Zhao J, Leemann T, Dayer P
Division of Clinical Pharmacology, University Hospital, Geneva, Switzerland.
Life Sci. 1992;51(8):575-81. doi: 10.1016/0024-3205(92)90226-f.
The nature of the enzyme(s) catalyzing the major metabolic pathway (5'-hydroxylation) of oxicam NSAIDs was investigated in subcellular preparations of human liver tissue. Microsomal, but not cytosolic, fractions catalyzed the 5'-hydroxylation of tenoxicam. This reaction required NADPH and was inhibited by various nonselective P450 inhibitors (CO, SKF-525A, ketoconazole), but not by the peroxidase inhibitor NaN3. Tenoxicam 5'-hydroxylation exhibited simple Michaelis-menten kinetics compatible with catalysis by a single enzyme, but it strongly inhibited its own oxidation at concentrations higher than 100-150 microM. Piroxicam competitively inhibited tenoxicam 5'-hydroxylation and, conversely, tenoxicam competitively inhibited piroxicam 5'-hydroxylation. Tenoxicam 5'-hydroxylation kinetics were similar in microsomes from one poor and five extensive metabolizers of debrisoquin (CYP2D6). Dextromethorphan (CYP2D6 prototype substrate) and midazolam (CYP3A prototype substrate) had no influence on tenoxicam 5'-hydroxylation, whereas mephenytoin, tolbutamide and sulfaphenazole (Ki = 0.1 microM) inhibited it. This indicates that the 5'-hydroxylation of both piroxicam and tenoxicam is predominantly catalyzed by at least one cytochrome P450 isozyme of the CYP2C subfamily.
在人肝组织的亚细胞制剂中研究了催化昔康类非甾体抗炎药主要代谢途径（5'-羟基化）的酶的性质。微粒体部分而非胞质部分催化替诺昔康的5'-羟基化。该反应需要NADPH，并受到各种非选择性P450抑制剂（一氧化碳、SKF-525A、酮康唑）的抑制，但不受过氧化物酶抑制剂叠氮化钠的抑制。替诺昔康5'-羟基化表现出与单一酶催化相符的简单米氏动力学，但在浓度高于100-150微摩尔时强烈抑制其自身氧化。吡罗昔康竞争性抑制替诺昔康5'-羟基化，反之，替诺昔康竞争性抑制吡罗昔康5'-羟基化。在来自一名异喹胍慢代谢者和五名异喹胍快代谢者（CYP2D6）的微粒体中，替诺昔康5'-羟基化动力学相似。右美沙芬（CYP2D6原型底物）和咪达唑仑（CYP3A原型底物）对替诺昔康5'-羟基化没有影响，而美芬妥英、甲苯磺丁脲和磺胺苯吡唑（Ki = 0.1微摩尔）抑制该反应。这表明吡罗昔康和替诺昔康的5'-羟基化主要由CYP2C亚家族的至少一种细胞色素P450同工酶催化。
