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
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
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DOI：
10.1124/dmd.104.002634
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发表时间：
2005-08-01
影响因子：
3.9
通讯作者：
Ohta, S
中科院分区：
文献类型：
--
作者：
Kohno, Y;Kitamura, S;Ohta, S
当查尔酮和反式-4-苯基-3-丁烯-2-酮 (PBO) 在 NADPH 存在下与未治疗大鼠的肝微粒体一起孵育时，分别形成 4-羟基查耳酮和反式-4-(4-羟基苯基)-3-丁烯-2-酮 (4-OH-PBO) 作为主要代谢物。还观察到查耳酮的两种次要代谢物，4'-羟基查耳酮和2-羟基查耳酮。 SKF 525-A、双硫仑、酮康唑和 α-萘黄酮可抑制提供 4-羟基查尔酮的氧化酶活性。 3-甲基胆蒽和苯巴比妥治疗的大鼠肝微粒体中产生 4-羟基查尔酮和 4'-羟基查尔酮的氧化酶活性分别增强。 3-甲基胆蒽和地塞米松治疗的大鼠肝微粒体中产生 2-羟基查耳酮的活性增强。 SKF 525-A、酮康唑、双硫仑和磺胺苯唑可抑制 PBO 氧化为 4-OH-PBO。在 3-甲基胆蒽、丙酮和苯巴比妥处理的大鼠的肝微粒体中，这种活性得到增强。大鼠重组细胞色素 P450 1A1、1A2 和 2C6 催化查耳酮的 4-羟基化、4'-羟基化和 2-羟基化；由1A1及2C6；分别由1A1和3A1表示。 PBO 被细胞色素 P450 1A1、1A2、2C6 和 2E1 氧化。使用雌激素反应性人乳腺癌细胞系 MCF-7 进行雌激素报告基因检测，查耳酮和 PBO 呈阴性。然而，4-羟基查耳酮、2-羟基查耳酮、4'-羟基查耳酮和4-OH-PBO表现出雌激素活性。
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 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.