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Uroporphyria in the Cyp1a2-/- mouse
John D Phillips1, James P Kushner, Hector A Bergonia
1University of Utah School of Medicine, Department of Internal Medicine, Division of Hematology, Salt Lake City, UT 84132, USA. john.phillips@hsc.utah.edu
Blood Cells, Molecules & Diseases
|September 2, 2011
Summary
Cytochrome P4501A2 (Cyp1a2) is not essential for developing uroporphyria in mice when genetic factors like hemochromatosis (Hfe) and uroporphyrinogen decarboxylase (Urod) are manipulated, revealing an iron-dependent pathway.
Area of Science:
- Biochemistry
- Genetics
- Toxicology
Background:
- Cytochrome P4501A2 (Cyp1a2) plays a role in uroporphyria development in mice, a model for human porphyria cutanea tarda.
- Mice lacking Cyp1a2 typically do not develop uroporphyria under standard conditions.
Purpose of the Study:
- To investigate if Cyp1a2 is essential for uroporphyria development in mice with combined genetic predispositions.
- To explore the role of iron and other factors in triggering uroporphyria in genetically modified mice.
Main Methods:
- Generation of triple mutant mice (Cyp1a2-/-;Hfe-/-;Urod+/-).
- Treatment of mice with iron-enriched diets, parenteral iron-dextran, δ-aminolevulinic acid, and Aroclor 1254.
- Analysis of uroporphyrin accumulation and UROD activity.
Main Results:
- Uroporphyria developed in Cyp1a2-/-;Hfe-/-;Urod+/- mice treated with iron and δ-aminolevulinic acid, irrespective of Aroclor 1254.
- Hepatic porphyrin levels correlated with low UROD activity and high levels of a UROD inhibitor.
- Variability in porphyric response was observed, independent of major gene expression differences or hepatic iron concentration.
Conclusions:
- Cyp1a2 is not essential for uroporphyria development when specific genetic manipulations (Hfe, Urod) are present.
- An iron-dependent pathway, independent of Cyp1a2, likely contributes to the generation of the UROD inhibitor, driving uroporphyria.
