Rat Liver Hyperplasia: Polyamine Concentrations Maintained Despite Ornithine Decarboxylase Inhibition

Abstract

The polyamines (putrescine, spermidine, spermine) and the key enzyme controlling their synthesis (ornithine decarboxylase, ODC) are considered important for many adaptive growth responses. In most epithelial cell populations enhanced proliferation is preceded by or associated with elevated ODC activity. We investigated whether inhibition of ODC activity reduces hepatic proliferation after mitogenic challenge. Rats maintained on a 2% oral solution of the L-ornithine analogue α-difluoromethylornithine (DFMO) were compared to positive controls in their response to mitogenic challenge. Adaptive growth was induced by partial hepatectomy (PH), or by a single dose of either phenobarbital (PB) (100 mg kg-1, gastric tube), cyproterone acetate (CPA) (100 mg kg-1, ip) or clofibrate (500 mg kg-1, gastric tube). Although these stimuli normally elevate ODC levels, DFMO proved to be a powerful inhibitor. Inhibition of ODC activity correlated with the absence of detectable levels of putrescine; without DFMO, putrescine levels were approximately 200 nmol g-1 wet weight in each case following mitogenic challenge. Proliferation, as measured by 5-bromo-2′-deoxyuridine (BrdUrd) labeling at 24 h following stimulation, was largely unaffected by DFMO, and hepatic levels of spermidine and spermine were not significantly reduced. The hepatic levels of these downstream polyamines were high despite ODC inhibition, indicating an important role for them in these adaptive growth responses. These data suggest that an alternative polyamine metabolism pathway not affected by DFMO might be in operation here, or that an exogenous source of polyamines might exist.