DISORDERS OF PORPHYRIN METABOLISM

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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.