Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
J Pineal Res. 2010 Jan;48(1):55-64. doi: 10.1111/j.1600-079X.2009.00724.x. Epub 2009 Nov 16.
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 microm) 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 microm (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 microm) 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.
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. 给啮齿动物施用褪黑素可降低苯并[a]芘或 7,12-二甲基苯并[a]蒽引发的肿瘤形成的发生率，这需要细胞色素 P450 酶（如 CYP1A1、CYP1A2 和 CYP1B1）的生物活化作用，以产生致癌代谢物。
The present study tested the hypothesis that melatonin is a modulator of human CYP1 catalytic activity and gene expression. 本研究旨在验证褪黑素是人类 CYP1 催化活性和基因表达调节剂的假设。
As a comparison, we also investigated the effect of melatonin on the catalytic activity of CYP2A6, which is also a procarcinogen-bioactivating enzyme. 作为比较，我们还研究了褪黑素对 CYP2A6 的催化活性的影响，CYP2A6 也是一种前致癌物生物激活酶。
Melatonin (3-300 microm) 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. 褪黑素（3-300 µm）降低了人肝微粒体和重组 CYP1A1、CYP1A2 和 CYP1B1 催化的 7-乙氧基resorufin O-脱烷基化，而对肝微粒体或重组 CYP2A6 催化的香豆素 7-羟化没有影响。
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 microm (hepatic microsomes). 褪黑素通过混合抑制抑制 CYP1 酶，CYP1A1、CYP1A2、CYP1B1 的表观 K(i) 值（平均值 +/- S.E.M.）分别为 59 +/- 1、12 +/- 1、14 +/- 2 µm，肝微粒体的 K(i) 值为 46 +/- 8 µm。
Additional experiments indicated that melatonin decreased benzo[a]pyrene hydroxylation catalyzed by hepatic microsomes and CYP1A2 but not by CYP1A1 or CYP1B1. 进一步的实验表明，褪黑素降低了肝微粒体和 CYP1A2 催化的苯并[a]芘羟化，但不降低 CYP1A1 或 CYP1B1。
Treatment of MCF-10A human mammary epithelial cells with melatonin (up to 300 microm) did not affect basal or benzo[a]pyrene-inducible CYP1A1 or CYP1B1 gene expression. 用褪黑素（高达 300 µm）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。
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. 与这一发现一致，褪黑素在体外细胞 luciferase 报告基因测定中不影响苯并[a]芘处理或未处理的依赖芳烃受体的 pGudluc6.1 转染 MCF-10A 细胞中的报告基因活性。
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. 总的来说，褪黑素是一种体外人 CYP1 催化活性抑制剂，作为潜在的癌症化学预防剂，开发强效褪黑素类似物可能有助于阻断 CYP1 介导的化学致癌作用。
