DISORDERS OF PORPHYRIN METABOLISM

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。迟发性皮肤卟啉症（PCT）是影响人类的卟啉症的最常见形式。PCT的发生率为1 - 5/25，000高加索人，临床特征为皮肤脆弱、大疱（水泡样）病变和阳光暴露区域的增生（毛发生长增加）。这种疾病的遗传缺陷是影响尿卟啉原脱羧酶（URO-D）基因的突变，但大多数URO-D突变杂合子受试者不表达疾病的体征或症状。该疾病的表达通常与肝脏铁过载、暴露于肝毒素如酒精、丙型肝炎病毒和药用雌激素以及该疾病的家族史相关。Kushner和Philllips博士正试图确定这种疾病表达的原因，他们正在测试一种假设，即当肝脏铁过载时，在遗传上易患PCT的个体的肝脏中产生URO-D抑制剂。他们已经开始表征从肝活检标本中提取的低分子量分子，该分子具有体外抑制重组人URO-D活性的能力。已经从URO-D敲除小鼠的肝脏中分离出具有相同物理性质的化合物，所述小鼠与血色素沉着症基因敲除小鼠杂交。结果是这些动物（URO-D基因敲除的杂合子和血色素沉着症基因敲除的纯合子）在肝脏中积累尿卟啉。质谱法和串联质谱法被用来确定URO-D抑制剂的结构。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Porphyria cutanea tarda (PCT) is the most common form of porphyria affecting humans. PCT occurs with the prevalence of 1 to 5/25,000 Caucasians and is clinically characterized by skin fragility, bullous (blister-like) lesions and hypertrichosis (increased hair growth) on sun-exposed areas. The genetic defects underlying this disorder are mutations affecting the uroporphyrinogen decarboxylase (URO-D) gene but most subjects heterozygous for URO-D mutations do not express signs or symptoms of the disease. Expression of the disorder generally is associated with liver iron overload, exposure to liver toxins such as alcohol, the hepatitis C virus and medicinal estrogens, and a familial history of the disorder. Drs. Kushner and Philllips are attempting to determine why the disease is expressed and they are testing the hypothesis that an inhibitor of URO-D is generated in the liver of individuals genetically predisposed to develop PCT when liver iron overload occurs. They have begun to characterize a low molecular weight molecule extracted from liver biopsy specimens that has the ability to inhibit the activity of recombinant human URO-D in vitro. A compound with identical physical properties has been isolated from the livers of URO-D knockout mice that have been crossbred with hemochromatosis gene knockout mice. The result is that these animals (heterozygous for the URO-D knockout and homozygous for the hemochromatosis gene knockout) accumulate uroporphyrin in the liver. Mass spectrometry and tandem mass spectrometry are being employed to establish the structure of the URO-Dinhibitor.