BACKGROUND/AIMS Long-term feeding of mice with a diet containing griseofulvin results in the formation of Mallory bodies, keratin K8 and K18 containing aggregates in hepatocytes. These bodies are biochemically and morphologically identical to the Mallory bodies that emerge in several human liver disorders. The aim of this study was to examine the contribution of K8 and K18 and actin to Mallory body formation. METHODS Mice were fed griseofulvin over a period ranging from 1 day to 20 months. Hepatocyte morphology was monitored by immunocytochemistry, gene expression by Northern and run-off transcription assays, and protein level by Western blotting. RESULTS Griseofulvin feeding induced a series of morphological alterations in hepatocytes that could be grouped into 3 phases: appearance of cholestasis during the first week (phase I), partial hepatocyte recovery at 3 months (phase II), and development of typical Mallory bodies after 3 to 5 months (phase III). All these cellular alterations were associated with perturbations in keratin and actin fibrillar status, coupled with increases in K8, K18 and actin mRNA steady-state level and, in K8 and K18 protein content. The transcriptional activity of the genes was not affected. CONCLUSIONS Perturbations in keratin and actin gene expression and fibrillar organisation constitute early events in the griseofulvin-induced pathological process that in the long-term leads to Mallory body formation. The higher keratin and actin mRNA levels reflect significant increases in mRNA stability taking place at the early phase of griseofulvin intoxication in hepatocytes.