Inhibition of CYP1A1-dependent activity by the polynuclear aromatic hydrocarbon (PAH) fluoranthene.
Inhibition of CYP1A1-dependent activity by the polynuclear aromatic hydrocarbon (PAH) fluoranthene.
复制标题
多核芳香烃 (PAH) 荧蒽抑制 CYP1A1 依赖性活性。
DOI：
10.1016/s0006-2952(97)00561-3
复制
发表时间：
1998
影响因子：
5.8
通讯作者：
Safe,SH
中科院分区：
文献类型：
--
作者：
Willett,KL;Randerath,K;Zhou,GD;Safe,SH
多环芳烃（PAHs）是普遍存在的环境污染物，最近的生物测定为基础的诱导研究已被用来确定暴露于复杂的混合物的多环芳烃。在H4 IIE大鼠肝癌细胞中诱导CYP 1A 1依赖性活性已被广泛用于卤代芳烃的生物测定，最近用于多环芳烃。荧蒽（FL）是一种常见的多环芳烃污染物，在不同的环境样品中，FL没有诱导CYP 1A 1依赖的乙氧基试卤灵O-脱乙基酶（EROD）的活性显着在H4 IIE细胞。然而，在用2 × 10− 5 M FL和有效诱导剂2，3，7，8-四氯二苯并-p-二恶英（TCDD）或苯并[k]荧蒽（BkF）（2 × 10− 8 M）共同处理的细胞中，EROD活性显著降低。此外，治疗TCDD诱导的大鼠微粒体与FL引起EROD活性下降80%。研究表明，FL对H4 IIE细胞CYP 1A 1蛋白或mRNA的诱导无影响，对CYP 1A 1酶抑制数据的分析表明，FL非竞争性抑制CYP 1A 1依赖的活性，32 P-Postlabeling显示FL处理的H4 IIE细胞中没有明显的FL-DNA加合物形成，而FL与BkF或BaP共处理的细胞中，某些PAH-DNA加合物被诱导2倍。这项研究表明，FL是一种抑制剂的CYP 1A 1依赖的酶活性在大鼠肝癌H4 IIE细胞和一些致癌的多环芳烃的遗传毒性可能会调制FL在混合物中含有相对较高水平的这种化合物。
Polynuclear aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, and recently bioassay-based induction studies have been used to determine exposures to complex mixtures of PAHs. Induction of CYP1A1-dependent activity in H4IIE rat hepatoma cells has been used extensively as a bioassay for halogenated aromatic hydrocarbons and more recently for PAHs. Fluoranthene (FL) is a prevalent PAH contaminant in diverse environmental samples, and FL did not induce CYP1A1-dependent ethoxyresorufin O-deethylase (EROD) activity significantly in H4IIE cells. However, in cells cotreated with 2 × 10−5M FL plus the potent inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or benzo[k]fluoranthene (BkF) (2 × 10−8M), there was a significant decrease in EROD activities. Furthermore, treatment of TCDD-induced rat microsomes with FL caused an 80% decrease in EROD activity. Studies showed that FL did not affect induction of CYP1A1 protein or mRNA levels in H4IIE cells, and analysis of enzyme inhibition data using microsomal CYP1A1 indicated that FL noncompetitively inhibited CYP1A1-dependent activity.32P-Postlabeling revealed no significant FL–DNA adduct formation in H4IIE cells treated with FL. However, in cells cotreated with FL plus BkF or benzo[a]pyrene (BaP), certain PAH–DNA adducts were induced 2-fold. This study demonstrated that FL is an inhibitor of CYP1A1-dependent enzyme activity in rat hepatoma H4IIE cells and that the genotoxic potency of some carcinogenic PAHs may be modulated by FL in mixtures containing relatively high levels of this compound.