Die Hemmung der Riesenzellbildung durch das sogenannte Compound 48/80 nach der Infektion mit dem Herpesvirus hominis

Es wurde uber die Wirkung des Histamin-Liberators Compound 48/80 auf die Phasen der Synthese des Herpesvirus hominis und auf normale Zellstoffwechselprozessein vitro berichtet.

Differential inhibition of biphenyl hydroxylation in perfused rat liver

A differential inhibition of biphenyl hydroxylation by alpha-naphthoflavone and metyrapone was observed in isolated perfused rat liver. alpha-Naphthoflavone inhibited 2- and 4-hydroxylation in livers from beta-naphthoflavone-pretreated animals but had no effect on both reactions in livers from phenobarbital-pretreated animals. Metyrapone inhibited 2- and 4-hydroxylation in phenobarbital-stimulated livers, but only insignificant inhibition of 2-hydroxylation and a slight enhancement of 4-hydroxylation by metyrapone was observed in beta-naphthoflavone-stimulated livers. Conjugation of 2-hydroxybiphenyl and 4-hydroxybiphenyl by isolated perfused livers was also studied. 4-Hydroxybiphenyl prefe…

Wirkungen von Metyrapon auf den Arzneimittelstoffwechsel und einige andere Funktionen der Leberzelle

Arzneimittelaufnahme und -abbau w�hrend der Fetalperiode

Fur den mit dem Problem der Arzneitherapie wahrend der Schwangerschaft konfrontierten Arzt ergibt sich ein Bild, das noch erhebliche Erkenntnislucken aufweist. Man mus davon ausgehen, das jedes an die Mutter verabreichte Pharmakon und seine Metaboliten auch den Fetus erreichen, wenn auch in Konzentrationen, die haufig geringer sind als diejenigen im mutterlichen Blut. Da aber Starke und Art der Wirkung auf den Feten weitgehend unbekannt sind, mus man mit unvorhersehbaren Effekten auf den Feten rechnen. Der „Schutz“ durch die Stoffwechselleistung der vorgeschalteten Placenta ist nach den bisher vorliegenden Kenntnissen gering zu veranschlagen, zumal da der Fetus selber Pharmaka nicht inaktiv…

Pharmakologisch aktive Polymere, 14. Modellsysteme zur Untersuchung der Abspaltung niedermolekularer Komponenten von polymeren Pharmaka

Interrelationship between demethylation of p-nitroanisole and conjugation of p-nitrophenol in rat liver

The metabolism of p-nitroanisole (pNA) and p-nitrophenol (pNP) was studied in isolated rat livers perfused with a hemoglobin-free medium. The activity and viability of the surviving organ was tested by recording pH, “arterial” and “venous” oxygen tension as well as the disappearance of added pNP. pNA is converted to its primary metabolite pNP which, in turn, is excreted into the perfusion medium as conjugates. The coordination of pNA oxidation and the conjugation reactions of pNP were investigated. When 50 μM pNA is added as substrate 0.4±0.1 nmoles×ml−1×(g liver)−1 are excreted as pNP-glucuronide and 3.5±0.2 nmoles×ml−1×(g liver)−1 as the sulphate within 90 min. When pNP itself (50 μM) is …

The induction of hepatic microsomal metabolism in rats following acute administration of a mixture of polybrominated biphenyls.

Abstract Firemaster BP6, a mixture of polybrominated biphenyls (PBBs), was administered to female Sprague-Dawley rats (170–180 g) as a single ip injection at 25 and 150 mg/kg. Other animals received phenobarbital (PB), 3-methylcholanthrene (3MC), or PB and 3MC together. Animals were killed at intervals of 12, 24, 48, 192, and 336 hr after treatment with PBBs, or 24 hr after PB, MC, or PB-MC, and various hepatic microsomal parameters were measured. After 150 mg/kg of PBBs, cytochrome P450 concentrations reached a maximum by 48 hr (225% of control), then remained elevated through 336 hr. A similar pattern of induction was observed for epoxide hydratase and aniline hydroxylase activities. In c…

Significance of Induction Phenomena

A number of foreign compounds induce the proliferation of the hepatic smooth endoplasmatic reticulum and thereby increase the activity of monooxygenases that metabolize drugs and other foreign compound. With reference to the safety of food additives some antioxidants have been examined by various authors for their inducing capacity, in doses well above those ingested with treated food and above the stipulated accepted daily intake (ADI). Thus feeding of rats with the very high dose of 500 mg/kg body weight of butylated hydroxtoluene (BHT) resulted in an increase in its own oxidative metabolism. Also in monkeys BHT produces an inductive increase of microsomal enzyme activity, cytochrome P 45…

