Acute Dosage With Dexrazoxane,but not Doxorubicin,Is Associated With Increased Rates of Hepatic Protein Synthesis in vivo

Abstract

An investigation was carried out into the effects of dexrazoxane and doxorubicin on hepatic protein synthesis in vivo. The protocol included 8 groups of rats and involved a pretreatment stage of 30 min followed by a treatment stage of either 2.5 or 24 h. Male Wistar rats (≅0.15-0.20 kg) were pretreated with either dexrazoxane (100 mg/kg; 5 ml/kg) or saline (0.15 mol/l NaCl; 5 ml/kg). At 30 min after the pretreatment, rats were again injected with either doxorubicin (5 mg/kg; 10 ml/kg) or saline (0.15 mol/l NaCl; 10 ml/kg) in the treatment phase. Rats were sacrifi ced at either 2.5 or 24 h after the last doxorubicin or saline injection. Rate of protein synthesis were measured 10 min prior to sacrifi cing rats, with a fl ooding dose of L-[4-³H]phenylalanine. Liver was analyzed for the protein synthetic capacity (C_s , mg RNA/g protein), the fractional rate of protein synthesis (k_s, %/d), and the RNA activity (k_RNA mg protein/d/mg RNA). Complementary analysis included plasma albumin, total protein and activities of alkaline phosphatase, and aspartate aminotransferase. In the 2.5-h study, doxorubici n alone had no effect on any of the above variables. Dexrazoxane alone increased C_s, k_s and k_RNA at 2.5 h. Combined dexrazoxane + doxorubicin increased hepatic C_S and k_s with concomitant reductions in total plasma protein. In the 24-h study, doxorubicin alone had no effect on any of the variables. Dexrazoxane alone had no effect on either C_S, k_s , or k_RNA but raised plasma activities of alkaline phosphatase and aspartate aminotransferase. Combined dexrazoxane + doxorubicin increased C_s and k_s and decreased total plasma protein and increased plasma aspartate aminotransferase activities at 24 h. In conclusion, there is no evidence that acutely doxorubicin per se has measurable effects on hepatic protein synthesis in vivo in an acute period. However, acutely dexrazoxane increases hepatic protein synthesis, which may represent its putative cytotoxic effects, as indicated by raised serum activities of liver enzymes. A combination of both dexrazoxane + doxorubicin appears to have a greater effect in increasing liver protein synthesis than dexrazoxane alone.