Vogel C, Schuhmacher U S, Degen G H, Bolt H M, Pineau T, Abel J
Division of Toxicology, Heinrich-Heine-University of Düsseldorf, Auf'm Hennekamp 50, Düsseldorf, 40225, Germany.
Arch Biochem Biophys. 1998 Mar 15;351(2):265-71. doi: 10.1006/abbi.1997.0555.
Prostaglandin endoperoxide H synthases (PGHS-1 and PGHS-2) catalyze an intermediate step in the biosynthesis of prostaglandins and thromboxanes. Recently, it was observed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) modulates the expression of PGHS-2 mRNA in different cell lines. The main aim of this study was to examine whether PGHS-2 mRNA expression can be changed by acute TCDD in vivo and, second, we were also interested in whether modulation of PGHS-2 is mediated by the aryl hydrocarbon receptor (AhR) which is known to be involved in the transcriptional control of TCDD-induced phase 1 and phase 2 enzymes. Initially C57BL/6J mice were treated with a single dose of 10,000 ng TCDD/kg and the PGHS-1 and PGHS-2 mRNAs were analyzed in liver, lung, thymus, kidney, and spleen. In all tissues examined the expression of PGHS-1 mRNA was not affected by TCDD. However, TCDD treatment enhanced the PGHS-2 mRNA levels in lung and spleen. No effect of TCDD on PGHS-2 expression was found in liver and kidney. For dose-response studies C57BL/6J and DBA/2J mice were treated for 24 h with various doses of TCDD (1-50,000 ng/kg) and the PGHS-2 mRNA increases were analyzed in lungs and spleens. A significant increase of PGHS-2 mRNA in lungs of C57BL/6J mice was found at a dose of 100 ng TCDD/kg, whereas a nearly 100-fold higher TCDD dose was needed to increase PGHS-2 in DBA/2J mice. A similar dose-dependent induction of PGHS-2 was found in spleens of C57BL/6J mice; however, no significant increase of PGHS-2 was found in spleens of DBA/2 mice. These results indicate an involvement of AhR in TCDD-mediated changes of PGHS-2 expression. This suggestion is supported by studies in AhR-deficient animals which showed that TCDD had no effect on PGHS-2 mRNA. When changes of PGHS-2 mRNA expression are compared with those of CYP1A1 between 4 and 72 h after TCDD, it is noteworthy that TCDD led to a delayed and more transient increase of PGHS-2. These data suggest that the mechanism of modulation of both genes by TCDD may be different.
前列腺素内过氧化物H合酶（PGHS - 1和PGHS - 2）催化前列腺素和血栓素生物合成的中间步骤。最近，有人观察到2,3,7,8 - 四氯二苯并 - p - 二恶英（TCDD）可调节不同细胞系中PGHS - 2 mRNA的表达。本研究的主要目的是检测急性TCDD在体内是否能改变PGHS - 2 mRNA的表达，其次，我们也想了解PGHS - 2的调节是否由芳烃受体（AhR）介导，已知AhR参与TCDD诱导的1期和2期酶的转录调控。最初，给C57BL / 6J小鼠单次注射10,000 ng TCDD / kg，然后分析肝脏、肺、胸腺、肾脏和脾脏中的PGHS - 1和PGHS - 2 mRNA。在所有检测的组织中，PGHS - 1 mRNA的表达不受TCDD影响。然而，TCDD处理可提高肺和脾脏中PGHS - 2 mRNA的水平。未发现TCDD对肝脏和肾脏中PGHS - 2表达有影响。为了进行剂量反应研究，给C57BL / 6J和DBA / 2J小鼠用不同剂量的TCDD（1 - 50,000 ng / kg）处理24小时，然后分析肺和脾脏中PGHS - 2 mRNA的增加情况。在C57BL / 6J小鼠肺中，当TCDD剂量为100 ng / kg时，PGHS - 2 mRNA显著增加，而在DBA / 2J小鼠中，需要近100倍高的TCDD剂量才能增加PGHS - 2。在C57BL / 6J小鼠脾脏中也发现了类似的PGHS - 2剂量依赖性诱导；然而，在DBA / 2小鼠脾脏中未发现PGHS - 2有显著增加。这些结果表明AhR参与了TCDD介导的PGHS - 2表达变化。AhR缺陷动物的研究支持了这一观点，该研究表明TCDD对PGHS - 2 mRNA没有影响。当比较TCDD处理后4至72小时内PGHS - 2 mRNA表达变化与CYP1A1的变化时，值得注意的是，TCDD导致PGHS - 2的增加延迟且更短暂。这些数据表明TCDD对这两个基因的调节机制可能不同。
