AROMATIC HYDROCARBON RESPONSIVENESS-RECEPTOR AGONISTS GENERATED FROM INDOLE-3-CARBINOL INVITRO AND INVIVO - COMPARISONS WITH 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN
AROMATIC HYDROCARBON RESPONSIVENESS-RECEPTOR AGONISTS GENERATED FROM INDOLE-3-CARBINOL INVITRO AND INVIVO - COMPARISONS WITH 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN
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DOI：
10.1073/pnas.88.21.9543
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发表时间：
1991-11-01
影响因子：
11.1
通讯作者：
BRADFIELD, CA
中科院分区：
文献类型：
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作者：
BJELDANES, LF;KIM, JY;BRADFIELD, CA
吲哚-3-甲醇（I3C）是一种在芸苔属蔬菜中产生的次生植物代谢物，包括卷心菜、花椰菜和球芽甘蓝。I3C是致癌的抗引发剂和促进剂。人类和啮齿类动物摄入I3C可导致细胞色素p -450依赖性单加氧酶和多种II期药物代谢酶的活性显著增加。我们之前报道过13C的酶诱导活性是通过一种需要将化合物暴露于胃的低ph环境的机制介导的。本文报告了用C57BL/6J小鼠肝细胞质测定的芳烃响应性受体K(d)值（22 nM-90 nM），以及13C主要酸缩合产物的体外和体内摩尔产率（0.1-6%）。我们还表明，吲哚[3,2-b]咔唑（ICZ）是由13C合成的，体外产率约为0.01%，口服插管后，体内产率为0.01%。通过小鼠肝癌Hepa 1c1c7细胞中乙氧基间苯二酚o -去乙基化酶活性测定，ICZ对芳烃反应受体结合的K(d)为190 pM，对细胞色素P4501A1的诱导作用的EC50为269 nM。ICZ的结合亲和力仅比高毒性环境污染物和癌症启动子2,3,7,8-四氯二苯并-对二恶英的结合亲和力低3.7 × 10（-2）倍。ICZ和相关缩合产物似乎是日粮I3C诱导酶作用的原因。
Indole-3-carbinol (I3C) is a secondary plant metabolite produced in vegetables of the Brassica genus, including cabbage, cauliflower, and brussels sprouts. I3C is both an anti-initiator and a promoter of carcinogenesis. Consumption of I3C by humans and rodents can lead to marked increases in activities of cytochrome P-450-dependent monooxygenases and in a variety of phase II drug-metabolizing enzymes. We have reported previously that the enzyme-inducing activity of 13C is mediated through a mechanism requiring exposure of the compound to the low-pH environment of the stomach. We report here the aromatic hydrocarbon responsiveness-receptor K(d) values (22 nM-90 nM), determined with C57BL/6J mouse liver cytosol and the in vitro- and in vivo-molar yields (0.1-6%) of the major acid condensation products of 13C. We also show that indolo[3,2-b]carbazole (ICZ) is produced from 13C in yields on the order of 0.01% in vitro and, after oral intubation, in vivo. ICZ has a K(d) Of 190 pM for aromatic hydrocarbon responsiveness-receptor binding and an EC50 of 269 nM for induction of cytochrome P4501A1, as measured by ethoxyresorufin O-deethylase activity in murine hepatoma Hepa 1c1c7 cells. The binding affinity of ICZ is only a factor of 3.7 x 10(-2) lower than that of the highly toxic environmental contaminant and cancer promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin. ICZ and related condensation products appear responsible for the enzyme-inducing effects of dietary I3C.