N, N-diethyl-2 - [4 - (phenylmethyl)苯氧基]ethanamine (DPPE) chemopotentiating和cytoprotective剂临床试验:与组胺在细胞色素P450 3 a4和其他同功酶代谢抗肿瘤的药物。

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女王Brandes LJ通用,LaBella FS

N, N-diethyl-2 - [4 - (phenylmethyl)苯氧基]ethanamine (DPPE) chemopotentiating和cytoprotective剂临床试验:与组胺在细胞色素P450 3 a4和其他同功酶代谢抗肿瘤的药物。

癌症Chemother杂志。2000;45 (4):298 - 304。

PubMed ID

10755318 (在PubMed

]

文摘

目的:N, N-diethyl-2 - [4 - (phenylmethyl)苯氧基]ethanamine盐酸(DPPE),一个细胞内组胺(HA)拮抗剂和chemopotentiating cytoprotective属性,目前在2和3期临床试验在乳腺癌和前列腺癌。DPPE浓度调节生长在体外对抗公顷绑定到细胞色素P450在大鼠肝微粒体。HA抑制P450酶代谢的药物。最近的人类结肠癌细胞体外研究有关DPPE增强紫杉醇、阿霉素、长春花碱细胞毒性的抑制22 (P-gp)泵。许多基质P-gp也是CYP3A4的基质,P450酶同工酶,代谢多种抗肿瘤的药物和一些恶性组织中高度表达。因此,我们评估是否(a) DPPE和HA交互CYP3A4和其他人类同功酶P450,和(b) DPPE抑制CYP3A4的催化活性。方法:使用光谱分析时,我们测量DPPE和HA绑定到昆虫表达人类的微粒体P450酶同功酶1 a1, 2 b6, 2 d6或3 a4。采用薄层色谱法,我们评估了每个同工酶和DPPE DPPE代谢的抑制睾酮代谢CYP3A4和大鼠肝微粒体。结果:(1)DPPE诱发“I型”(衬底站点绑定)与CYP2D6 absorbance-difference光谱(K (S) = 4.1 + / - 0.4 microM), CYP3A4 (K (S) = 31 + / - 15 microM)和CYP1A1 (K (S) = 40 + / - 9 microM),但不是CYP2B6。(2)与绑定对应研究,DPPE被CYP2D6代谢,CYP3A4和CYP1A1; no metabolism occurred with CYP2B6. (3) HA evoked "type II" (heme iron binding) absorbance-difference spectra with all four isozymes, with K(S) values in the range 80-600 microM. DPPE inhibited HA (600 microM) binding to CYP2D6 (IC50 = 4 microM, 95% CI= 1.8-8.9 microM) and CYP1A1 (IC50 = 135 microM: 95% CI = 100-177 microM), but stimulated HA (500 and 1000 microM) binding to CYP3A4 (EC50 = 155 microM, 95% CI = 104-231 microM). DPPE did not affect HA binding to CYP2B6. (4) DPPE inhibited the metabolism of testosterone by CYP3A4. The concentration/effect curve was biphasic: DPPE inhibited metabolism by 30% at the first site (IC50 = 3 microM, 95% CI = 0.5-25.5 microM), and an additional 70% inhibition occurred at the second site (IC50 = 350 microM, 95% CI = 215-570 microM). A similar result was observed with rat liver microsomes. CONCLUSION: DPPE is a substrate for CYP3A4, CYP2D6 and CYP1A1, but not CYP2B6. DPPE inhibits testosterone metabolism by interacting at two sites on CYP3A4, the first correlating with its K(S) value to bind the substrate site and the second, with its EC50 value to enhance HA binding to the heme iron. We postulate that (1) the inhibitory effect of DPPE on CYP3A4 activity is mediated directly at the substrate site and indirectly by its enhancement of the binding of HA to the heme moiety; (2) in tumor cells that express high constitutive levels of CYP3A4, potentiation of chemotherapy cytotoxicity by DPPE results, in part, from inhibition of CYP3A4-mediated metabolism and P-gp-mediated efflux of antineoplastic drugs; (3) in normal cells that express low constitutive levels of the isozyme, cytoprotection by DPPE results, in part, from induction of CYP3A4 and P-gp, resulting in an increase both in metabolism and efflux of antineoplastic drugs.

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药物

Tesmilifene

药物靶点

药物	目标	类	生物	药理作用	行动
Tesmilifene	22 - 1	蛋白质	人类	是的	诱导物	细节

药物酶

药物	酶	类	生物	药理作用	行动
Tesmilifene	细胞色素P450 1 a1	蛋白质	人类	未知的	底物	细节
Tesmilifene	细胞色素P450 2 d6	蛋白质	人类	未知的	底物	细节
Tesmilifene	细胞色素P450 3 a4	蛋白质	人类	未知的	底物 抑制剂 诱导物	细节