1. Sponsor Organization: NIH/NIEHS

2. Project Title: 06263-04 MECHANISM OF PORPHYRIA CAUSED BY TCDD

3. Project Focus:

• Project Primary Focus: Human Health Effects
• Project Secondary Focus:

4. Description:

Hepatic porphyria, indistinguishable in its symptoms from clinical Porphyria Cutanea Tarda, is a toxic effect of TCDD and other planar polyhalogenated hydrocarbons. This porphyria is characterized by massive hepatic accumulation of uroporphyrin (URO), produced by oxidation of uroporphyrinogen (UROgen), the first cyclic tetrapyrrole of the heme biosynthetic pathway. Hepatic UROgen decarboxylase (URO-D) is highly decreased in this condition. Previous years of this project have established (using mice, rats and chick in vivo and in hepatocytes in culture) that this porphyria is due to several factors which include the induction of liver specific cytochrome P4501A2 and the amount of UROgen made in the liver. We were the first to show that P4501A2 oxidizes UROgen to URO, and that ALA feeding of mice induced for p4501A2, decreases the time to onset of massive uroporphyria from 5 to less than 2 weeks, indicating the importae of UROgen availability. An important preliminary finding for this proposal is that ascorbic acid prevents URO accumulation in chick hepatocyte cultures and inhibits UROgen oxidation by isolated microsomes from animals induced for P4501A2. Specific Aims: [1] We will continue investigations of the mechanism of the UROgen oxidation in culture and in cell free systems and examine how this oxidation leads to the inhibition of URO-D. [2] We will investigate the possible physiological role of ascorbic acid in preventing URO accumulation in hepatocyte cultures and in intact animals (mice and guinea pigs). [3] We will determine the relationship to human disease of these previous findings with experimental systems, in particular to show that human P4501A2 catalyzes UROgen oxidation and that human hepatocytes accumulate URO when treated with inducers of P4501A2 and ALA. [4] Patients with PCT will be evaluated to see if their plasma ascorbic levels are below normal and whether hepatic P4501A2 is elevated. We will also determine if there is a correlation between P4501A2 phenotype dietary AscA deficiency and urinary excretion of URO.

5. References:

6. Inventory Category:

• Primary: Models
• Secondary:

7. Inventory Subcategory:

• Primary: BASIC RESEARCH
• Secondary:

8. Keywords for Experimental System/Species:

• Species:
• Study Type:
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
• Hormonal Measures:
• Level Of Study:
• Chemistry Metabolism:
• Life Stage:
• Risk Assessment:

10. Chemical Agents:

11. Performing Institution:

• DARTMOUTH COLLEGE

12. Contact:

• CONTACT PERSON: DR. HEINDEL, NIEHS, PO BOX 12233, RESEARCH TRIANGLE PARK, NC 27709, 919-541-0781, HEINDEL_J@NIEHS.NIH.GOV

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