OVEREXPRESSION OF ANTIOXIDANT ENZYMES IN TRANSGENIC MICE DECREASES CELLULAR PLOIDY DURING LIVER-REGENERATION

Reactive oxygen species (ROS) and antioxidant enzymes have been implic ated in control mechanisms of cellular growth and proliferation, We in vestigated the influence of levels of endogenous antioxidant enzymes o n liver regeneration in transgenic mice overexpressing human Cu,Zn-sup eroxide dismutase (SOD) and intracellular glutathione peroxidase (GP1) as a model system. After a two-thirds partial hepatectomy (PH), no si gnificant difference was observed in rate of liver mass restoration am ong nontransgenic, SOD, and GP1 mice, In contrast, the level of polypl oidization was significantly reduced in transgenic animals after PH, w ith a concomitant increase in 2N nuclei. The portion of 8N nuclei afte r 72 h reached 33.1, 15.8, and 22.1%, whereas the portion of 2N nuclei reached 7.5, 13.8, and 12.3% in nontransgenic, SOD, and GP1 mice, res pectively. A similar effect was observed in another model of liver pro liferation, during normal development around weaning time. Measurement s of ROS production during PH indicate that overexpression of SOD lead s to the decreased production of O-2(-) and elevation of H2O2. Unexpec tably, overexpression of GP in transgenic mice also results in increas ed production of H2O2 in hepatocytes. Finally, our data demonstrate th at levels of endogenous antioxidant enzymes might influence the rate o f hepatocyte polyploidization during liver proliferation. (C) 1997 Aca demic Press.