Early perturbations in keratin and actin gene expression and fibrillar organisation in griseofulvin-fed mouse liver

Background/Aims: Long-term feeding of mice with a diet containing griseoful vin results in the formation of Mallory bodies, keratin K8 and K18 containi ng aggregates in hepatocytes. These bodies are biochemically and morphologi cally identical to the Mallory bodies that emerge in several human liver di sorders, The aim of this study was to examine the contribution of K8 and K1 8 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 ex pression 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 cholesta sis during the first meek (phase I), partial hepatocyte recovery at 3 month s (phase II), and development of typical Mallory bodies after 3 to 5 months (phase III), All these cellular alterations mere associated with perturbat ions in keratin and actin fibrillar status, coupled with increases in K8, K 18 and actin mRNA steady-state level and, in K8 and K18 protein content. Th e transcriptional activity of the genes was not affected, Conclusions: Perturbations in keratin and actin gene expression and fibrill ar organisation constitute early events in the griseofulvin-induced patholo gical process that in the long-term leads to Mallory body formation, The hi gher keratin and actin mRNA levels reflect significant increases in mRNA st ability taking place at the early phase of griseofulvin intoxication in hep atocytes.