Cholesterol biosynthesis in transplantable hepatomas: evidence for impairment of uptake and storage of dietary cholesterol

Cholesterol feeding inhibits cholesterol biosynthesis in normal but not in malignant liver tissue. It has been postulated that hepatomas have suffered a specific intracellular deletion of the cholesterol feedback control mechanism, but there is little direct evidence to support this hypothesis. Rats bearing Morris transplantable hepatomas were fed high cholesterol diets for periods of up to 21 days. Cholesterol biosynthesis, as expected, was suppressed in the normal liver but not in hepatomas. The livers accumulated large amounts of cholesteryl ester but the hepatomas showed little or no increase in ester content. Cholesterol-1alpha-(3)H was administered intragastrically to other tumor-bearing rats. Uptake of radioactivity by the tumors was much slower than by normal liver. Comparison of the specific activities of liver and tumor cholesterol with that of the plasma suggested that the liver took up dietary cholesterol selectively from the blood, while the appearance of radioactivity in the tumors could be explained by slow equilibration with plasma cholesterol. Our results suggest that the insensitivity of cholesterol biosynthesis to dietary cholesterol in hepatomas could be explained by an impairment in the uptake and storage of dietary cholesterol and that the concept of an intracellular deletion of the feedback mechanism requires further evidence.     

Autoradiographische Untersuchungen über die Hemmung der Noradrenalin-Aufnahme durch Desmethylimipramin und Normetanephrin

Zusammenfassung Die Aufnahme von i. v. injiziertem ¹⁴C- und ³H- markiertem Noradrenalin (10–400 g/kg Körpergewicht) wurde an Ratten a) nach Verabreichung von Desmethylimipramin und b) von Normetanephrin autoradiographisch untersucht. a) Desmethylimipramin-HCl (2–40 mg/kg Ratte) bewirkte eine starke Hemmung der intraneuralen Aufnahme und Stapelung von Noradrenalin. Trotzdem wurden das Myokard und andere extraneurale Organgewebe radioaktiv markiert. b) Normetanephrin (33 mg/kg Körpergewicht) verminderte lediglich die Aufnahme von radioaktiv markiertem Noradrenalin in die Myokardfasern, während die intraneurale Aufnahme unbeeinflußt blieb. Beide Substanzen verbesserten die periphere Durchblutung nach toxischen Dosen von Noradrenalin.

---

Inhibition of the uptake of norepinephrine by desmethylimipramine and normetanephrine, an autoradiographic investigation

Summary The uptake of ¹⁴C- or ³H-labelled norepinephrine (dose 10 to 400 g/kg body weight) injected intravenously into rats was studied after the application a) of desmethylimipramine and b) of normetanephrine by autoradiography. a) Desmethylimipramine-HCl (2–40 mg/kg body weight) caused a strong inhibition of the intraneuronal uptake and storage of norepinephrine. b) Normetanephrine (dose 33 mg/kg body weight) on the other side diminished only the uptake into the myocardial fibers without an effect of the intraneuronal uptake. Both substances, desmethylimipramine and normetanephrine, improved the peripheral circulation after toxic doses of norepinephrine.

---

---

Die Untersuchungen wurden mit Unterstützung durch das Bundesministerium für Wissenschaft und Forschung durchgeführt. Ein vorläufiger Bericht wurde schon anläßlich der 34. Tagung der Deutschen Physiologischen Gesellschaft (Mainz 27.–29.3.1968) sowie auf der 6. Jahrestagung der Gesellschaft für Nuclearmedizin (Wiesbaden 26.–28.9.1968) gegeben (vgl. Leder u. Harms, 1968 a, b). Wesentliche Teile der Arbeit wurden von Herrn E. Harms der Medizinischen Fakultät i. Br. als Dissertation eingereicht.     

Effect of Diurnal Temperature Cycles on the Production of Aflatoxin

Exposures to short periods of high temperature (40 to 50 C) in each 24-hr diurnal temperature cycle (average temperature ca. 25 C) reduced growth of Aspergillus parasiticus and production and accumulation of the aflatoxins when compared with cultures held continuously at 25 C. In contrast, diurnal cycles with an average temperature of ca. 25 C but with minima as low as 10 C did not appreciably affect either growth or toxin production. The ratio of production of aflatoxin B to aflatoxin G increased as the maximal temperature was raised but remained essentially unchanged with decreasing minimal temperatures.     

Quantification of propranolol enantiomers in small blood samples from rats by reversed-phase high-performance liquid chromatography after chiral derivatization

A high-performance liquid chromatographic (HPLC) technique is described for quantification of R(+)- and S(−)-propranolol from 100-μl rat blood samples. The procedure involves chiral derivatization with tert.-butoxycarbonyl- -leucine anhydride to form diastereomeric propranolol- -leucine derivatives which are separated on a reversed-phase HPLC column. The method as previously reported has been modified for assaying serial blood microsamples obtained from the rat for pharmacokinetic studies. An internal standard, cyclopentyldesisopropylpropranolol, has been incorporated into the assay and several derivatization parameters have been altered. Standard curves for both enantiomers were linear over a 60-fold concentration range in 100-μl samples of whole rat blood (12.5–750 ng/ml; r=0.9992 for each enantiomer). Inter- and intra-assay variability was less than 12% for each enantiomer at 25 ng/ml. No enantiomeric interference or racemization was observed as a result of the derivatization. No analytical interference was noted from endogenous components in rat blood samples. Preliminary data from two male Sprague-Dawley rats given a 2.0 mg/kg intravenous dose of racemic propranolol revealed differential disposition of the two enantiomers. R(+)-Propranolol achieved higher initial concentration but was eliminated more rapidly than S(−)-propranolol. Terminal half-lives of R(+)- and S(−)-propranolol were 19.23 and 51.95 min, respectively, in one rat, and 14.50 and 52.07 min, respectively, in the other.     

Down''s Syndrome Individuals Begin Life with Normal Levels of Brain Cholinergic Markers

We measured the activities of the cholinergic marker enzymes choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in autopsied brains of seven infants (age range 3 months to 1 year) with Down's syndrome (DS), a disorder in which virtually all individuals will develop by middle age the neuropathological changes of Alzheimer's disease accompanied by a marked brain cholinergic reduction. When compared with age-matched controls cholinergic enzyme activity was normal in all brain regions of the individuals with infant DS with the exception of above-normal activity in the putamen (ChAT) and the occipital cortex (AChE). Our neurochemical observations suggest that DS individuals begin life with a normal complement of brain cholinergic neurons. This opens the possibility of early therapeutic intervention to prevent the development of brain cholinergic changes in patients with DS.