscles of myotonic rats demonstrated a decrease of Ca2+-dependent ATPase and Ca2+-transport activities as well as a decrease of immunoreactivity with anti-rabbit SR fast Ca2+-ATPase antibody. These results suggest that the increased electrical activity brought about by 20,25-diazacholesterol-induced myotonia, caused a fast to slow transition in the phenotypic expression of myosin and sarcoplasmic reticulum proteins.
Topics: Adenosine Triphosphatases; Animals; Azacosterol; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Histocytochemistry; Male; Muscles; Myofibrils; Myosins; Myotonia; Rats; Rats, Inbred Strains; Sarcoplasmic Reticulum
PubMed: 2938075
DOI: 10.1007/BF00640912 -
Japanese Journal of Cancer Research :... Jul 1987Repeated topical application of 3-methylcholanthrene to the backs of BALB/c mice lowered the tissue levels of lathosterol and provitamin D3, intermediates in one of the...
Repeated topical application of 3-methylcholanthrene to the backs of BALB/c mice lowered the tissue levels of lathosterol and provitamin D3, intermediates in one of the cholesterol biosynthetic pathways (the delta 7 pathway), though the activities of lathosterol 5-desaturase and provitamin D3 7-reductase were similar to those of control animals. These results seemed to indicate that carcinogen treatment exerted a depressive effect at some earlier step(s) than lathosterol synthesis. However, the content of cholesterol in mouse skin was not lowered in these animals, suggesting that another biosynthetic pathway might be activated. When diazacholesterol, which is known to inhibit the conversion of desmosterol to cholesterol, was administered together with the carcinogen, a marked accumulation of desmosterol was observed compared to animals given only diazacholesterol. Since desmosterol is an intermediate in the pathway in which the delta 24 double bond is reduced at the final step (the delta 24 pathway), this seemed to suggest that the delta 24 pathway was activated by carcinogen treatment.
Topics: Administration, Topical; Animals; Azacosterol; Cholecalciferol; Cholesterol; Chromatography, Gas; Desmosterol; Female; Lanosterol; Methylcholanthrene; Mice; Mice, Inbred BALB C; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Skin
PubMed: 3040651
DOI: No ID Found -
Archives of Dermatology Mar 1984Although the new synthetic retinoids are effective when administered systemically, they have not been shown to be effective as topical agents. We compared the topical... (Comparative Study)
Comparative Study
Although the new synthetic retinoids are effective when administered systemically, they have not been shown to be effective as topical agents. We compared the topical activity of six synthetic retinoids (two arotinoids, etretinate, all-trans- and 13-cis-tetrazole-retinamide, isotretinoin, and tretinoin) on tail skin in the diazacholesterol-fed mouse model of ichthyosis. Responses were assessed clinically and by measurement of stratum corneum thickness. Although the arotinoids dramatically reduced scaling, they were toxic at concentrations above 0.1%, as was etretinate at 1.0% or greater. Lower concentrations were effective without producing local or systemic toxic reactions. Clinical responses were paralleled by equivalent decrements in stratum corneum thickness, which also permitted quantitative comparisons. The order of potency for the retinoids was as follows: arotinoids, etretinate, tetrazole-retinamides, tretinoin = isotretinoin, vehicle. These results demonstrate that (1) the synthetic retinoids hold promise as topical agents; (2) irritation is not an absolute requirement for topical retinoid activity; and (3) the diazacholesterol-fed mouse offers a new assay of topical retinoid potency in a well-defined animal model of ichthyosis.
Topics: Administration, Topical; Animals; Azacosterol; Cholesterol; Dose-Response Relationship, Drug; Etretinate; Ichthyosis; Male; Mice; Mice, Hairless; Retinoids; Structure-Activity Relationship; Tretinoin
PubMed: 6703735
DOI: No ID Found -
Archives of Oral Biology 1986Sterol components of mouse submandibular, sublingual and parotid glands were studied by thin-layer and gas-liquid chromatography. The major sterol was cholesterol...
Sterol components of mouse submandibular, sublingual and parotid glands were studied by thin-layer and gas-liquid chromatography. The major sterol was cholesterol (5-cholesten-3 beta-ol; 26.7, 28.0, 18.8 micrograms/mg protein respectively), with minor amounts of squalene, lathosterol (5 alpha-cholest-7-en-3 beta-ol), desmosterol (cholesta-5,24-dien-3 beta-ol), lanosterol (4,4',14-trimethyl-5 alpha-cholesta-8,24-dien-3 beta-ol), dihydrolanosterol (4,4',14-trimethyl-5 alpha-cholest-8-en-3 beta-ol) and methylstenol. Chromatograms of salivary sterols were similar to those of liver, and different from those of skin in which the amount of lathosterol was much higher. Administration of the anticholesterolaemic agent, 20,25-diazacholesterol, resulted in accumulation of desmosterol in all tissues tested, and additional sterols also accumulated in skin. The gas-liquid chromatographic profiles of salivary sterols from the treated animals were similar to those of liver, but different from those of skin. Thus sterols were synthesized in salivary glands and the biosynthetic pathway was via C24-unsaturated side-chain intermediates, as in liver. This was verified by showing that [2-14C]-mevalonate was incorporated into sterols in vitro when it was incubated with homogenates of these glands.
