INHIBITION AND INACTIVATION OF MURINE HEPATIC ETHOXYRESORUFIN AND PENTOXYRESORUFIN O-DEALKYLASE BY NATURALLY-OCCURRING COUMARINS
INHIBITION AND INACTIVATION OF MURINE HEPATIC ETHOXYRESORUFIN AND PENTOXYRESORUFIN O-DEALKYLASE BY NATURALLY-OCCURRING COUMARINS
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DOI：
10.1021/tx00036a018
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发表时间：
1993-11-01
影响因子：
4.1
通讯作者：
DIGIOVANNI, J
中科院分区：
文献类型：
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作者：
CAI, YN;BENNETT, D;DIGIOVANNI, J
本研究旨在评价一系列天然香豆素对senar小鼠肝组织乙氧基间苯二酚0-脱烷基酶（EROD）和戊氧基间苯二酚0-脱烷基酶（PROD）活性的影响。研究了15种不同香豆素的潜在调节活性。在人类饮食中发现的几种天然香豆素，在体外是肝脏EROD活性的有效抑制剂，包括芫荽素、佛手柑素、异欧前胡素和ostrutin。值得注意的是，香菜素和佛手柑素与7,8-苯甲黄酮（一种相对选择性的细胞色素P450 1A1抑制剂）的效力大致相同。几种天然存在的香豆素也是肝脏PROD活性的有效抑制剂，包括欧前胡素、佛手柑素、异opopimpinellin和当归素。抑制类型的动力学研究表明，这些化合物通过多种方式而不是单一的方式抑制肝脏EROD和PROD活性。此外，采用两阶段孵化法的实验表明，香菜素、欧前胡素、ostrutin和其他几种天然香豆素使肝脏EROD活性失活（即主要由细胞色素P450 1a1介导），异opimpinellin使肝脏PROD活性失活（即主要由细胞色素P450 2b1介导）。最后，研究结果表明，一些香豆素对EROD和PROD具有选择性抑制作用，初步分析表明这种差异可能存在结构基础。目前的数据表明，人类在饮食中接触到的某些天然香豆素是细胞色素P450的有效调节剂。此外，这些化合物可能能够影响其他外源物的代谢激活，包括化学致癌物。
The present study was designed to evaluate the effects of a series of natural coumarins on ethoxyresorufin 0-dealkylase (EROD) and pentoxyresorufin 0-dealkylase (PROD) activities in vitro using hepatic tissues from SENCAR mice. Fifteen different coumarins were examined for potential modulating activities. Several naturally occurring coumarins, found in the human diet, were effective inhibitors of hepatic EROD activity in vitro, including coriandrin, bergamottin, isoimperatorin, and ostruthin. Notably, coriandrin and bergamottin were approximately as potent as 7,8-benzoflavone, a relatively selective inhibitor of cytochrome P450 1A1. Several naturally occurring coumarins were also potent inhibitors of hepatic PROD activity, including imperatorin, bergamottin, isopimpinellin, and angelicin. Kinetic studies of the type of inhibition revealed that these compounds inhibited hepatic EROD and PROD activity by a variety of modes rather than by a uniform one. Furthermore, experiments using a two-stage incubation assay revealed that coriandrin, imperatorin, ostruthin, and several other natural coumarins inactivated hepatic EROD activity (i.e., predominantly cytochrome P450 1A1-mediated) and that isopimpinellin inactivated hepatic PROD activity (i.e., predominantly cytochrome P450 2B1-mediated). Finally, the results indicate that some coumarins had selective inhibitory effects for EROD vs PROD and preliminary analyses suggested a possible structural basis for the observed differences. The current data suggest that certain naturally occurring coumarins, to which humans are exposed in the diet, are potent modulators of cytochrome P450. Furthermore, these compounds may be capable of influencing the metabolic activation of other xenobiotics, including chemical carcinogens.