Estrogenic activity of styrene oligomers after metabolic activation by rat liver microsomes
Estrogenic activity of styrene oligomers after metabolic activation by rat liver microsomes
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DOI：
10.1289/ehp.5723
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发表时间：
2003-03-01
影响因子：
10.4
通讯作者：
Ohta, S
中科院分区：
文献类型：
--
作者：
Kitamura, S;Ohmegi, M;Ohta, S
在这项研究中，我们研究了大鼠肝微粒体代谢活化后苯乙烯低聚物的雌激素活性。反式-1，2-二苯基环丁烷（TCB）、顺式-1，2-二苯基环丁烷（CCB）、1，3-二苯基丙烷、2，4-二苯基-1-丁烯、2，4，6-三苯基-1-己烯和1 α-苯基-4 β-（1 '-苯乙基）四氢化萘在酵母雌激素筛选试验和使用雌激素应答人乳腺癌细胞系MCF-7的雌激素报告基因试验中均为阴性。然而，TCB与苯巴比妥处理的大鼠的肝微粒体在还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的存在下孵育后表现出雌激素活性。当使用未处理或3-甲基胆蒽处理大鼠的肝微粒体代替苯巴比妥处理大鼠的肝微粒体时，观察到轻微的活性。CCB、1，3-二苯基丙烷和2，4-二苯基-1-丁烯经肝微粒体代谢活化后也表现出雌激素活性，但活性低于TCB。2，4，6-三苯基-1-己烯和1 α-苯基-4 β-（1 '-苯乙基）四氢化萘在这样的孵育后没有显示雌激素活性。当TCB与苯巴比妥处理的大鼠的肝微粒体在NADPH的存在下孵育时，通过高效液相色谱法（HPLC）检测到三种代谢产物。通过HPLC分离的一种代谢产物表现出显着的雌激素活性。通过质谱和核磁共振谱分析，确定活性代谢产物为反式-1-（4-羟基苯基）-2-苯基环丁烷。这些结果表明，TCB的雌激素活性是由4-羟基化代谢产物的形成引起的。
In this study we examined estrogenic activity of styrene oligomers after metabolic activation by rat liver microsomes. trans-1,2-Diphenylcyclobutane (TCB), cis-1,2-diphenylcyclobutane (CCB), 1,3-diphenylpropane, 2,4-diphenyl-1-butene, 2,4,6-triphenyl-1-hexene, and 1alpha-phenyl-4beta-(1'-phenylethyl)tetralin were negative in the yeast estrogen screening assay and estrogen reporter assay using estrogen-responsive human breast cancer cell line MCF-7. However, TCB exhibited estrogenic activity after incubation with liver microsomes of phenobarbital-treated rats in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH). Minor activity was observed when liver microsomes of untreated or 3-methylcholanthrene-treated rats were used instead of those from phenobarbital-treated rats. CCB, 1,3-diphenylpropane, and 2,4-diphenyl-1-butene also exhibited estrogenic activity after metabolic activation by liver microsomes, but the activity was lower than that of TCB. 2,4,6-Triphenyl-1-hexene and 1alpha-phenyl-4beta-(1'-phenylethyl)tetralin did not show estrogenic activity after such incubation. When TCB was incubated with liver microsomes of phenobarbital-treated rats in the presence of NADPH, three metabolites were detected by high-performance liquid chromatography (HPLC). One metabolite isolated by HPLC exhibited a significant estrogenic activity. The active metabolite was identified as trans- 1-(4-hydroxyphenyl)-2-phenylcyclobutane by mass and nuclear magnetic resonance spectral analysis. These results suggest that the estrogenic activity of TCB was caused by the formation of the 4-hydroxylated metabolite.