Topics: Animals; Azacosterol; Cholesterol; Chromatography, Gas; Chromatography, Thin Layer; In Vitro Techniques; Liver; Male; Mevalonic Acid; Mice; Mice, Inbred Strains; Salivary Glands; Skin; Sterols
PubMed: 3460541
DOI: 10.1016/0003-9969(86)90031-2 -
Biochemical Pharmacology Jan 1982Effects of 20,25-diazacholesterol (DAC), a myotonia-inducing drug, were evaluated on certain biochemical and morphological properties of embryonic rat muscle cells grown...
Effects of 20,25-diazacholesterol (DAC), a myotonia-inducing drug, were evaluated on certain biochemical and morphological properties of embryonic rat muscle cells grown in tissue culture. During DAC treatment, muscle fibers exhibited spontaneous contractions that changed from coarse twitches to finer fibrillation movements, The ultrastructural alterations produced by DAC were smeared Z-lines, disorganized myofibrils, occasional honeycomb appearance of membranes and large vacuoles connected to zipper-like structures. Biochemically, a microsomal fraction prepared from DAC-treated cells (compared to that of normal cells) showed a 30-45 per cent decrease in the isoproterenol-enhanced and the NaF-enhanced adenylate cyclase activity. however, the beta-adrenergic receptors, through which isoproterenol activates the enzyme, showed no change in density or affinity as judged by the binding of [125I]iodohydroxybenzylpindolol. That indicated that DAC treatment caused an uncoupling of beta-receptor-adenylate cyclase interaction. Guanylate cyclase and cyclic GMP-phosphodiesterase were both markedly increased in DAC-treated cells, indicating a greater turnover of cyclic GMP. Binding of [3H]concanavalin A to DAC-treated muscle membranes was decreased 20-40 per cent. The data indicate that DAC exert a direct influence on muscle fibers, affecting their functional, biochemical and morphological properties.
Topics: Animals; Azacosterol; Cells, Cultured; Cholesterol; Muscle Contraction; Muscles; Rats
PubMed: 7059357
DOI: 10.1016/0006-2952(82)90242-8 -
Muscle & Nerve Feb 1982In rats treated biweekly with 20,25-diazacholesterol (200 mg/kg orally), the desmosterol level in skeletal muscle sarcolemma increased progressively to about 80% of...
In rats treated biweekly with 20,25-diazacholesterol (200 mg/kg orally), the desmosterol level in skeletal muscle sarcolemma increased progressively to about 80% of membrane sterol while total sterol levels remained constant. Following a single oral dose of 20,25-D, the kinetics of desmosterol accumulation and subsequent loss in sarcolemma were more rapid than in whole muscle homogenates. The anisotropy of diphenylhexatriene fluorescence and the calculated microviscosity of the probe's microenvironment decreased significantly with increasing desmosterol levels in a temperature-dependent manner, although fluorescent lifetimes were not altered. Fluorescent probes which localize in more superficial regions of the membrane detected no change. Studies with erythrocyte ghost membranes yielded results comparable to sarcolemma. Replacement of membrane yielded results comparable to sarcolemma. Replacement of membrane cholesterol with desmosterol reduced the local microviscosity of membrane cholesterol with desmosterol reduced the local microviscosity of the membrane hydrophobic region associated with phospholipid acyl chains and sterol side chains, but had little apparent effect on more superficial, polar regions. These observations can be correlated with the membrane location of the unsaturated side chain in desmosterol.
Topics: Animals; Azacosterol; Cell Membrane; Cholesterol; Desmosterol; Male; Membrane Lipids; Muscles; Myotonia; Rats; Rats, Inbred Strains; Sarcolemma; Viscosity
PubMed: 7070392
DOI: 10.1002/mus.880050207 -
Journal of Agricultural and Food... Jan 200320,25-Diazacholesterol is being evaluated as a contraceptive for the nonlethal control of avian and mammalian wildlife pests. The identification of an analyte in blood...
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.
Topics: Animals; Azacosterol; Biomarkers; Chromatography, High Pressure Liquid; Contraceptive Agents; Coturnix; Deer; Desmosterol; Female; Gas Chromatography-Mass Spectrometry; Male; Pest Control
PubMed: 12502398
DOI: 10.1021/jf020731d -
Experimental Neurology Sep 1982
Topics: Animals; Azacosterol; Cell Membrane; Cholesterol; Desmosterol; Kinetics; Male; Membrane Lipids; Muscles; Myotonia; Ouabain; Phosphorylation; Rats; Rats, Inbred Strains; Sarcolemma; Sodium-Potassium-Exchanging ATPase; Thermodynamics
PubMed: 6288437
DOI: 10.1016/0014-4886(82)90229-1 -
Experimental Neurology Oct 1982
Topics: Action Potentials; Animals; Azacosterol; Chlorides; Cholesterol; Desmosterol; Electromyography; Male; Muscle Contraction; Muscles; Myotonia; Rats; Rats, Inbred Strains; Sarcolemma
PubMed: 7117485
DOI: 10.1016/0014-4886(82)90188-1