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Timothy W. Gant,¹ Petra R. Baus,¹ Bruce Clothier,¹ Joan Riley,¹ Reginald Davies,¹ David J. Judah,¹ Richard E. Edwards,¹ Elisabeth George,² Peter Greaves,¹ and Andrew G. Smith¹

¹MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom; ²GlaxoSmithKline, Ware, Hertfordshire, United Kingdom

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. Key words: fibrosis, inflammation, liver, microarray, protoporphyria. Environ Health Perspect 111:847-853 (2003) .