Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin
Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin
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DOI：
10.1111/j.1600-079x.2009.00724.x
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发表时间：
2010-01-01
影响因子：
10.3
通讯作者：
Yeung, Eugene Y. H.
中科院分区：
文献类型：
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作者：
Chang, Thomas K. H.;Chen, Jie;Yeung, Eugene Y. H.
给啮齿动物注射褪黑素可以减少苯并[a]芘或7，12-二甲基苯并[a]茂引起的肿瘤发生，这些肿瘤需要细胞色素P450酶的生物激活，如细胞色素P450酶，如细胞色素P1A1、细胞色素P1A2和细胞色素P1B1，以产生致癌代谢物。本研究验证了褪黑素是人类CYP1催化活性和基因表达的调节剂的假设。作为对比，我们还考察了褪黑素对同样是致癌原生物活化酶的CYP2A6催化活性的影响。褪黑素(3-300 mU/m)可抑制人肝微粒体及重组细胞色素P1A1、细胞色素P1A2和细胞色素P1B1催化的7-乙氧基间苯二酚O-脱烷基化反应，但不影响香豆素7-羟基化反应。褪黑素以混合抑制方式抑制CYP1酶，其表观K(I)值(Mean+/-S.E.M.)其中59+/-1(细胞色素P1A1)、12+/-1(细胞色素P1A2)、14+/-2(细胞色素P1B1)和46+/-8微米(肝微粒体)。进一步的实验表明，褪黑素降低了由肝微粒体和CYP1A2催化的苯并[a]芘羟化，但不能抑制由CYP1A1或CYP1B1催化的苯并[a]芘的羟化。褪黑素(最大300微米)处理MCF-10A人乳腺上皮细胞不影响基础或苯并[a]芘诱导的CYP1A1或CYP1B1基因表达。与这一发现一致的是，在体外基于细胞的荧光素酶报告基因检测中，褪黑素并不影响芳烃受体依赖的pGudLuc6.1转基因的MCF-10A细胞在苯并[a]芘处理或不处理的情况下的报告活性。总体而言，褪黑素是一种体外抑制人CYP1催化活性的药物，开发有效的褪黑素类似物作为潜在的癌症化学预防药物可能是有用的，以阻断CYP1介导的化学致癌。
Administration of melatonin to rodents decreases the incidence of tumorigenesis initiated by benzo[a]pyrene or 7,12-dimethylbenz[a]anthracene, which requires bioactivation by cytochrome P450 enzymes, such as CYP1A1, CYP1A2 and CYP1B1, to produce carcinogenic metabolites. The present study tested the hypothesis that melatonin is a modulator of human CYP1 catalytic activity and gene expression. As a comparison, we also investigated the effect of melatonin on the catalytic activity of CYP2A6, which is also a procarcinogen-bioactivating enzyme. Melatonin (3-300 mu m) decreased 7-ethoxyresorufin O-dealkylation catalyzed by human hepatic microsomes and recombinant CYP1A1, CYP1A2 and CYP1B1, whereas it did not affect coumarin 7-hydroxylation catalyzed by hepatic microsomes or recombinant CYP2A6. Melatonin inhibited CYP1 enzymes by mixed inhibition, with apparent K(i) values (mean +/- S.E.M.) of 59 +/- 1 (CYP1A1), 12 +/- 1 (CYP1A2), 14 +/- 2 (CYP1B1) and 46 +/- 8 mu m (hepatic microsomes). Additional experiments indicated that melatonin decreased benzo[a]pyrene hydroxylation catalyzed by hepatic microsomes and CYP1A2 but not by CYP1A1 or CYP1B1. Treatment of MCF-10A human mammary epithelial cells with melatonin (up to 300 mu m) did not affect basal or benzo[a]pyrene-inducible CYP1A1 or CYP1B1 gene expression. Consistent with this finding, melatonin did not influence reporter activity in aryl hydrocarbon receptor-dependent pGudluc6.1-transfected MCF-10A cells treated with or without benzo[a]pyrene, as assessed in an in vitro cell-based luciferase reporter gene assay. Overall, melatonin is an in vitro inhibitor of human CYP1 catalytic activity, and it may be useful to develop potent analogues of melatonin as potential cancer chemopreventive agents that block CYP1-mediated chemical carcinogenesis.