Summary
Kinetic experiments on the inhibition of oxidative microsomal O- and N-demethylations by metyrapone (2-methyl-1,2-bis(3-pyridyl)-1-propanone, Su 4885) were carried out using mouse liver microsomes as the enzyme source. The model substrates were p-nitroanisole and N-monomethyl-p-nitroaniline. It was shown that the inhibition is competitive. Thek i for metyrapone is 0.42 × 10−4 M and for the reduced metabolite of metyrapone 1.15×10−4M. Their spectral dissociation constants as determined from difference spectra, have almost the same values. From this it is concluded that the degree of inhibition is correlated to the amount of metyrapone bound to cytochrome P-450. Metyrapone does not seem to displace naphthalene from its binding to cytochrome P-450. Assuming the simultaneous binding of substrate and inhibitor to different binding sites of the same enzyme, possible mechanisms for explaining competitive inhibition are discussed.
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The experiments were carried out with the generous support of the Deutsche Forschungsgemeinschaft, Bad Godesberg, Germany.
We thank Mrs. I. Geissler for her skilful and able technical assistance.
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Netter, K.J., Kahl, G.F. & Magnussen, M.P. Kinetic experiments on the binding of metyrapone to liver microsomes. Naunyn-Schmiedebergs Arch. Pharmak. 265, 205–215 (1969). https://doi.org/10.1007/BF01002335
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DOI: https://doi.org/10.1007/BF01002335