Diether Neubert

Vergleichende Untersuchungen der oxydativen Leistungen von Mitochondrien und Mikrosomen bei experimenteller Leberschdigung

Summary1. The influence of experimental liver injury has been compared on distinct enzymatic oxidations in microsomes and mitochondria. Oxidative reactions in these two cellfractions can be damaged independently on each other. There is no rule that the energy supplying oxidative system in mitochondria is inhibited earliest.2. Inhibition of O2-consumption or oxidative phosphorylation can not be observed in all cases of experimental induced fatty degeneration of liver.Uncoupling of respiration and phosphorylation is neither the general cause nor the unavoidable consequence of fatty degeneration.1. The influence of experimental liver injury has been compared on distinct enzymatic oxidations in microsomes and mitochondria. Oxidative reactions in these two cellfractions can be damaged independently on each other. There is no rule that the energy supplying oxidative system in mitochondria is inhibited earliest.

Pharmakologische Untersuchungen bei der experimentellen Leberverfettung

Summary1. Remarkable quantitative differences exist between both sexes in the fatty degeneration of liver during the acute toxic action of ethionine in rats. It has been investigated by extraction and gravimetric estimation of the liver-fat whether similar sex-differences in fatty-degeneration appear after application of other agents which are toxic to the liver.After administration of CCl4, phosphorus and in fatty degeneration induced by diet the concentration of fat in the liver of females is higher than in males.Even in untreated rats there is a trend to this difference of sex. The more pronounced deposition of fat in the liver appears to be a common property of female rats rather than attributable to the specific action of ethionine.2. In all kinds of fatty degeneration examined the activity of an enzyme-system has been deminished which is situated in liver microsomes and involved in the break-down of certain drugs.There is no evidence for a clear cut quantitative relation between fatty degeneration and enzyme-substitution.3. The effects of derivatives of phenyl-ethyl-acetic acid upon the concentration of fat and cholesterol in the liver has been studied and the meaning of the results is discussed.4. The enzyme-system of liver microsomes can be inhibited in vivo by esters of phenyl-acetic acid only (CFT 1201, SKF 525 A) wheras in vitro the acid component of CFT 1201 is as effective. The sodium salt of phenyl-ethyl-acetic acid however does not inhibit.

Der Acetylcholingehalt des Gehirns bei verschiedenen Funktionszuständen

Acetylcholin wurde im Zentralnervensystem von Warmblfitern mit chemischen und biologischen Methoden einwandfrei nachgewiesen. Diese Befunde gaben den AnlaB zu einer grolten Zahl voa Untersuchungen, die sich mit der Bedeutung dieser Substanz ffir den Ablauf zentralnervfser Funkt ionen befa[~ten. Sowohl erregende als auch hemmende zentrale Wirkungen des Acetylcholins wurden beschrieben. Die komplizierte funktionelle Struktur des Zentralnervensystems und die gro~en Unterschiede in der Empfindlichkeit der verschiedenen zentralen Regionen erschwerten die Deutung der Befunde, so da~ bis heute noch kein endgfiltiger Beweis vorliegt, ob Acetylcholin ffir Funktionsi~nderungen im Zentralnervensystem die gleiche Bedeutung hat, die O. LOEWI bei seinen grundlegenden Untersuchungen fiber humorale (~bertragbarkeit der Herznervenwirkung entdeckt hat. So war es verst~ndlich, da~ eine Arbeit von D. RICHTER u. J. CROSSLAND viel Beachtung land, in der Zusammenh~nge zwischen Funktions~nderungen des Gehirns und seinem Gehalt an Acetylcholin mi t besonderer lgethodik ermittelt wurden. Die Verfasser t f t e t en die Versuchstiere durch Einbringen in flfissige Luft, wobei sie den Vorteil des Verfahrens in der schnellen Fixierung des Gehirns und dem damit verbundenen schlagartigen Stillstand aller fermentat iven Vorg~nge in den Gehirnzellen sahen. I m Zusammenhang mit unseren eigenen Untersuchungen fiber die chemische Differenzierung der Wirkung von Krampfgif ten mit Hexachlorcyclohexanen (H. HERKEN, H. KEWITZ, I. KLEMPAU, 1952) interessierte besonders die Feststellung, da~ RICHTER U. CROSSLAND im Krampfzustand sehr niedrige Acetylcholinwerte des Gehirns fanden. Sie wurden von den Autoren so gedeutet, dab die Synthese des Acetylcholins mit dem Verbrauch w~hrend der Kri~mpfe nicht Schritt h~lt. Die Konvulsionen sollen dadurch zum Stillstand kommen, da~ Acetylcholin nicht mehr in genfigender Menge zur Verffigung steht. Demnach

Intracellulre Lokalisation von Fettsubstanzen bei experimenteller Leberverfettung

The intracellular localization of lipids in the rat liver cells has been studied. Fatty degeneration of liver was developed by yellow phosphorus, carbon tetrachloride, ethionine, rare earths, infection, β-diethylaminoethylphenyldiallylacetate (CFT 1201) and a special diet.SummaryThe intracellular localization of lipids in the rat liver cells has been studied. Fatty degeneration of liver was developed by yellow phosphorus, carbon tetrachloride, ethionine, rare earths, infection, β-diethylaminoethylphenyldiallylacetate (CFT 1201) and a special diet.In general fatty degeneration has been combined with an increased concentration of lipids in the microsomal fraction. Certain experimental conditions (CFT 1201, rare earths) also produce a high lipide content in the mitochondria.The significance of these results is discussed.

