title: Inhibition of cytochrome P450c11 by biogenic amines and an aziridine precursor, 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride.
abstract: The interaction of several biogenic amines and Compound A (2-(4-acetoxyphenyl)-2-chloro- N-methyl-ethylammonium chloride), an analogue of the active substance in a HPLC fraction isolated from the shrub, Salsola tuberculatiformis Botsch., with cytochrome P450c11 was investigated. Noradrenaline, octopamine and Compound A inhibited the type I DOC induced difference spectrum of 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 mM and 0.36 mM, respectively. Dopamine, adrenaline and synephrine did not interact with, or inhibit, P450c11. Further investigation of Compound A indicated that it is a mixed inhibitor of sheep P450c11 with a stronger competitive (Kic = 106-110 microM) than uncompetitive (Kiu = 667-737 microM) element, and that it inhibits the conversion of deoxycorticosterone to corticosterone by human 11beta-hydroxylase and aldosterone synthase with EC50 values of 97 microM and 190 microM, respectively, in fetal calf serum.
authors.affiliation: Department of Biochemistry, University of Stellenbosch, South Africa.
authors.forename: A
authors.initials: A
authors.lastname: Louw
authors.forename: F
authors.initials: F
authors.lastname: Allie
authors.forename: A C
authors.initials: AC
authors.lastname: Swart
authors.forename: P
authors.initials: P
authors.lastname: Swart
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D015306:Biogenic Monoamines / Q000494:pharmacology*; D002460:Cell Line; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019405:Cytochrome P-450 CYP11B2 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D003900:Desoxycorticosterone / Q000378:metabolism; D005021:Ethylamines / Q000494:pharmacology*; D006801:Humans; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D012756:Sheep; D013252:Steroid 11-beta-Hydroxylase / Q000378:metabolism; D014439:Tyramine / Q000031:analogs & derivatives
chemical_list: C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; D000085:Acetates; D015306:Biogenic Monoamines; D065607:Cytochrome P-450 Enzyme Inhibitors; D005021:Ethylamines; D003900:Desoxycorticosterone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C421925:cytochrome P450 C11; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D003345:Corticosterone; D014439:Tyramine