Protoporphyria is a genetic disorder in humans and cattle in which there is excessive accumulation and excretion of protoporphyrin because of a defect in the enzyme ferrochelatase (heme synthase). This research will focus on two aspects of protoporphyria: 1) characterization of the ferrochelatase defect and 2) pathogenesis of hepatobiliary disease. Ferrochelatase will be purified from livers of normal and protoporphyric cattle by chromatography on blue Sepharose. Comparison of purified normal and protoporphyric enzymes will include study of kinetic properties, study of sulfhydryl groups which are felt to be located at the active site, determination of isoelectric points, examination of molecular size and detergent binding properties, and peptides mapping. Based on the findings with the bovine enzyme preparations, select studies of the human ferrochelatase defect will be carried out using enzymes purified from human normal and protoporphyric liver tissue. Antibody will be prepared against the purified bovine enzyme in order to compare immunologic reacting material in tissues from normal cattle with tissues from cattle with protoporphyria. Similar studies in human tissues will be done using antibody prepared against the human enzyme. Three types of study will be done to examine the hypothesis that protoporphyrin solubility in bile may be a determinant of hepatobiliary disease in protoporphyria. Crystals will be isolated from the liver of a patient with protoporphyria who underwent liver transplantation and will be characterized to confirm if they are composed of protoporphyrin. Solubility of protoporphyrin in model bile solutions will be examined and correlated with the composition of bile in patients with protoporphyria. Using protoporphyric calves in which bile fistulas are surgically implanted, studies will be done to determine the enterohepatic circulation of protoporphyrin, the effect of bile salts on protoporphyrin excretion in bile, and the effect of hematin administration on protoporphyrin production. Through these studies the pathogenesis and consequences of abnormal protoporphyrin metabolism in protoporphyria will be better defined. This will lead to better therapy of the disease.
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