Hormonal regulation of the zonated expression of cytochrome P-450 3A in rat liver.
Hormonal regulation of the zonated expression of cytochrome P-450 3A in rat liver.
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DOI：
10.1042/bj3090055
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发表时间：
1995-07
期刊：
影响因子：
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通讯作者：
T. Oinonen;K. Lindros
中科院分区：
文献类型：
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作者：
T. Oinonen;K. Lindros
大多数细胞色素 P-450 酶在肝脏中以分区模式特征性表达。造成这种异质表达的因素很大程度上未知。在此，我们报告生长激素和三碘甲状腺原氨酸如何调节类固醇羟基化细胞色素 P-450 (CYP) 3A 形式，该形式主要在静脉周围（下游）肝脏区域组成型表达。通过比较从门静脉周围和静脉周围腺泡区域获得的细胞裂解物，我们观察到垂体切除术后观察到的 CYP3A 表达升高主要是由于通常沉默的门静脉周围区域的急剧增加。这种效应在女性中尤其强烈。生长激素治疗重新建立了静脉周围表达模式，肝切片的免疫组织化学分析证实了这一发现。通过逆转录酶 PCR 对门静脉周围和静脉周围 mRNA 的分析表明，在男性中，CYP3A2 mRNA 的变化与蛋白质水平的变化平行。在女性中，只有在垂体切除术后才检测到 CYP3A2 mRNA，带状蛋白变化似乎受 CYP3A1 mRNA 水平变化的控制。用三碘甲腺原氨酸治疗垂体切除的动物也抑制了雄性和雌性中 CYP3A 的表达。然而，这种情况几乎只发生在门静脉周围区域。通过免疫印迹和免疫组织化学测定，在蛋白质水平以及 CYP3A1 和 3A2 mRNA 水平上都观察到了这一点。这些结果表明，生长激素和甲状腺激素通过抑制肝脏门脉周围（上游）区域的转录来调节 CYP3A 基因的区域特异性表达。
Most cytochrome P-450 enzymes are expressed characteristically in a zonated pattern in the liver. The factors responsible for this heterogenous expression are largely unknown. Here we report how growth hormone and tri-iodothyronine regulate the steroid-hydroxylating cytochrome P-450 (CYP) 3A forms, which are constitutively expressed mainly in the perivenous (downstream) liver region. By comparing cell lysates obtained from the periportal and perivenous acinar regions we observed that the elevated CYP3A expression observed after hypophysectomy was due mainly to a dramatic increase in the normally silent periportal region. This effect was particularly strong in females. Treatment with growth hormone re-established the perivenous expression pattern, a finding corroborated by immunohistochemical analysis of liver sections. Analysis of periportal and perivenous mRNA by reverse-transcriptase PCR demonstrated that in males the changes in CYP3A2 mRNA paralleled the changes at the protein level. In females, CYP3A2 mRNA was detected only after hypophysectomy, and the zonal protein changes seemed to be governed by changes in CYP3A1 mRNA levels. Treatment of hypophysectomized animals with tri-iodothyronine also suppressed the expression of CYP3A, both in males and females. However, this occurred almost exclusively in the periportal region. This was observed both at the protein level, as determined by immunoblotting and immunohistochemically, and at the CYP3A1 and 3A2 mRNA level. These results indicate that growth hormone and thyroid hormone regulate the expression of CYP3A genes zone-specifically by suppressing their transcription in the periportal (upstream) region of the liver.