Faculty of Pharmacy, University of Mostar, Matice Hrvatske bb, 88000 Mostar, Bosnia and Herzegovina.
University of Zagreb Faculty of Pharmacy and Biochemistry, Ante Kovačića 1, 10000 Zagreb, Croatia.
Molecules. 2021 May 19;26(10):3018. doi: 10.3390/molecules26103018.
Acacetin, apigenin, chrysin, and pinocembrin are flavonoid aglycones found in foods such as parsley, honey, celery, and chamomile tea. Flavonoids can act as substrates and inhibitors of the CYP3A4 enzyme, a heme containing enzyme responsible for the metabolism of one third of drugs on the market. The aim of this study was to investigate the inhibitory effect of selected flavonoids on the CYP3A4 enzyme, the kinetics of inhibition, the possible covalent binding of the inhibitor to the enzyme, and whether flavonoids can act as pseudo-irreversible inhibitors. For the determination of inhibition kinetics, nifedipine oxidation was used as a marker reaction. A hemochromopyridine test was used to assess the possible covalent binding to the heme, and incubation with dialysis was used in order to assess the reversibility of the inhibition. All the tested flavonoids inhibited the CYP3A4 enzyme activity. Chrysin was the most potent inhibitor: = 2.5 ± 0.6 µM, = 2.4 ± 1.0 µM, = 0.07 ± 0.01 min, / = 0.03 min µM. Chrysin caused the highest reduction of heme (94.5 ± 0.5% residual concentration). None of the tested flavonoids showed pseudo-irreversible inhibition. Although the inactivation of the CYP3A4 enzyme is caused by interaction with heme, inhibitor-heme adducts could not be trapped. These results indicate that flavonoids have the potential to inhibit the CYP3A4 enzyme and interact with other drugs and medications. However, possible food-drug interactions have to be assessed clinically.
芹菜素、芹菜素、白杨素和松属素是存在于欧芹、蜂蜜、芹菜和甘菊茶等食物中的黄酮类糖苷配基。黄酮类化合物可以作为细胞色素 P4503A4（CYP3A4）酶的底物和抑制剂，CYP3A4 酶是一种含有血红素的酶，负责代谢市场上三分之一的药物。本研究旨在研究选定的黄酮类化合物对 CYP3A4 酶的抑制作用、抑制动力学、抑制剂与酶的可能共价结合以及黄酮类化合物是否可以作为伪不可逆抑制剂。为了确定抑制动力学，使用硝苯地平氧化作为标记反应。使用亚铁血红素吡咯试验来评估与血红素的可能共价结合，并用透析孵育来评估抑制的可逆性。所有测试的黄酮类化合物均抑制 CYP3A4 酶的活性。白杨素是最有效的抑制剂：Ki = 2.5 ± 0.6 µM，Ki = 2.4 ± 1.0 µM，Ki = 0.07 ± 0.01 min，Ki = 0.03 min µM。白杨素导致血红素的还原最高（94.5 ± 0.5%残留浓度）。没有一种黄酮类化合物表现出伪不可逆抑制。尽管 CYP3A4 酶的失活是由于与血红素的相互作用引起的，但抑制剂-血红素加合物不能被捕获。这些结果表明，黄酮类化合物具有抑制 CYP3A4 酶并与其他药物相互作用的潜力。然而，必须在临床上评估可能的食物-药物相互作用。
