REGULATION OF HEME METABOLISM IN THE LIVER

血红素是血红素蛋白的辅基，其参与重要的细胞免疫调节。 所有需氧生物的功能。 因此，它的新陈代谢非常精细 调节以满足生物体的主要细胞需求。 遗传 血红素合成中的病变发生在人类中，并且是 血红素缺乏的状态，被称为卟啉症。 在斑状个体中， 包括药物和饮食在内的多种因素经常诱发急性 危及生命的发作，其特征为严重的神经精神和 腹部症状 在这些个体中，葡萄糖治疗是 有益的，而在那些谁仍然顽固，静脉血红素被发现 以显著缓解这些症状。 然而，无论是 葡萄糖或血红素介导的改善仍然难以捉摸， 不被理解 不相信现有的机械解释， 为了寻找病因学线索，我们重新检查了代谢效应， 急性血红素缺乏症 这种重新评估导致了我们的工作 假设增强L-色氨酸，导致肝损害 色氨酸吡咯酶在急性血红素缺乏症，是一个共同的分母， 血红素可逆性生化异常和神经精神异常 急性肝卟啉症的病理学。 现在建议进行研究， 确定L-色氨酸是否也可能是肝神经连接到 腹部症状，急性肝卟啉症的主要特征， 阐明葡萄糖介导的神经系统症状改善 这可能是由于绕过了一个Dahan介导的阻滞， 异源发生 肝血红素也是必不可少的装配肝血红素蛋白 细胞色素P-450和色氨酸吡咯酶是其最狂热的消费者。 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血红素可用性的调节。 建议进行研究，以探讨这些具体方面，以及 阐明当细胞色素P-450（s） 血红素部分被非天然类似物中血红素取代。 最后， 提出研究以检查底物介导的某些 细胞色素P-450同工酶，这种失活的贡献，急性 肝血红素缺乏和色氨酸吡咯酶受损。

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.