Kinetic experiments on the binding of metyrapone to liver microsomes

Kinetic experiments on the inhibition of oxidative microsomal O- and N-demethylations by metyrapone (2-methyl-1, 2-bis(3-pyridyl)-l-propanone, Su 4885) were carried out using mouse liver microsomes as the enzyme source. The model substrates were p-nitroanisole and N-monomethyl-p-nitroaniline. It was shown that the inhibition is competitive. The K i for metyrapone is 0.42 × 10−4 M and for the reduced metabolite of metyrapone 1.15×10−4 M. Their spectral dissooiation constants as determined from difference spectra have almost the same values. From this it is concluded that the degree of inhibition is correlated to the amount of metyrapone bound to cytochrome P-450. Metyrapone does not seem to …

A novel haemoprotein induced by isosafrole pretreatment in the rat

Abstract Sodium dodecyl sulphate-polyacrylamide gel electrophoresis has been used to demonstrate that pretreatment of rats with isosafrole results in the formation of a novel species of cytochrome P-450 (mol. wt. 54,000) quite distinct from that induced by phenobarbitone pretreatment (mol. wt. 50,000) or 3-methylcholanthrene (mol. wt. 58,000).

Ethoxyquin as an inducer and inhibitor of phenobarbital-type cytochrome P-450 in rat liver microsomes.

Abstract The effect of ethoxyquin in vivo and in vitro on drug metabolism in rat liver microsomes was studied. In feeding experiments, a threshold dose of induction was found at 0.05% ethoxyquin for 14 days. At 0.5% ethoxyquin, relative liver weight, cytochrome P-450 content, cytochrome b5 content, ethylmorphine demethylation, and ethoxycoumarin deethylation were increased by a factor of 1.5 to 2. Aryl hydrocarbon hydroxylase activity was, however, not induced but even decreased by 0.5% ethoxyquin in food. Induction of epoxide hydratase was marked, amounting to 400% of control after 0.5% ethoxyquin. The induced enzyme was similar to the phenobarbital-inducible cytochrome P-450 in its CO spe…

SEX DIFFERENCES IN THE PATTERN OF CYTOCHROMES P-450 IN RAT LIVER MICROSOMES

ABSTRACT A number of sex differences in the spectral and enzymic properties of rat liver microsomes have been observed which may reflect differences in the population of hepatic cytochromes P 450 of male and female rats: 1. a blue shift in the spectrum of the reduced P 450-CO complex in females as compared to males, 2. lower ΔA max values in the binding of metyrapone to reduced microsomes in females as compared to males, 3. a higher proportion of 2-hydroxylation in the metabolism of biphenyl in females as compared to males, 4. preferential inhibition of ethoxycoumarin deethylation, benzpyrene hydroxylation and biphenyl-4-hydroxylation by α-naphthoflavone in females but by metyrapone in male…

Verleihung des Fritz-K�lz-Preises 1969

Kinetic experiments on the synergistic effect of NADH on microsomal drug oxidation.

Abstract1. The synergistic effect of NADH on the NADPH-dependent mixed function oxidation of p-nitroanisole and hexobarbital can be measured both photometrically and by following the substrate-induced oxygen consumption. The increase in reaction rate is about 50% and lasts as long as NADH is present in the microsomal suspension.2. The oxidation of added NADH is increased by hexobarbital, ethylmorphine and SKF 525-A. Lineweaver-Burk transformation of the NADH oxidation rates yields straight lines for xenobiotic substrates suggesting Michaelis constants similar to those obtained from metabolic experiments. NADH oxidation in the absence of NADPH is about half as rapid as in its presence.3. Som…

On the spectral intermediate at 440 nm formed during mixed function substrate oxidation.

Abstract The spectral shoulder formed at 440 nm in microsomes oxidising hexobarbital and other drugs has been investigated and some of its properties characterised. Hexobarbital, pentobarbital, ethylmorphine and barbital produce this shoulder, while acetanilide, aniline, desmethylimipramine, imipramine, metyrapone and SKF 525-A do not. The formation of the 440 nm shoulder depends on the presence of NADPH and oxygen and is reduced in size when NADH is also present. At saturating substrate concentrations the size of the 440 nm shoulder is correlated to the cytochrome P-450 content. The hexobarbital induced shoulder can be inhibited by drug metabolism inhibitors such as metyrapone, imipramine …

Fluorimetrische Messungen zur Naphthalin-Hydroxylierung

Effect of polybrominated biphenyls on bromobenzene lethality in mice.

Polybrominated biphenyls (PBBs) are inducers of hepatic microsomal cytochrome P450 and P1 450 in rats and mice. The purpose of this study was to determine, in mice, the effect of PBBs on the lethality of the hepatotoxin bromobenzene. Female NMRI mice were administered a single ip injection of 150 mg/kg PBBs and other mice received phenobarbital (PB), 100 mg/kg daily for 3 days, or 3‐methylcholanthrene (MC), 20 mg/kg daily for 3 days. At 24 hr after PB or MC and 24, 48, and 96 hr after PBBs animals received 3,150 mg/kg bromobenzene ip (LD85) and the time to death was recorded. Both PB and MC enhanced bromobenzene lethality and decreased the median time to death (LT50) from 23 hr in controls …

Influence of disulfiram on oxidative drug demethylation.

