DIFFERENTIAL-EFFECTS OF CREATINE-KINASE ISOENZYMES AND SUBSTRATES ON REGENERATION IN LIVERS OF TRANSGENIC MICE

Creatine kinase (CK) has been implicated in affecting cell growth, and the CK substrates creatine (Cr) and cyclocreatine (CyCr) have been sh own to have anti-tumor activity. The influence of Cr and CyCr on liver regeneration following major hepatectomy was evaluated in normal and transgenic mice expressing the human ubiquitous mitochondrial isoform of CK (CK-mit) or the brain isoform of CK (CK-B) or livers expressing both CK-mit and CK-B (CK-comb). Expression of CK isoenzymes had little effect on liver regeneration in the absence of dietary supplementatio n with Cr or CyCr as assayed by the increase in liver mass. Dietary su pplementation with Cr and CyCr significantly reduced liver growth in n ormal mice. Liver regeneration was almost completely inhibited in mice expressing CK-mit in the presence of Cr. Livers expressing CK-mit reg enerated better than normal livers in the presence of CyCr. In mice ex pressing CK-B, Cr and CyCr had opposite effects from those found in CK -mit mice. In the presence of CyCr, regeneration was inhibited in live rs expressing CK-B, and, in the presence of Cr, CK-B-expressing livers regenerated better than normal livers. The amount of DNA synthesized 2 days after hepatectomy confirmed the results obtained from measureme nts of liver mass for all groups. Growth and DNA synthesis were comple tely abolished by Cr in CK-mit mice, whereas CyCr mainly affected grow th 2 days after hepatectomy in CK-B-expressing mice. Coexpression of t he CK isoforms in CK-comb mice ameliorated the effects detected with e ither isoform alone. Inhibition of growth by Cr and CyCr was not corre lated to water accumulation. These results clearly demonstrate isoenzy me and substrate-specific effects of CK on cell growth.