INHIBITION OF THE MONOOXYGENASE-DEPENDENT METABOLISM OF COUMARINS IN MAN AND MOUSE BY AZOLE ANALOGS OF METYRAPONE

Metyrapone is known as an inhibitor of cytochrome P450-dependent monoo xygenases which are involved in the metabolism of xenobiotics and ster oids (endobiotics) in mammals, and in that of ecdysteroids in insects. Recently, derivatives of A-phenyl-B-imidazolyl- and A-phenyl-B-triazo lyl-metyrapone were described to inhibit the development of insects. T hey show effective inhibitory actions against hydroxylating enzymes of Musca domestica, Diploptera punctata, and Neobellieria bullata. The a im was to find out if the metyrapone derivatives act selectively again st insects. Experiments with murine liver microsomes show that the met yrapone analogues are up to 50 times more potent with respect to the 7 -ethoxycoumarin O-deethylation than metyrapone. Their inhibitory poten cies in man are almost identical. With respect to the coumarin 7-hydro xylation, mouse is much more susceptible for the inhibitors than man, whereas compounds without alpha substituents enhance the coumarin 7-hy droxylation up to 20% in both species. It is remarkable that the antie cdysteroidal compounds show a greater affinity toward the insect targe t enzyme, namely the cytochrome P450-dependent ecdysone 20-monooxygena se, than toward mammalian microsomal monooxygenases. These facts clear ly indicate that it is possible to synthesize selective inhibitors of the key enzyme of the biosynthesis of the moulting hormone, 20-hydroxy ecdysone. Furthermore, it does not seem probable that sufficient amoun ts applied to insects affect mammalian (hepatic) monooxygenase systems . (C) 1996 Academic Press.