A MORPHOLOGICAL STUDY OF THE HEPATIC RESPONSE TO A SINGLE INJECTION OF THIOACETAMIDE.

Abstract

A single injection of thioacetamide (TAA) induces a significant increase in hepatocytes' DNA synthesis and mitosis within 48 hours without accompanying pathology. The present study explores this mitogen system by characterizing several changes in the livers of young adult SD rats following an injection of TAA under controlled conditions. Radioautography of ('3)H-thymidine labeled livers showed an initial depression in the number of hepatocytes in S phase after TAA. This was followed by a significant increase in DNA synthesis beginning by 24 hours. The hepatocytes entering DNA synthesis and subsequently undergoing mitosis were localized initially to zone 1, followed by zone 2. The labeled hepatocytes remained localized for at least 8 weeks. The hepatocyte mitotic index was slightly depressed for 30 hours after TAA and then increased for 36 hours. The increase in the mitotic index followed that in the DNA synthetic index by 8 to 12 hours. The natural synchrony of hepatocytes' cell cycles was verified. The increased proliferative response after TAA was also synchronous, although a slight lengthening of the S + G(,2) interval may have occurred. The percentage of binucleated hepatocytes decreased between 24 and 30 hours after TAA; possibly indicating that binucleated cells enter a round of cell division more readily than other hepatocytes. Plasma alpha-fetoprotein (AFP) concentrations increased significantly during the first and third days after TAA. The first wave was a G(,1) event indicating that hepatocytes in young adult rats remain capable of synthesizing AFP and that they need not have entered a round of DNA synthesis and mitosis prior to secreting AFP. Immunofluorescent labeling specific for AFP verified that virtually all of the differentiated hepatocytes were responsible for the AFP synthesis. This mitogen system to explore liver proliferation and growth control is proposed as an alternative to partial hepatectomy. The regimen of a single low dose of TAA creates a model system of cellular proliferation with which to study the earliest changes leading to DNA synthesis and mitosis and the enhanced expression of AFP genes without the requirement of extended time periods as with chronic administration of hepatocarcinogens.