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), 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.
Footnotes
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This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Japanese Ministry of Education, Science, Sports and Culture, and a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.002634.
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ABBREVIATIONS: PBO, trans-4-phenyl-3-buten-2-one; PBA, 4-phenyl-2-butanone; PBOL, trans-4-phenyl-3-buten-2-ol; P450, cytochrome P450; ERE, estrogen-responsive element; 4-OH-PBO, trans-4-(4-hydroxyphenyl-3-buten-2-one; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography-mass spectrometry operated in tandem; SKF 525-A, N,N-diethylaminoethyl-2,2-diphenylvalerate hydrochloride.
- Received October 14, 2004.
- Accepted April 21, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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