Die enzymatische N-Demethylierung durch Leber-Mikrosomen bei der Morphin-Gewhnung

SummaryThe observation of Komlós has been confirmed that in morphine tolerance the effect of morphine can be increased by CCl4. This action is certainly not based on the „abolishment of tolerance“ but caused by the deminished inactivation in liver which does not depend on tolerance.The effectiveness of certain phenylacetic acid-derivatives to increase the analgesic action of morphine and similar acting substances is not correlated to the inhibition of enzymatic N-demethylation which they cause in liver microsomes.Morphine-tolerance is frequently combined with decreased N-demethylation but there is no close relation between these reactions as Axelrod assumed. In a few cases of pronounced tolerance we found that the N-demethylating ability of the liver was quite normal. If there is a decreased N-demethylation it is not limited to morphine and compounds which show a „crossed tolerance“ with morphine but is also observed with substances like cocaine and dimethylaminoantipyrine. Therefore it is not possible to use the studied enzyme systems as a „model“ for the processes which occurs at the receptors of the morphine action in brain.Even with brain tissue of rats a rather small but remarkable demethylation of Pethidin has been demonstrated. The possible significance of this observation is discussed.

Der Einflu von thionin und anderen Lebergiften auf Fermentsysteme der Lebermikrosomen

SummaryThe activity of enzyme-systems located in liver microsomes which take part in the metabolism of several drugs has been tested during injury of liver experimentally caused.In ethionine-poisoned rats the sleeping time after Hexobarbital administration is markedly increased. This effect is due to the decreased enzymeactivity in the microsomes of liver cells. The action is of no specific significance because quite different kinds of liver injury f.i. caused by carbon tetrachloride or yellow phosphorus lead as well to an impairment of enzyme function.Little effect occurs after application of allyl-alcohol.The enzyme-system investigated is thought to be of no importance according to conversion or detoxification of ethionine.The activity of enzyme-systems located in liver microsomes which take part in the metabolism of several drugs has been tested during injury of liver experimentally caused.

Wirkungsverlust des Dithyl-p-Nitrophenylphosphats und Oktamethylphyrophosphoramids nach Vorbehandlung mit ?-Hexachlorcyclohexan

Pretreatment with β-hexachlorcyclohexane in mice yields a protection against inhibitors of acetylcholinesterase as Paraoxon and OMPA after a latency of some days.SummaryPretreatment with β-hexachlorcyclohexane in mice yields a protection against inhibitors of acetylcholinesterase as Paraoxon and OMPA after a latency of some days.Besides a lowering in toxicity there is a much smaller inhibition of cholinesterase in brain and skeletal muscle in pretreated animals compared to the controls, which received the anticholinesteratic drug only.Under the same experimental conditions no differences between the activities in serum, diaphragm and heart muscle could be observed.This protective effect is probably due to a reactivation of the inhibited enzyme by physiological metabolites, which cumulate during HCH treatment.Similiar distinct effects against the poisoning with DFP could not be found.These results lead to the conclusion, that HCH has not only an effect on the central nervous system but also on peripheral organs, like muscle.Therefore the protective effect of HCH against anticholinesterases will mainly depend on the reactivation of the inhibited enzyme in the periphery, while that against convulsant drugs takes place in some parts of the central nervous system.

Eigenwirkungen radioaktiven Phosphates (P32) auf oxydative Leistungen von Mitochondrien und Mikrosomen der Rattenleber

SummaryThe influence of high doses of intraperitoneally applicated radioactive phosphorus (1; 10; 12; 15 mC/kg) on the oxidative processes of microsomes and mitochondria of rat liver has been investigated. — It could be shown, that 16–18 hrs after the injection of 15 mC/kg P32 the oxidative phosphorylation is not impaired. Whereas the ability of the liver microsomes is diminished to N-demethylate dimethylaminoantipyrine. Even as low doses as 1 mC/kg have a clearcut effect. Histological changes could only be observed in the seminal epithelium. — The significance of a possible disturbance of important metabolic steps by the application of P32 is stressed.

Aktivität einiger TPN-bedürftiger, leberspezifischer Fermentsysteme in der „Mikrosomen“-Fraktion eines experimentellen Ratten-Hepatoms

SummaryIt has been tested wether the microsomes of a hepatome of a rat are still able to oxydize drugs like normal livermicrosomes do.We tested oxydation of side-chains, hydroxylations and various N-and O-demethylations. Among these breakdown-reactions the N-demethylation of cocain has been the only one left but it was on a lower level.As far as the dependence on TPNH and O2 is concerned or the localization within the microsomes or the blockade by certain derivatives of phenyl-acetic-acid-derivatives like CFT 1201 the cocain-demethylating system equals other demethylating groups of enzymes.Obviously, there are more than one enzyme-system within the microsomes which catalize oxydative N-demethylations. Individual enzymes may be damaged whereas others can still be active under the same conditions.A tumor in the rat-liver leads like several other disturbances to a fall of breakdown-activities located in the microsomes.

Ausscheidung von C14-Succinyl-bis-cholin und seiner Spaltprodukte Succinyl-mono-cholin und Cholin im Urin der Ratte

SummaryIt is reported on the excretion of radioactive succinyldicholine and its degradation products in the urine of the rat after intraperitoneal application. The compounds could easily be separated from each other by the means of high-voltage paper electrophoresis. The muscle relaxing drug had been synthesized by incorporating C14-methyljodide into the bis-dimethylaminoethylester of succinic acid. — Less than 15% of the activity injected was excreted thirty minutes after its application. Nearly equal amounts of succinyl-mono-choline and succinyl-di-choline could be shown to appear in the urine of the animals, choline could not be detected. — It was concluded that the rate of hydrolysis of succinyldi-choline had to be smaller than generally supposed.