Beyeler S, Testa B, Perrissoud D
School of Pharmacy, University of Lausanne, Switzerland.
Biochem Pharmacol. 1988 May 15;37(10):1971-9. doi: 10.1016/0006-2952(88)90544-8.
Flavanone and six hydroxylated derivatives, and cianidanol and eight ethers and esters thereof, were investigated as inhibitors of cytochrome P-450 mediated reactions in rat liver microsomes. The IC50 values towards aminopyrine N-demethylation varied over a 20-fold range and were shown to depend on the pattern of hydroxylation (flavanone derivatives) and on lipophilicity (cianidanol derivatives). In the latter case, a bilinear relationship exists, the optimal log P being 2.92. Using selected compounds, IC50, Km and Vmax values were determined for aminopyrine N-demethylation, biphenyl 4-hydroxylation, and biphenyl 2-hydroxylation. Depending on the inhibitor and on the activity examined, non-competitive, competitive, or mixed inhibition was seen. Interaction with cytochrome P-450 was also studied spectrally and was always found to result in a modified type II difference spectrum (ligand binding). A dual binding mode is postulated, involving electrostatic and lipophilic interactions.
研究了黄烷酮及其六种羟基化衍生物，以及刺槐素及其八种醚和酯作为大鼠肝微粒体中细胞色素P-450介导反应抑制剂的作用。对氨基比林N-去甲基化的IC50值在20倍范围内变化，结果表明其取决于羟基化模式（黄烷酮衍生物）和亲脂性（刺槐素衍生物）。在后一种情况下，存在双线性关系，最佳log P为2.92。使用选定的化合物，测定了氨基比林N-去甲基化、联苯4-羟基化和联苯2-羟基化的IC50、Km和Vmax值。根据抑制剂和所检测的活性，观察到非竞争性、竞争性或混合性抑制。还通过光谱研究了与细胞色素P-450的相互作用，并且总是发现会产生修饰的II型差光谱（配体结合）。推测存在一种双重结合模式，涉及静电和脂ophilic相互作用。
