Inhibition of cytochrome P450c11 by biogenic amines and an aziridine precursor, 2-(4-acetoxyphenyl)-2-chloro-nmethyl-ethylammonium chloride

The interaction of several biogenic amines and Compound A (2-(4-acetoxyphen yl)-2-chloro- N-methyl-ethylammonium chloride), an analogue of the active s ubstance in a HPLC fraction isolated from the shrub, Salsola tuberculatifor mis Botsch., with cytochrome P450c11 was investigated. Noradrenaline, octop amine and Compound A inhibited the type I DOC induced difference spectrum o f P450c11 and elicited a type II difference spectrum when added alone. The Ks-values for noradrenaline, octopamine, and Compound A were 0.8 mM, 0.16 m M and 0.36 mM, respectively. Dopamine, adrenaline and synephrine did not in teract with, or inhibit, P450c11. Further investigation of Compound A indic ated that it is a mixed inhibitor of sheep P450c11 with a stronger competit ive (Kic = 106-110 muM) than uncompetitive (Kiu = 667-737 muM) element, and that it inhibits the conversion of deoxycorticosterone to corticosterone b y human 11 beta -hydroxylase and aldosterone synthase with EC50 values of 9 7 muM and 190 muM, respectively, in fetal calf serum.