Structure-activity relationships in the inhibitory effects of ellipticines on benzo(a)pyrene hydroxylase activity and 3-methylcholanthrene mutagenicity
| Autor: | D. Pelaprat, Pierre Lesca, Daniel Mansuy, C. Paoletti, Pierre Lecointe |
|---|---|
| Rok vydání: | 1980 |
| Předmět: |
Male
Cytochrome Stereochemistry In Vitro Techniques Biochemistry Ames test Hydroxylation Ellipticines chemistry.chemical_compound Structure-Activity Relationship Alkaloids Cytochrome P-450 Enzyme System Animals Benzopyrene Hydroxylase Pharmacology biology Carcinogen Metabolism Rats chemistry Methylcholanthrene biology.protein Microsome Microsomes Liver Pyrene Aryl Hydrocarbon Hydroxylases Mutagens |
| Zdroj: | Biochemical pharmacology. 29(24) |
| ISSN: | 0006-2952 |
| Popis: | The structural features which determine the ability of ellipticine (5,11dimethyl6Hpyrido[4-3b] carbazole) and its derivatives to interact with cytochrome P-450 and to inhibit rat liver microsomal benzo(a)pyrene hydroxylase as well as to inhibit the mutagenicity of 3-methylcholanthrene have been studied. Spectral interactions studies were carried out with either Aroclor 1254-, 3-methylcholanthrene-or phenobarbital-induced microsomes. Inhibitory activities towards benzo(a)pyrene hydroxylase and 3-methylcholanthrene mutagenicity (Ames test), were determined using Aroclor 1254-induced microsomes. It appears that every ellipticine derivative having significant inhibitory effects on hydroxylation of benzo(a)pyrene or mutagenicity of 3-methylcholanthrene also exhibits a very good affinity for microsomal cytochromes P-450. The accessibility of the pyridinic nitrogen of ellipticine derivatives appears as the most important factor for their binding to cytochromes P-450 and the presence of methyl groups in 5 and 11 positions of ellipticine derivatives is an essential condition for the expression of the inhibitory power. Various substitutions in the A ring of ellipticine appear to be of secondary importance. On the other hand the location of the pyridinic ring and consequently the arrangement of the molecule within the hydrophobic pocket of cytochrome P-450 seems also to play an important role in the inhibitory power since isoellipticines are devoid of such properties. These results should help in the design of particularly efficient inhibitors of drug and carcinogen metabolism. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|