Heme oxygenase in the brain

血红素加氧酶是血红素催化剂中的一种必需酶，它能裂解血红素释放一氧化碳、铁和胆绿素。至少有两种类型的血红素加氧酶同工酶，诱导型血红素加氧酶-1和组成型表达血红素加氧酶-2。我们发现NO供体硝普钠可诱导人胶质母细胞瘤细胞（T98 G和A172）、人宫颈癌细胞（HeLa）、黑色素瘤细胞（MeWo）和结肠癌细胞（DLD- 1）表达血红素加氧酶-1。DLD-1细胞瞬时转染实验表明，硝普钠对血红素加氧酶-1的诱导作用是由人血红素加氧酶-1基因启动子区（约-4.0kb）的镉响应元件和AP-1介导的。此外，我们发现，在人类血红素加氧酶-1基因启动子区（约-200 B）的（GT）n重复是高度多态性。另一方面，血红素氧合酶-1 mRNA的表达在T98 G细胞中被干扰素-γ显著抑制，表明脑中存在血红素氧合酶-1过表达的调节系统。虽然肾上腺髓质素最初被报道在大脑中是不存在的，我们发现，肾上腺髓质素和它的mRNA在人脑和垂体中高度表达。肾上腺髓质素可由胶质母细胞瘤、脉络丛癌和结肠癌等多种肿瘤产生，提示肾上腺髓质素与肿瘤细胞的生长和增殖有关。血红素氧合酶-1已知由缺氧诱导。我们发现肾上腺髓质素也被缺氧诱导。肾上腺髓质素具有扩张血管和支气管的作用，这种诱导可能是对缺氧的一种防御反应。

Heme oxygenase is an essential enzyme in heme catabolism that cleaves heme to release carbon monoxide, iron and biliverdin. There are at least two types of heme oxygenase isozymes, inducible heme oxygenase-1 and constitutively expressed heme oxygenase-2. We have found that expression heme oxygenase-l is induced by NO donors, such as sodium nitroprusside, in variouskinds of cultured cells including human glioblastoma cells (T98G and A 172), human cervical cancer cells (HeLa), melanoma cells (MeWo) and colonic carcinoma cells (DLD)- 1). Transient transfection assays using DLD-1 cells revealed that heme oxygenase-1 induction by sodium nitroprusside was mediated by cadmium-responsive element and AP-1, which are located in the promoter region of human heme oxygenase-1 gene (about -4.0 kb). In addition, we showed that a(GT)n repeat in the human heme oxygenase-1 gene promotor region (about -200 b) is highly polymorphic. On the other hand, expression of heme oxygenase-1 mRNA was considerably suppressed by interferon-gamma in T98G cells, suggesting the presence of a regulatory system for heme oxygenase-l overexpression in the brain.Adrenomedullin is a vasodilator peptide isolated from pheochromocytoma. Although adrenomedullin was initially reported to be absent in the brain, we showed that adrenomedullinand its mRNA were highly expressed in the human brain and pituitary. Adrenomedullin is produced by various kinds of tumors including glioblastoma, choroid plexus carcinoma and colonic carcinoma, suggesting that adrenomedullin is related to the growth and proliferation of tumor cells. Heme oxygenase-1 is known to be induced by hypoxia. We showed that adrenomedullin was also induced by hypoxia. This induction may be a defense reaction agaist hypoxia, because adrenomedullin has vasodilator and bronchodilator actions.