REGULATION OF HEME METABOLISM IN THE LIVER

血红素是参与生命细胞的血红素蛋白的修复体。 所有需氧生物的功能。因此，它的新陈代谢非常好 调节以满足生物体的普遍细胞需求。遗传 血红素合成中的损伤发生在人类身上，是 血红素缺乏症，也就是所谓的卟啉症。在有斑点的个体中， 包括药物和饮食在内的各种因素经常导致急性 危及生命的攻击以严重的神经精神障碍和 腹部症状。在其中一些人中，葡萄糖疗法是 有益的，而在那些仍然难治的人中，静脉注射的血红素被发现 来戏剧性地缓解这些症状。然而，无论是哪种机制， 葡萄糖或血红素介导的改善仍然难以捉摸，而且 听不懂。不相信现有的机械解释和 为了寻找病因学线索，我们重新检查了代谢的影响 急性血红素缺乏症。这样的重新评估导致了我们的工作 肝损伤导致L-色氨酸升高的假说 色氨酸焦解酶在急性血红素缺乏症中是 血红素可逆性生化异常与神经精神病学 急性肝性门静脉病的症状学。现在建议进行研究，以 确定L-色氨酸是否也可能是肝神经连接到 腹部症状，急性肝门静脉症的主要特征，并 阐明葡萄糖是否能改善神经症状 可能是由于绕过了色氨酸介导的阻滞剂 糖异生作用。 肝脏的血红素也是肝脏血液蛋白组装所必需的。 细胞色素P-450和色氨酸焦解酶，是它最狂热的消费者。 然而，人们对实际组装的机械原理知之甚少 这些血红素蛋白是否受肝脏中可获得的血红素的调节。 建议进行研究，以探索这些特定方面以及 阐明细胞色素P-450的结构与功能关系(S) 亚铁血红素部分被非天然类似物中的亚铁血红素取代。最后， 建议进行研究以检查底物介导的某些特定的失活 细胞色素P-450同工酶，这种失活对急性 肝脏血红素缺乏症与色氨酸焦解酶损伤有关。

Heme is the prosthetic moiety of hemoproteins involved in vital cellular functions of all aerobic organisms. As such, its metabolism is very finely regulated to meet the prevailing cellular needs of the organism. Genetic lesions in heme synthesis occur in humans, and are characteristic of the heme-deficient states, known as the porphyrias. In porphyric individuals, a variety of factors including drugs and diet frequently precipitate acute life-threatening attacks characterized by grave neuropsychiatric and abdominal symptoms. In some of these individuals, glucose therapy is beneficial, while in those who remain refractory, intravenous heme is found to dramatically relieve such symptoms. However, the mechanisms of either glucose- or heme-mediated amelioration have remained elusive and ill-understood. Unconvinced by the existing mechanistic explanations and in search of etiological clues, we have re-examined the metabolic effects of acute heme-deficient states. Such reappraisal has led to our working hypothesis that enhanced L-tryptophan, resulting from impairment of hepatic tryptophan pyrrolase in acute heme deficiency, is a common denominator of the heme-reversible biochemical abnormalities and the neuropsychiatric symptomatology of acute hepatic porphyrias. Studies are now proposed to determine whether L-tryptophan might also be the hepatoneural link to the abdominal symptoms, a cardinal feature of acute hepatic porphyrias, and to elucidate whether glucose-mediated amelioration of neurologic symptoms might be due to circumvention of a tryptophan-mediated block in gluconeogenesis. Hepatic heme is also essential for the assembly of hepatic hemoproteins cytochrome P-450s and tryptophan pyrrolase, its most avid consumers. However very little is known about the mechanics of actual assembly and whether these hemoproteins are regulated by hepatic heme availability. Studies are proposed to probe those particular aspects as well as to elucidate the structure-function relationships when cytochrome P-450(s) heme moiety is substituted by the unnatural analog mesohemin. Finally, studies are proposed to examine substrate-mediated inactivation of certain cytochrome P-450 isozymes, the contributions of such inactivation to acute hepatic heme deficiency and to impairment of tryptophan pyrrolase.