Anticancer drugs as inhibitors of two polymorphic cytochrome P450 enzymes, debrisoquin and mephenytoin hydroxylase, in human liver microsomes.
Anticancer drugs as inhibitors of two polymorphic cytochrome P450 enzymes, debrisoquin and mephenytoin hydroxylase, in human liver microsomes.
复制标题
抗癌药物，作为人肝微粒体中两种多态性细胞色素 P450 酶（异喹啉和美芬妥英羟化酶）的抑制剂。
作者：
M. Relling;W. Evans;R. Fonné‐Pfister;U. Meyer
为了确定碎片醌和甲苯妥英羟基化多态性的潜在底物，我们在几种抗癌药物不存在和不存在的情况下，对人肝微粒体和各自的原型底物进行了体外抑制研究。（+）-Bufuralol 1'-羟基化（作为debrisoquin多态性的原型反应）在5微米的底物浓度和存在环磷酰胺（0至200微米），天尼泊苷（0至100微米），长春花碱（0至220微米），依托泊苷（0至200微米），黄酮乙酸（0至1000微米），或异磷酰胺（0至200微米）的情况下进行测试。(S)在60微米底物浓度下，在与上述药物相同的情况下，对甲苯妥英4-羟基化进行了测试；长春新碱也在0 ~ 200微米下进行了测试。天竺葵苷竞争性地抑制(S)-甲苯妥英的4-羟基化，Ki为12微米（反应Km = 65微米）。依托泊苷和黄酮乙酸是较弱的抑制剂。只有长春花碱能抑制丁醛羟基化，其Ki值为90 μ m（酶对底物的Km = 12 μ m）。我们得出结论，天尼泊苷和高浓度的黄酮乙酸可能会改变癌症患者的甲苯妥英表型测定，天尼泊苷作为基因调控的甲苯妥英羟化酶的可能底物值得进一步研究。
To identify potential substrates for the debrisoquin and mephenytoin hydroxylation polymorphisms, we performed in vitro inhibition studies with human liver microsomes and the respective prototype substrates in the absence and presence of several anticancer drugs. (+)-Bufuralol 1'-hydroxylation (as the prototype reaction for the debrisoquin polymorphism) was tested at 5 microM substrate concentration and in the presence of cyclophosphamide (0 to 200 microM), teniposide (0 to 100 microM), vinblastine (0 to 220 microM), etoposide (0 to 200 microM), flavone acetic acid (0 to 1000 microM), or ifosphamide (0 to 200 microM). (S)-Mephenytoin 4-hydroxylation was tested at 60 microM substrate concentration and in the presence of the same drugs as above; vincristine was also tested at 0 to 200 microM. Teniposide competitively inhibited the 4-hydroxylation of (S)-mephenytoin, with a Ki of 12 microM (Km of the reaction = 65 microM). Etoposide and flavone acetic acid were weaker inhibitors of this reaction. The only agent to inhibit bufuralol hydroxylation was vinblastine, which did so with a Ki of 90 microM (Km of the enzyme for the substrate = 12 microM). We conclude that teniposide and high concentrations of flavone acetic acid could spuriously alter mephenytoin phenotype determination in cancer patients, and that teniposide deserves further investigation as a possible substrate for the genetically regulated mephenytoin hydroxylase.
登录
查看更多内容
影响因子：
3.6
作者：
F. Guengerich;D. Müller-Enoch;I. Blair
通讯作者：
F. Guengerich;D. Müller-Enoch;I. Blair
连续输注替尼泊苷的临床药效学：全身暴露作为 I 期试验中反应的决定因素。
DOI：
10.1200/jco.1987.5.7.1007
发表时间：
1987
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Rodman,JH;Abromowitch,M;Sinkule,JA;Hayes,FA;Rivera,GK;Evans,WE
通讯作者：
Evans,WE
影响因子：
11.2
作者：
A. Kaisary;P. Smith;Evelyne Jaczq;C. Mcallister;G. Wilkinson;W. Ray;R. Branch
通讯作者：
A. Kaisary;P. Smith;Evelyne Jaczq;C. Mcallister;G. Wilkinson;W. Ray;R. Branch
影响因子：
11.2
作者：
F. Guengerich
通讯作者：
F. Guengerich