title: Inactivation of cytochrome P450 by the food-derived complex phenol oleuropein.
abstract: Complex phenols, such as the glycoside oleuropein and hydroxytyrosol, are found in high concentrations in the typical components of the Mediterranean diet. We have previously reported that oleuropein inhibits androstenedione 6 beta-hydroxylase activity, a CYP3A marker in human liver microsomes (Stupans, I., Stretch, G., Hayball, P., 2000. Olive oil phenols inhibit human hepatic microsomal activity. Journal of Nutrition. 130 2367-2370). Oleuropein, but not the structurally similar compounds hydroxytyrosol and secologanin, was found to be a mechanism-based inhibitor of androstenedione 6 beta-hydroxylase activity. Preincubation with 100 microM oleuropein and NADPH resulted in a significantly lower androstenedione 6 beta-hydroxylase activity when compared to preincubation carried out with oleuropein without NADPH, 0.11+/-0.01 nmol/mg microsomal protein/min compared with 0.29+/-0.03 nmol/mg microsomal protein/min (P<0.05). The inactivation exhibited pseudo-first-order kinetics. The maximal rate constant for inactivation (k(inactivation)) was calculated to be 0.09 min(-1) and the concentration of inactivator required for half maximal inactivation (Ki) was calculated to be 22.2 microM. Oleuropein was found to be a relatively weak inhibitor of CYP1A2-mediated 7-methoxyresorufin-O-deethylation (24% inhibition at 100 microM oleuropein), but not CYP2E1-mediated chlorzoxazone 6-hydroxylation. CYP1A2 did not undergo mechanism-based inactivation by oleuropein.
authors.affiliation: Center for Pharmaceutical Research, School of Pharmaceutical, Molecular and Biomedical Sciences, University of South Australia, SA 5000, Australia. ieva.stupens@unisa.edu.au
authors.forename: I
authors.initials: I
authors.lastname: Stupans
authors.forename: M
authors.initials: M
authors.lastname: Murray
authors.forename: A
authors.initials: A
authors.lastname: Kirlich
authors.forename: K L
authors.initials: KL
authors.lastname: Tuck
authors.forename: P J
authors.initials: PJ
authors.lastname: Hayball
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004032:Diet; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D057888:Iridoid Glucosides; D039823:Iridoids; D007700:Kinetics; D008297:Male; D019083:Mediterranean Region; D008862:Microsomes, Liver / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D011714:Pyrans / Q000494:pharmacology*; D013250:Steroid Hydroxylases / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D057888:Iridoid Glucosides; D039823:Iridoids; D011714:Pyrans; C002769:oleuropein; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating