THE ACTION OF ALPHA-PROPYNYLOXYTOLUENES ON MOUSE LIVER MIXED FUNCTION OXYGENASE

The spectral dissociation constants (K(,s)) of the complexes formed by mouse liver cytochrome P-450 and a number of alpha propynyloxylated toluenes were obtained. In this group of compounds were (alpha)-propynyloxytoluene, (alpha),(alpha)-dipropynyloxytoluene, (alpha),(alpha),(alpha)-tripropynyloxytoluene and a number of their ring substituted derivatives. The stabilities of these complexes was seen to increase with an increasing number of alpha propynyloxy substituents. Electron attracting substituents especially at ortho position increased the affinity of (alpha)-propynyloxytoluenes for MFO but not to as great a degree as did the increase in the number of propynyloxy groups at the alpha position. The inhibitory action of several alpha propynyloxylated toluenes was investigated in vitro and in vivo. The in vitro effects of these inhibitors on hexobarbital hydroxylase using ('14)C- hexobarbital as substrate showed the I(,50) values to be 2.3 x 10('-4), 1.7 x 10('-5), 8.9 x 10('-6) respectively for (alpha)-propynyloxy-, (alpha),(alpha)-dipropynyloxy- and (alpha),(alpha),(alpha)-tripropynyloxy- toluene. The results of a study of NADPH oxidation by oxygen with mouse liver microsomes as inhibited by 4-Cl-(alpha),(alpha)-dipropynyloxytoluene are interpreted as evidence for formation from the inhibitor of a metabolite which irreversibly inactivates the MFO enzyme system. The extension of the time of seconal induced sleep in mice produced by prior dosage with alpha propynyloxylated toluenes was seen generally to increase with decreasing K(,s) values for the test compounds. Factors other than the affinity of the drug extenders for the cytochrome P-450 seemed to have some bearing on the observed results. The lethality to mice of both dimetilan and seconal was increased by one hour prior administration of (alpha),(alpha)- and (alpha),(alpha),(alpha)-propynyloxylated toluenes, the latter having the more pronounced effect. The result obtained in attempts to induce MFO by repeated dosing with the alpha propynyloxylated toluenes on the three successive days followed by a twelve hour lapse period before dosing with secobarbital supported the hypothesis of irreversible inactivation of the MFO since secobarbital induced sleep was significantly extended rather than shortened.