Reversible inhibition of rat hepatocyte proliferation by hydrocortisone and its effect on cell cycle-dependent hepatocarcinogenesis by N-methyl-N-nitrosourea.

The susceptibility of hepatocytes to carcinogenesis in vivo may be influenced by the phase of the cell cycle at which carcinogen-induced damage is incurred. In order to better understand this relationship, hepatic cell proliferation in juvenile male Fischer 344 rats was charted following a two-thirds partial hepatectomy. For hepatocytes, two distinct waves of DNA synthesis occurred which were followed after 6 to 8 hr by waves of mitotic cell division. In contrast to this kinetic pattern, when hydrocortisone was given after the partial hepatectomy, the initial waves of DNA synthesis and mitosis by hepatocytes were each delayed by about 15 hr. In rats not given hydrocortisone, susceptibility to heptocarcinogenesis by N-methyl-N-nitrosourea was greatest at 20 hr after partial hepatectomy when the peak fraction of proliferating hepatocytes was in the S phase. By shifting the time of onset of DNA synthesis, the hydrocortisone treatments also shifted the time with greatest sensitivity to N-methyl-N-nitrosourea, with hepatocytes in late G1 or S again the most susceptible. Numerous tumors were also induced by N-methyl-N-nitrosourea in extrahepatic tissues, including intestine, Zymbal's gland, nervous system, kidneys, odontogenic tissues, and peritesticular mesothelium. The results illustrate the importance of cell proliferation in carcinogenesis and further point to the specific sensitivity of certain cell cycle phases.