N,N-二乙基-2-[4-(苯甲基)苯氧基]乙胺(DPPE)在临床试验中的化学增强剂和细胞保护剂:与组胺在细胞色素P450 3A4和其他代谢抗肿瘤药物的同工酶相互作用。

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Brandes LJ, Queen GM, LaBella FS

N,N-二乙基-2-[4-(苯甲基)苯氧基]乙胺(DPPE)在临床试验中的化学增强剂和细胞保护剂:与组胺在细胞色素P450 3A4和其他代谢抗肿瘤药物的同工酶相互作用。

中国癌症杂志。2000;45(4):298-304。

PubMed ID

10755318 (PubMed视图

］

摘要

目的:N,N-二乙基-2-[4-(苯甲基)苯氧基]乙胺HCl (DPPE)，一种具有化学增强和细胞保护特性的细胞内组胺(HA)拮抗剂，目前正在乳腺癌和前列腺癌的2期和3期临床试验中。DPPE在体外浓度下调节大鼠肝微粒体中HA与细胞色素P450的结合。HA可抑制某些药物的P450代谢。最近对人类结肠癌细胞的体外研究表明，DPPE增强紫杉醇、阿霉素和长春碱的细胞毒性与抑制p -糖蛋白(P-gp)泵有关。P-gp的许多底物也是CYP3A4的底物，CYP3A4是一种P450同工酶，代谢多种抗肿瘤药物，在一些恶性组织中高表达。因此，我们评估了(a) DPPE和HA是否在CYP3A4和其他P450人同工酶上相互作用，(b) DPPE是否抑制CYP3A4的催化活性。方法:利用光谱分析，我们测量了DPPE和HA与表达人P450同工酶1A1, 2B6, 2D6或3A4的昆虫微粒体的结合。利用薄层色谱法，我们评估了每种同工酶对DPPE的代谢，以及DPPE对CYP3A4和大鼠肝微粒体睾酮代谢的抑制作用。结果:(1)DPPE对CYP2D6 (K(S) = 4.1 +/- 0.4 microM)、CYP3A4 (K(S) = 31 +/- 15 microM)和CYP1A1 (K(S) = 40 +/- 9 microM)均诱发了“I型”(底物位点结合)吸光差谱，而对CYP2B6无作用。(2)结合研究表明，DPPE由CYP2D6、CYP3A4和CYP1A1代谢; 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.

引用本文的药物库数据

药物

Tesmilifene

药物靶点

药物	目标	种类	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	种类	生物	药理作用	行动
Tesmilifene	细胞色素P450 1A1	蛋白质	人类	未知的	底物	细节
Tesmilifene	细胞色素P450 2D6	蛋白质	人类	未知的	底物	细节
Tesmilifene	细胞色素P450 3A4	蛋白质	人类	未知的	底物 抑制剂 诱导物	细节