Inhibition of increases in ornithine decarboxylase and putrescine has no effect on rat liver regeneration

Abstract

Polyamines are considered critical for cell proliferation. During liver regeneration in the rat, ornithine decarboxylase (ODC) mRNA and enzyme activity and polyamines (primarily putrescine and spermidine) are known to increase substantially. We examined the effect of inhibition of polyamine synthesis with alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of the ODC enzyme, on regenerating liver weight and total DNA, RNA, and protein, [3H]thymidine and [14C]leucine incorporation, number of mitotic figures, and putrescine, spermidine, and spermine contents. Rats received DFMO beginning 4 days before or immediately after two-thirds partial hepatectomy. In control rats, ODC activity, putrescine, and spermidine increased significantly during regeneration, whereas spermine was unchanged. In rats receiving DFMO, ODC and putrescine changed minimally but spermidine increased as usual. Spermine levels were modestly higher in rats receiving DFMO beginning 4 days before partial hepatectomy. However, despite ODC inhibition and substantially lower levels of putrescine, the course of liver regeneration in rats treated with DFMO was not affected. Total liver mass, DNA, RNA, and protein increased over 5 days equally in rats receiving DFMO and control rats. In addition, there were no differences in [3H]thymidine incorporation into DNA, [14C]leucine incorporation into protein or mitotic indexes between DFMO-treated and control rats at 24 and 48 h after partial hepatectomy. These results suggest that the well-known increases in ODC activity and polyamines that occur during regeneration are not required for liver to undergo its proliferative response to partial hepatectomy.