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Alteration of Differentiation State of Human Hepatocytes Cultured with Novobiocin and Butyrate¹

First Department of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan 113

Chang liver cells cultured in the simultaneous presence of novobiocin and butyrate stopped proliferating and changed into fibroblast-like cells with remarkably elongated cytoplasm. In these fibroblast-like cells, the cellular content of both protein and DNA was increased 2- to 3-fold. In addition, the production of specific proteins such as type III procollagen, actin, and tubulin was increased and the expression of proliferation-associated nuclear antigen which was reactive with Ki-67 monoclonal antibody was reduced remarkably. Therefore, Chang liver cells cultured with novobiocin and butyrate were considered to be arrested at the premitotic G₂ phase of the cell cycle and then enter into the noncycling resting state. These actions of novobiocin and butyrate were not mediated by the pathway of epidermal growth factor action or modulated by the diacylglycerol agonist 1-oleoyl-2-acetylglycerol and the C kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine. On the other hand, novobiocin was disclosed to be a stimulator of [³H]acetate uptake and acted synergistically with butyrate in enhancing nuclear protein acetylation. From these results it can be speculated that novobiocin and butyrate chemically modulate nuclear proteins and thereby alter the gene expression and the differentiation state of Chang liver cells.

¹ This work was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare for the Comprehensive 10-year strategy for Cancer Control and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.

Received 8/ 4/89. Revised 1/ 4/90.