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First published on April 29, 2005; DOI: 10.1124/dmd.104.002634

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Received for publication October 15, 2004.
Revised April 20, 2005.
Accepted for publication April 21, 2005.

Metabolism of {alpha},{beta}-Unsaturated Ketones, Chalcone and trans-4-Phenyl-3-buten-2-one, by Rat Liver Microsomes and Estrogenic Activity of the Metabolites

Yoichi Kohno 1, Shigeyuki Kitamura 1*, Seigo Sanoh 1, Kazumi Sugihara 1, Nariaki Fujimoto 2, Shigeru Ohta 1

1 Hiroshima University, Graduate School of Biomedical Sciences 2 Hiroshima University, Research Institute for Radiation Biology and Medicine

* Address correspondence to: E-mail: skitamu{at}hiroshima-u.ac.jp

Abstract

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) were formed as major metabolites, respectively. 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 {alpha}-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.


Key words: cytochrome P450, cytochrome P450 catalyzed oxidations, environmental toxicology, microsomes




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