Inhibition of the Monooxygenase-Dependent Metabolism of Coumarins in Man and Mouse by Azole Analogues of Metyrapone

Abstract

Metyrapone is known as an inhibitor of cytochrome P450-dependent monooxygenases which are involved in the metabolism of xenobiotics and steroids (endobiotics) in mammals, and in that of ecdysteroids in insects. Recently, derivatives of A-phenyl-B-imidazolyl- and A-phenyl-B-triazolyl-metyrapone were described to inhibit the development of insects. They show effective inhibitory actions against hydroxylating enzymes ofMusca domestica, Diploptera punctata,andNeobellieria bullata.The aim was to find out if the metyrapone derivatives act selectively against insects. Experiments with murine liver microsomes show that the metyrapone analogues are up to 50 times more potent with respect to the 7-ethoxycoumarin O-deethylation than metyrapone. Their inhibitory potencies in man are almost identical. With respect to the coumarin 7-hydroxylation, mouse is much more susceptible for the inhibitors than man, whereas compounds without alpha substituents enhance the coumarin 7-hydroxylation up to 20% in both species. It is remarkable that the antiecdysteroidal compounds show a greater affinity toward the insect target enzyme, namely the cytochrome P450-dependent ecdysone 20-monooxygenase, than toward mammalian microsomal monooxygenases. These facts clearly indicate that it is possible to synthesize selective inhibitors of the key enzyme of the biosynthesis of the moulting hormone, 20-hydroxyecdysone. Furthermore, it does not seem probable that sufficient amounts applied to insects affect mammalian (hepatic) monooxygenase systems.