Hepatic accumulation and urinary excretion of uroporphyrin derived from perturbation of the heme biosynthetic pathway is referred to as uroporphyria. The long term goals of this research are 1) to understand the mechanism of hepatic uroporphyria produced in humans and animals by halogenated environmental contaminants such as polyhalogenated aromatic hydrocarbons (PHA) including TCDD and 2) to understand the relationship of this experimental uroporphyria to the common human uroporphyria known as porphyria cutanea tarda which is usually associated with consumption of alcoholic beverages, and hepatitis C infection. Induced CYP1A2 has been previously shown to be involved in the PHA-induced uroporphyria, this role being to catalyze the oxidation of UROgen, the substrate of the enzyme, UROgen decarboxylase (URO-D). There is evidence for a role of iron (Fe) that is not yet understood. The hypotheses to be examined here are 1. That PHA induced uroporphyria is due to CYP1A2-catalyzed oxidation of UROgen that causes inhibition of URO-D and hence uroporphyria; other CYP isoforms may be involved but these roles are minor. 2. That the mechanistic conclusions derived from animal models, especially those concerning the role of CYP1A2 and Fe, are also valid for human uroporphyria.
Specific Aims : I. To use knockout mice to determine whether CYP1A2 or CYP2E have essential roles in uroporphyria in animal models. II. To determine whether human CYP1A2 has an essential role in UROgen oxidation and the development of uroporphyria. III. To study the interaction of Fe and CYP1A2 in the development of uroporphyria.
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