RT Journal Article SR Electronic T1 METABOLISM OF THE α,β-UNSATURATED KETONES, CHALCONE AND TRANS-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 FD American Society for Pharmacology and Experimental Therapeutics SP 1115 OP 1123 DO 10.1124/dmd.104.002634 VO 33 IS 8 A1 Kohno, Yoichi A1 Kitamura, Shigeyuki A1 Sanoh, Seigo A1 Sugihara, Kazumi A1 Fujimoto, Nariaki A1 Ohta, Shigeru YR 2005 UL http://dmd.aspetjournals.org/content/33/8/1115.abstract AB 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