Effects of monoterpenoids on in vivo DMBA-DNA adduct formation and on phase I hepatic metabolizing enzymes.
Effects of monoterpenoids on in vivo DMBA-DNA adduct formation and on phase I hepatic metabolizing enzymes.
复制标题
单萜类化合物对体内 DMBA-DNA 加合物形成和 I 相肝代谢酶的影响。
DOI：
10.1093/carcin/12.11.2081
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发表时间：
1991
期刊：
影响因子：
4.7
通讯作者：
Jefcoate,CR
中科院分区：
文献类型：
--
作者：
Maltzman,TH;Christou,M;Gould,MN;Jefcoate,CR
我们先前已经证明，在7，12-二甲基苯并[a]菲(DMBA)诱导的Wistar-Furth(WF)大鼠乳腺癌的起始阶段给予柠檬烯等单环单萜类化合物具有抗癌作用。在这里，我们研究了这种化学预防活性的可能机制，包括柠檬烯对DMBA-DNA加合物的形成和DMBA的肝脏代谢的影响。染毒24小时后，对照组动物肝、脾、肾、肺中有50%的DMBA-˜加合物形成。尽管对照组和柠檬烯喂养的大鼠的循环中DMBA和/或其代谢产物的水平没有差异，但柠檬烯喂养的动物的尿中DMBA和/或DMBA衍生的代谢物增加了2.3倍。柠檬烯和Sobrerol是一种具有化学预防活性的羟化单环单萜类化合物，它们对I相代谢酶的影响研究表明，这些萜类化合物调节细胞色素P450(CYP)和环氧化物水合酶(EH)的活性。与对照组相比，5%的柠檬烯饮食使总CYP增加到与苯巴比妥(PB)处理相同的程度，而1%的Sobrerol(在化学预防方面与5%柠檬烯的效果相同)则没有。然而，与对照和PB处理相比，5%柠檬烯和1%Sobrerol处理都显著增加了微粒体EH蛋白的水平和与苯并[a]芘4，5-氧化物相关的水合活性。与PB处理或对照相比，这些变化也改变了DMBA代谢的速率和区域选择性。在蛋白质印迹分析和对微粒体DMBA代谢的抑制研究中，利用CYP同工酶抗体鉴定了这些萜类化合物诱导的CYP的特异性亚型。5%的柠檬烯在提高CYP2B和2C家族成员的水平方面比1%的Sobrerol更有效，但在增加EH方面同样有效。此外，两种萜类饮食都会增加最接近的致癌物质DMBA 3，4-二氢二醇的形成。虽然这些由萜类引起的肝脏CYP和EH的变化不能解释这些化学预防药物的抗癌机制，也不能系统地解释柠檬烯降低DMBA-DNA结合的能力，但它们确实揭示了肝酶的新的和选择性的诱导机制。
We have previously demonstrated the anticarcinogenk effects of monocyclic monoterpenes such as limonene when given during the initiation phase of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary cancer in Wistar-Furth (WF) rats. Here we investigated the possible mechanisms for this chemoprevention activity including limonene's effects on DMBA-DNA adduct formation and hepatic metabolism of DMBA. Twenty-four hours after carcinogen administration, there were ˜50% of the total DMBA-DNA adducts found in control animals formed in the liver, spleen, kidney and lung of limonene-fed animals. While circulating levels of DMBA and/or its metabolites were not different in control and limonene-fed rats, there was a 2.3-fold increase in DMBA and/or DMBA-derived metabolites in the urine of the limonene-fed animals. Studies of the effects of limonene and sobrerol, a hydroxylated monocyclic monoterpenoid with increased chemoprevention activity, on phase I metabolizing enzymes revealed that these terpenoids modulated cytochrome P450 (CYP) and epoxide hydratase (EH) activity. The 5% limonene diet increased total CYP to the same extent as phenobarbital (PB) treatment when compared to control, while 1% sobrerol (isoeffective in chemoprevention to 5% limonene) did not. However, both 5% limonene and 1% sobrerol diets greatly increased the levels of microsomal EH protein and associated hydrating activities towards benzo[a]pyrene 4,5-oxide when compared to control and PB treatment. These changes also modified the rate and regioselectivity ofin vitromicrosomal DMBA metabolism when compared to PB treatment or control. Identification of the specific isoforms of CYP induced by these terpenoids was performed using antibodies to CYP isozymes in Western blot analysis and inhibition studies of microsomal DMBA metabolism. Five per cent limonene was more effective than 1% sobrerol at increasing the levels of members of the CYP2B and 2C families but was equally effective at increasing EH. Furthermore, both terpenoid diets caused increased formation of the proximate carcinogen, DMBA 3,4-dihydrodiol. While these terpene-induced changes in hepatic CYP and EH do not explain the anticarcinogenic mechanism of these chemopreventive agents, or the ability of limonene systemically to reduce DMBA-DNA binding, they do reveal novel and selective induction mechanisms of hepatic enzymes.