Keratinosomen (Odland-bodies)

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Drug Absorption from the Small Intestine of the Triparanol–Treated Rat in Situ

Abstract The effect of treatment with triparanol (25 mg/kg by gavage every 24 hours for three weeks) on the absorption of phenobarbitone, sulphafurazole, isoniazid, mecamylamine and quinidine from the rat small intestine was studied in situ by measuring their disappearance from the intestinal lumen. The appearance of sulphafurazole and mecamylamine in the intestinal lumen was also studied after their intravenous administration, and the partitioning of mecamylamine between the buffer solution and the intestinal tissue was measured in vitro. Treatment with triparanol retarded the absorption of sulphafurazole, whereas the absorption of mecamylamine was accelerated. The amount of sulphafurazole and mecamylamine in the intestinal lumen after their intravenous administration was relatively slight. The in vitro partitioning of mecamylamine into the intestinal tissue was higher in triparanol–treated than in control intestines. Triparanol did not change the absorption of phenobarbitone, isoniazid or quinidine. Phenobarbitone in the whole blood at the end of the experiment was increased after triparanol, but the levels of other drugs were unchanged. Triparanol did not modify drug concentrations in the intestinal wall at the end of the experiment. The relatively slight changes in drug absorption induced by triparanol are probably due to changes in the morphology and composition of the intestinal wall.     

Adrenocortical function of rats under prolonged administration of lipidosis-inducing drugs

Summary The influence of three potent lipidosis-inducing agents, i.e. iprindole, triparanol and chloroquine, on the rat adrenal cortex was investigated by determination of the corticosterone excretion in the urine, the responsiveness to ACTH and by determination of the corticosterone content of the adrenals and of the corticosterone concentration in plasma. Administration of iprindole and triparanol left the function of the adrenal cortex unaffected, while under chloroquine treatment an activation with time was observed. Morphologically, similar degrees of lipidosis were found in all experiments. The results demonstrate that the functional capacity of the rat adrenal cortex is not directly correlated to lipidotic alterations.     

Regulation of cholesterol 7α-hydroxylation by cholesterol synthesis in rat liver

Hepatic cholesterol 7α-hydroxylation and cholesterogenesis were determined in vitro at various time intervals 6 hr after oral or intravenous administration to fasted rats. Glucose administration to fasted rats enhanced cholesterol 7α-hydroxylation as well as fatty acid or cholesterol synthesis in the liver, though significant changes were not demonstrated in the cholesterol content of liver and serum throughout the observed periods. Hepatic cholesterol synthesis increased 1 hr after oral glucose ingestion. On the other hand, cholesterol 7α-hydroxylation was stimulated 2 hr after oral glucose administration, with a lag phase of 1 hr following the induction of cholesterol synthesis. From the results of the experiments on the effect of glucose ingestion, it appeared that cholesterol 7α-hydroxylation was correlated with hepatic cholesterogenesis.Hepatic cholesterogenesis was decreased in triparanol-treated rats and was not stimulated by glucose administration. Triparanol did not affect cholesterol hydroxylation in the fasted state, but did abolish the stimulatory effect of glucose.Short-term feeding of a high-cholesterol diet, which suppressed hepatic cholesterol synthesis, stimulated cholesterol 7α-hydroxylation. Oral administration of glucose to cholesterol-fed rats still further accelerated hydroxylation.In rats with ligated bile ducts, hepatic cholesterogenesis increased 24 hr after bileduct ligation while hydroxylation decreased 24 hr after the operation but was stimulated after 72 hr. Glucose ingestion by these rats stimulated both cholesterol synthesis and hydroxylation.It is concluded that increased hepatic cholesterogenesis enhances cholesterol 7α-hydroxylase activity; this activity does not depend upon increased fatty acid or other lipid synthesis, altered bile flow or gastrointestinal factors. Increased dietary cholesterol intake also accelerates hydroxylase activity. These mechanisms may preserve homeostasis in the serum cholesterol level, and an altered balance between these two enzyme systems — anabolic and catabolic — probably induces a change in the size of the body cholesterol pool.     

Effects of zuclomiphene in combination with triparanol and AY-9944 on developing rat CNS morphology and biochemistry

Summary Developing rats were injected intraperitoneally twice weekly with a combination of three hypocholesterolemic agents: Zuclomiphene (formerly calledtrans-clomiphene; dosage, 30 mg/kg body weight), Triparanol (30 mg/kg body weight) and AY-9944 (3 mg/kg body weight). Treatment was initiated at 4 days of age. Biochemical and electron microscopic examination was conducted on animals sacrificed at 20 days of age. Cytoplasmic inclusion bodies were not seen in the CNS. Isolated edematous changes were seen in myelinated axons. Analysis of the sterol content of the brain and spinal cords of drugtreated animals indicated the presence of abnormal concentrations of five sterols, desmosterol, 5-cholesta-7,24-dien-3-ol, zymosterol (5-cholesta-8,24-dien-3-ol), 7-dehydrocholesterol (cholesta-5,7-dien-3-ol) and 7-dehydrodesmosterol (cholesta-5,7,24-trien-3-ol). Zymosterol and 5-cholesta-7,24-dien-3-ol were minor constituents (5–7% and 1–1.5% of total sterol, respectively). The 7-dehydrosterols represented approximately one-half (44–52%) of the total CNS sterol.