MOUSE MODELS FOR STUDYING THE EFFECTS OF ALCOHOL AND ASCORBIC ACID IN PCT

Peter R Sinclair, Nadia Gorman, Heidi W. Trask, Juliana G. Szakacs, George H. Elder, Dominic Balestra, Nicholas J. Jacobs, Judith M. Jacobs, Jacqueline F. Sinclair , and Glenn S. Gerhard

VA Medical Center, White River Junction, VT; Dartmouth Medical School, Hanover, NH; University of Utah Medical School, Salt Lake City, UT ; Geisinger Clinic, Danville, PA, USA and University of Wales College of Medicine, Cardiff, UK.

 

Although several risk factors in PCT have been recognized, consumption of alcoholic beverages is the main risk factor in PCT. The mechanism of the effect of alcohol remains unknown. One of the problems has been the lack of an animal model. Recently, we demonstrated that mice which are null mutants for the Hfe gene, and are used as models for studying hereditary hemochromatosis, accumulate large amounts of hepatic uroporphyrin after 5-7 months’ continual consumption of ethanol in the drinking water (1). This was associated with increased hepatocyte Perl staining for iron. There was no hepatic uroporphyrin accumulation in wild-type mice. This work was initially performed in 129S6 mice but has now been investigated in other mouse strains.

Another risk factor in PCT has been suggested to be low plasma ascorbate, based on studies in hepatocyte cultures, rat models and an initial study in patients. This work has now been extended to mice carrying null mutations in an enzyme required for ascorbate synthesis. In the absence of iron loading, decreased hepatic ascorbate increased sensitivity for development of uroporphyria. However, when iron overload was produced by administration of iron dextran, there was no further increase in uroporphyrin accumulation in ascorbate-deficient mice, beyond that produced in mice with normal hepatic ascorbate levels. There also was no depletion of hepatic ascorbate by the administered iron.

These results will be discussed and compared with other known risk factors in mouse PCT models and their applicability to the human disease.

 

1. Gorman N, Trask HW, Bement WJ, Szakacs JG, Elder GH, Balestra D, Jacobs NJ, Jacobs JM, Sinclair JF, Gerhard GS, Sinclair PR. Genetic factors influence ethanol-induced uroporphyria in Hfe(-/-) mice. Hepatology. 2004,40:942-50.