Abstract
Erythropoietic protoporphyria patients can develop cholestasis, severe hepatic damage, fibrosis, and cirrhosis. We modeled this hepatic pathology in C57BL/6J and BALB/c mice using griseofulvin and analyzed 3,127 genes for alteration of expression in the liver before and during the onset of protoporphyria, cholestasis, inflammation, and hepatic fibrosis. The two mouse strains developed different levels of pathologic damage in response to the griseofulvin. Characteristic gene expression profiles could be associated with griseofulvin-induced gene expression, disruption of lipid metabolism, and the pathologic states of inflammation, early fibrosis, and cholestasis. Additionally, some genes individually indicated an alteration of homeostasis. or pathologic state; for example, fibroblast proliferation was potentially indicated by increased calcyclin (SA100a6) expression. Changes in cytochrome P450 (Cyp) gene expression were particularly pronounced, with increased expression of the Cyp2a, Cyp2b, and Cyp3a families. Decreased Cyp4a10 and Cyp4a14 expression was observed that could be associated with early pathologic change. A potential decrease in bile acid and steroid biosynthesis was indicated by the decreased expression of Cyp7b1 and Hsd3b4, respectively. DNA damage was indicated by induction of GADD45. This study illustrates how transcriptional programs can be associated with different stimuli in the same experiment. The time course of change in the gene expression profile compared with changes in pathology and clinical chemistry shows the potential of this approach for modeling causative, predictive, and adaptive changes in gene expression during pathologic change.
Highlights
The relative importance of these genetic factors and the way they might interact are not fully understood
This porphyria is induced by the inhibition of ferrochelatase probably caused by a griseofulvin adduct of protoporphyrin IX produced in a cytochrome P450 (Cyp)-mediated suicide reaction (Bellingham et al 1995)
The changes in liver pathology with griseofulvin are similar to those found with human erythropoietic protoporphyria (EP)-associated liver failure that occurs in a subset of patients and probably depends on genetic and physiologic susceptibility factors to determine its onset (Bloomer et al 1998; Cox et al 1998; Kappas et al 1995)
Summary
The relative importance of these genetic factors and the way they might interact are not fully understood. None of the above studies have addressed the potential influence of cellular response, altered organ homeostasis, and resulting pathologic change on gene expression profiles This issue was addressed later by Hamadeh et al (2002c), who were able to associate gene expression profiles with pathologic change in the liver after methapyrilene exposure. CDNA microarray analysis was used to generate gene expression profiles associated with the early development of protoporphyria and the complex pattern of liver pathology that developed. These gene expression profiles were used to produce a molecular map of pathologic change and griseofulvin exposure in this system
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