Mechanism-based inhibition of CYP3A4 by constituents of Zingiber aromaticum.
Mechanism-based inhibition of CYP3A4 by constituents of Zingiber aromaticum.
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DOI：
10.1248/bpb.28.495
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发表时间：
2005-03
影响因子：
2
通讯作者：
T. Usia;T. Watabe;S. Kadota;Y. Tezuka
中科院分区：
文献类型：
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作者：
T. Usia;T. Watabe;S. Kadota;Y. Tezuka
分析了16种化合物分离自香子兰并显示浓度依赖性抑制，IC 50值小于100 μ M，其对CYP 3A 4的时间、浓度和NADPH依赖性抑制的可能性，并分析了4种化合物对CYP 2D 6的抑制。所有七种山奈酚糖苷和两种山奈酚衍生物（4、5、8-14）似乎是基于机制的CYP 3A 4酶抑制剂，其中抑制是不可逆的，并由催化过程驱动。其他化合物未显示NADPH依赖性抑制或可逆性抑制，因此似乎不是基于机制的抑制剂。化合物4、5、8-14的K（I）值在2.21-27.01 μ M的范围内，而k（inact）值为0.23-0.65 min（-1）。山奈酚-3-O-（2，3，4-三-O-乙酰基-α-L-吡喃鼠李糖苷）（5）是最有效的CYP 3A 4灭活剂，K（I）和k（inact）值分别为2.21 microM和0.45 min（-1）。
Sixteen compounds isolated from Zingiber aromaticum and showing concentration-dependent inhibition with IC50 values less than 100 microM, were analyzed for their possibility of time-, concentration-, and NADPH-dependent inhibition of CYP3A4 and four were analyzed for CYP2D6. All seven kaempferol glycosides and two kaempferol derivatives (4, 5, 8-14) appear to be the mechanism-based inhibitors of CYP3A4 enzyme in which the inhibition is irreversible and driven by the catalytic process. The other compounds showed no NADPH-dependent inhibition or reversible inhibition, and thus do not appear to be mechanism-based inhibitors. K(I) values for compounds 4, 5, 8-14 were in the range of 2.21-27.01 microM, whereas the k(inact) values were 0.23-0.65 min(-1). Kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-L-rhamnopyranoside) (5) was found to be the most potent CYP3A4 inactivator with K(I) and k(inact) values of 2.21 microM and 0.45 min(-1), respectively.