TY - JOUR T1 - METABOLISM OF THE α,β-UNSATURATED KETONES, CHALCONE AND <em>TRANS</em>-4-PHENYL-3-BUTEN-2-ONE, BY RAT LIVER MICROSOMES AND ESTROGENIC ACTIVITY OF THE METABOLITES JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1115 LP - 1123 DO - 10.1124/dmd.104.002634 VL - 33 IS - 8 AU - Yoichi Kohno AU - Shigeyuki Kitamura AU - Seigo Sanoh AU - Kazumi Sugihara AU - Nariaki Fujimoto AU - Shigeru Ohta Y1 - 2005/08/01 UR - http://dmd.aspetjournals.org/content/33/8/1115.abstract N2 - When chalcone and trans-4-phenyl-3-buten-2-one (PBO) were incubated with liver microsomes of untreated rats in the presence of NADPH, 4-hydroxychalcone and trans-4-(4-hydroxyphenyl)-3-buten-2-one (4-OH-PBO), respectively, were formed as major metabolites. Two minor metabolites of chalcone, 4′-hydroxychalcone and 2-hydroxychalcone, were also observed. The oxidase activity affording 4-hydroxychalcone was inhibited by SKF 525-A, disulfiram, ketoconazole, and α-naphthoflavone. The oxidase activities leading to 4-hydroxychalcone and 4′-hydroxychalcone were enhanced in liver microsomes of 3-methylcholanthrene- and phenobarbital-treated rats, respectively. The activity generating 2-hydroxychalcone was enhanced in liver microsomes of 3-methylcholanthrene- and dexamethasone-treated rats. The oxidation of PBO to 4-OH-PBO was inhibited by SKF 525-A, ketoconazole, disulfiram, and sulfaphenazole. This activity was enhanced in liver microsomes of 3-methylcholanthrene-, acetone- and phenobarbital-treated rats. 4-Hydroxylation, 4′-hydroxylation, and 2-hydroxylation of chalcone were catalyzed by rat recombinant cytochrome P450 1A1, 1A2, and 2C6; by 1A1 and 2C6; and by 1A1 and 3A1, respectively. PBO was oxidized by cytochrome P450 1A1, 1A2, 2C6, and 2E1. Chalcone and PBO were negative in an estrogen reporter assay using estrogen-responsive human breast cancer cell line MCF-7. However, 4-hydroxychalcone, 2-hydroxychalcone, 4′-hydroxychalcone, and 4-OH-PBO exhibited estrogenic activity. The American Society for Pharmacology and Experimental Therapeutics ER -