In clinical antiepileptie therapy it has been observed that the simultaneous administration of diphenylhydantoin and various other drugs causes toxic reactions to diphenylhydantoin. I t was found that disulfiram (Olesen, 1966) as well as ehloramphenieol (Christensen and Skovsted, 1969) cause toxic effects in patients treated with diphenylhydantoin. They are attributed to an increased concentration of diphenylhydantoin in the plasma. Analogous observations show that chloramphenieol enhances the clinical effects of tolbutamide and dicoumarol (Christensen and Skovsted, 1969). Since diphenylhydantoin is metabolized chiefly by p-hydroxylation to 5-(p-hydroxyphenyl)-5-phenyl-hydantoin (Butler, 19…

Measurement of substrate-induced oxygen uptake during microsomal drug oxidation using a gold micro-electrode.

1. A resin-coated gold micro-electrode has been used for polarographic determination of oxygen concentration in liver microsomal suspensions from phenobarbital-pretreated rats. 2. The rate of oxygen uptake on addition of an NADPH-regenerating system and the rate after addition of various substrates of the mixed function oxidase system were measured. The rate of oxygen uptake was faster in the presence of substrate than in the presence of NADPH alone. 3. Kinetic constants (Km and V max) for biphenyl, hexobarbital, ethylmorphine, naphthalene and SKF 525-A measured by this technique compare favourably with those obtained either by measurements of NADPH oxidation, or chemical measurements of su…

Zur Bildung hydroxylierter Zwischenprodukte bei der mikrosomalen Fremdstoffoxydation / On the Possible Formation of Hydroxylated Intermediates during Microsomal Drug Oxidation

Die oxydative Abspaltung von O-Methylgruppen ist eine haufig anzutreffende Arzneimittelabbaureaktion. Als Beispiel fur diesen Reaktionstyp diente uns die Demethylierung von p-substituierten Anisolen. Als instabiles Zwischenprodukt dieser Reaktion wurde schon lange eine C6H5−O−CH2OH-Gruppierung angenommen und 1965 von Renson et al. [1] wahrscheinlich gemacht durch 018-Einbauversuche an p-Methoxyacetanilid. Wenn diese Vorstellung richtig ist, mus das Ausmas der Abspaltung der Hydroxymethylgruppe als Formaldehyd von den Elektronen-aufnehmenden oder -abgebenden Eigenschaften eventueller p-Substituenten des Benzolrings abhangen: p-Nitroanisol mus Formaldehyd verlieren, wahrend sich bei p-Methyla…

Gemeinsame Tagung der Italienischen und Deutschen Pharmakologischen Gesellschaften Vom 27.?30. September 1970 in Heidelberg (33. Tagung der Deutschen Pharmakologischen Gesellschaft)

Untersuchungen zur mikrosomalen Naphthalinhydroxylierung

Die Hydroxylierung aromatischer Ringverbindungen durch mikrosomale Enzymsysteme wurde am Beispiel des Naphthalins untersucht. Als Parameter fur die Aktivitat wurde die Abnahme der Naphthalinkonzentration nach Ausschutteln in Butanol fluorimetrisch gemessen. Die Umsatzgeschwindigkeit von Naphthalin war hoher als die von p-Nitroanisol wahrend seiner oxydativen O-De-methylierung. Dies stimmt mit der Beobachtung einer kleineren Michaeliskonstanten fur Naphthalin uberein. Die Naphthalinhydroxylierung last sich durchVorbehandlung der Tiere mit DDT und Phenobarbital in ahnlicher Weise steigern wie die O-Demethylierung von p-Nitroanisol. Mausemikrosomen lassen sich durch DDT nicht stimulieren.

�ber die Wirkung von Metyrapon auf den mikrosomalen Arzneimittelabbau

The inhibitor of adrenal steroid-11-β-hydroxylation, Metyrapone (SU 4885), also decreases the rate of drug hydroxylation reactions, both in vitro and in vivo. The follwing oxidative microsomal reactions were studied: O-demethylation of p-nitroanisole, N-demethylation of amidopyrine, and ring hydroxylation of acetanilide. In all three cases Metyrapone inhibits the formation of the reaction products. The inhibitor concentrations required for reduction of the initial reaction rates to one half are 7.5 · 10−4 M, 5 · 10−4m and 20 · 10−4 M, respectively. Steroid C-11-β-hydroxylation is reduced to one half by 2.5 · 10−4 M Metyrapone.