Qualitative �nderungen in Lebermikrosomen Phenobarbital-behandelter Kaninchen

Kröber, F.; Lange, G.; Mathes, Stephanie; G, Mor

doi:10.1007/bf00999545

Naunyn-Schmiedebergs Arch. Pharmak.

1970

DOI: 10.1007/bf00999545

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Qualitative �nderungen in Lebermikrosomen Phenobarbital-behandelter Kaninchen

F. Kröber

G. Lange

Stephanie Mathes

et al.

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1972

1976

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Cited by 10 publications

(1 citation statement)

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“…The subsequent reactions in liver microsomes, drug hydroxylation and glucuronidation, are induced by phenobarbital (phenemalum NFN) and 3-methylcholanthrene conceivably by different mechanisms (AITIO VAINIO 1973;VAINIO et al 1973;for reviews see CONNFY 1967;REMMER 1972). Phenobarbital has been shown to cause an increase in liver weight ( KUNZ et al 1966), and in the lipid ( ORRENIUS et al 1965;SCHULZB & STAUDINGER 1970;KROBER et al 1970;YOUNG et al 1971) and protein tent of the hepatic microsomes. Polycyclic hydrocarbons increase liver size with a proportionate increase in total liver protein ( ARCOS et al 1961).…”

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confidence: 99%

Enhancement of Microsomal Drug Hydroxylation and Glucuronidation in Rat Liver by Phenobarbital and 3‐Methylcholanthrene in Combination

Vainio

Aitio

1974

Acta Pharmacologica et Toxicologica

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Absrruct:Both 3-methylcholanthrene and phenobarbital increased the O-demethylation of p-nitroanisole in rat liver microsomes (%fold and &fold, respectively), whereas 3-methylcholanthrene alone was able to enhance the aryl hydrocarbon hydroxylase activity (13-fold). When the inducers were administered to rats in combination, the enhancement in p-nitroanisole 0-demethylase activity was greater and in aryl hydrocarbon hydroxylase was smaller than when administered singly. Both 3-methylcholanthrene and phenobarbital also enhanced the microsomal UDP glucuronyltransferase activity when measured after in vitro activation of the latent enzyme. The pretreatment of rats with the combination brought about no additional effect, when calculated on a microsomal protein basis. If calculated on 100 gram of body weight basis, however, an additive effect was observed in UDP glucuronyltransferase activity due to the effects of the inducers on the liver weight-body weight ratio.

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confidence: 99%

Enhancement of Microsomal Drug Hydroxylation and Glucuronidation in Rat Liver by Phenobarbital and 3‐Methylcholanthrene in Combination

Vainio

Aitio

1974

Acta Pharmacologica et Toxicologica

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Active centers of microsomal cytochrome P-450 determined with metyrapone by mutual depletion system kinetics

Roots

Hildebrandt

1973

Naunyn-Schmiedeberg's Arch. Pharmacol.

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Effects of enzyme induction and inhibition on microsomal oxidation of 1,4-benzodiazepines

Sadée

et al. 1976

Naunyn-Schmiedeberg's Arch. Pharmacol.

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Metabolic oxidative profiles of diazepam (I) were obtained by aromatic C-4'-hydroxylation, N-1-demethylation, and 3-hydroxylation using a supernatant of rat liver. Incubation of 3-methyldiazepam (VI), which suppressed 3-hydroxylation, and N-1-nor-3-methyldiazepam (VII), were used to separately investigate these three oxidative pathways. Treatment of animals with phenobarbital enhanced N-1-demethylation and 3-hydroxylation, and to a variable extent C-4'-hydroxylation. Application of metyrapone reduced metabolite formation by 3-hydroxylation and N-1-demethylation, but had no effect on C-4'-hydroxylation. Metyrapone inhibition was more pronounced following than prior to phenobarbital treatment. C-2-hydroxylation was studied using medazepam (XX) incubations. This pathway was increased by phenobarbital pretreatment and reduced by metyrapone inhibition which was again more pronounced following than prior to phenobarbital pretreatment. These results support earlier conclusions on the heterogeneity of liver microsomes and suggests the presence of different species of hepatic microsomal terminal oxidases. Phenobarbital treatment and metyrapone change the metabolic profile via induction and inhibition, respectively, and, thus, in the case of 1,4-benzodiazepines, the formation of metabolites with varying pharmacological activity. This could become important in clinical situations as a diagnostic mean to determine induction under various treatment or, possibly, during cumulation of metabolites with a long half-life.

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Qualitative �nderungen in Lebermikrosomen Phenobarbital-behandelter Kaninchen

Cited by 10 publications

References 34 publications

Enhancement of Microsomal Drug Hydroxylation and Glucuronidation in Rat Liver by Phenobarbital and 3‐Methylcholanthrene in Combination

Enhancement of Microsomal Drug Hydroxylation and Glucuronidation in Rat Liver by Phenobarbital and 3‐Methylcholanthrene in Combination

Active centers of microsomal cytochrome P-450 determined with metyrapone by mutual depletion system kinetics

Effects of enzyme induction and inhibition on microsomal oxidation of 1,4-benzodiazepines

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