1. A class of strong inhibitors of microsomal monooxygenases: the ellipticines.
- Author
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Lesca P, Rafidinarivo E, Lecointe P, and Mansuy D
- Subjects
- Aminopyrine N-Demethylase antagonists & inhibitors, Aniline Hydroxylase antagonists & inhibitors, Animals, Benzopyrene Hydroxylase antagonists & inhibitors, Cytochrome P-450 Enzyme System metabolism, Dealkylation, Kinetics, Male, Microsomes, Liver enzymology, Rats, Alkaloids pharmacology, Ellipticines pharmacology, Microsomes, Liver drug effects, Mixed Function Oxygenases antagonists & inhibitors, Oxidoreductases antagonists & inhibitors
- Abstract
Ellipticine (E) and its 9-hydroxy derivative inhibit strongly various liver monooxygenase activities mediated by microsomes from control and phenobarbital (PB), benzo[alpha]pyrene (BP) or Aroclor 1254 (Aroclor)-pretreated rats. The inhibition constants, Ki, are remarkably low, and often smaller than 1 micron, particularly in the case of microsomes containing cytochrome P-448. The inhibitory potency (I50) of 9-hydroxyellipticine (9-OHE) is larger (about ten-fold) than the one of classical inhibitors (metyrapone or 7,8-benzoflavone (7,8-BF)), whatever the activities studied and the induction of microsomes. Differences exist between the mechanisms of inhibition according to the form of cytochrome P-450 present in microsomes of differently pretreated rats; whichever the activities studied, one observes: (a) a competitive inhibition towards the activity of non-induced or PB-induced microsomes and (b) a non-competitive inhibition towards the activity of Aroclor or BP-induced microsomes, at variance with 7,8-BF. These results are in good agreement with the interaction properties of the ellipticines with microsomal cytochromes P-450.
- Published
- 1979
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