Oral administration of naturally occurring coumarins leads to altered phase I and II enzyme activities and reduced DNA adduct formation by polycyclic aromatic hydrocarbons in various tissues of SENCAR mice
Oral administration of naturally occurring coumarins leads to altered phase I and II enzyme activities and reduced DNA adduct formation by polycyclic aromatic hydrocarbons in various tissues of SENCAR mice
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DOI：
10.1093/carcin/22.1.73
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发表时间：
2001-01-01
期刊：
影响因子：
4.7
通讯作者：
DiGiovanni, J
中科院分区：
文献类型：
--
作者：
Kleiner, HE;Vulimiri, SV;DiGiovanni, J
人类在饮食中经常接触的几种天然香豆素，以前被发现在体外抑制P450介导的苯并[a]芘(B[a]P)和7，12-二甲基苯并[a]蒽(DMBA)的代谢，阻断小鼠表皮DNA加合物的形成，并在小鼠局部应用时抑制B[a]P和/或DMBA引发的皮肤肿瘤。本研究旨在研究其中两个线性呋喃香豆素型化合物口服(70 mg/kg，连续4天)对小鼠不同组织中P450和谷胱甘肽S转移酶(GST)活性及DNA加合物形成的影响。苦参素和异胡萝卜素在给药后1h和2 4h可显著抑制表皮中乙氧基间苯二酚O-脱乙基酶(EROD)和戊氧基间苯二酚O-脱烷基酶(PROD)的活性。在末次给药后1h，欧前胡素和异胡萝卜素对小鼠肺和前胃组织的EROD活性有轻度抑制作用，而对肺和前胃组织的PROD活性有明显的抑制作用。末次口服欧前胡素或异胡萝卜素24小时后，表皮和肺组织中EROD和PROD活性仍然受到抑制。然而，前胃P450活性已恢复到对照水平。有趣的是，欧前胡素和异胡萝卜素在1h抑制肝脏EROD活性，对此时的PROD活性没有影响，但在24h使这两种酶的活性升高，EROD和PROD活性的升高与肝脏P450含量的升高相一致。与玉米油对照组相比，欧前胡素和异叶胡萝卜素可使大鼠肝细胞浆GST活性增加1.6倍，欧前胡素和异胡萝卜素对甲基溴并[a]P和DMBA所致DNA加合物的形成也有保护作用，欧前胡素可减少DMBA在前胃形成DNA加合物，异胡萝卜素可降低肝(B[a]P)、肺(B[a]P)和乳腺上皮细胞(DMBA)的DNA加合物水平。这些结果表明，欧前胡素和异胡萝卜素在饮食中可能具有潜在的化学预防作用。
Several naturally occurring coumarins, to which humans are routinely exposed in the diet, were previously found to inhibit P450-mediated metabolism of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) in vitro, block DNA adduct formation in mouse epidermis and inhibit skin tumor initiation by B[a]P and/or DMBA when applied topically to mice. The present study was designed to investigate the effects of two of these compounds, of the linear furanocoumarin type, when given orally (70 mg/kg per os, four successive daily doses), on P450 and glutathione S-transferase (GST) activities and DNA adduct formation by B[a]P and DMBA in various mouse tissues. Imperatorin and isopimpinellin significantly blocked ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activities in epidermis at 1 and 24 h after oral dosing. Imperatorin and isopimpinellin modestly inhibited EROD activities in lung and forestomach at 1 h and significantly inhibited PROD activities in lung and forestomach at 1 h after the final oral dose. Twenty-four hours after the final oral dose of imperatorin or isopimpinellin EROD and PROD activities remained inhibited in epidermis and lung. However, forestomach P450 activity had returned to control levels. Interestingly, imperatorin and isopimpinellin treatment inhibited liver EROD activity at 1 h, had no effect on PROD activity at this time point, but elevated both these enzyme activities at 24 h. Elevated EROD and PROD activities coincided with elevated hepatic P450 content. Imperatorin and isopimpinellin treatment also increased liver cytosolic GST activity at both 1 and 24 h after the final oral dose by 1.6-fold compared with corn oil controls, Oral administration of imperatorin and isopimpinellin also had a protective effect against DNA adduct formation by B[a]P and DMBA, Imperatorin pretreatment decreased formation of DNA adducts by DMBA in forestomach, Pretreatment with isopimpinellin led to reduced DNA adduct levels in liver (B[a]P), lung (B[a]P) and mammary epithelial cells (DMBA). These results suggest that imperatorin and isopimpinellin may have potential chemopreventive effects when administered in the diet.