Acute dosage with dexrazoxane, but not doxorubicin, is associated with increased rates of hepatic protein synthesis in vivo.
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 sacrificed at either 2.5 or 24 h after the last doxorubicin or saline injection. Rate of protein synthesis were measured 10 min prior to sacrificing rats, with a flooding dose of L-[4-3H]phenylalanine. Liver was analyzed for the protein synthetic capacity (Cs, mg RNA/g protein), the fractional rate of protein synthesis (k(s), %/d), and the RNA activity (kRNA 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, doxorubicin alone had no effect on any of the above variables. Dexrazoxane alone increased Cs, k(s) and kRNA at 2.5 h. Combined dexrazoxane + doxorubicin increased hepatic Cs 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 Cs, k(s), or kRNA but raised plasma activities of alkaline phosphatase and aspartate aminotransferase. Combined dexrazoxane + doxorubicin increased Cs 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.
Zima
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T
1st Institute of Clinical Chemistry and Biochemistry, First Faculty of Medicine, Charles University, Prague 2, Czech Republic.
Tesar
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V
Sherwood
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R
Sood
A
A
Au
L C
LC
Richardson
P J
PJ
Preedy
V R
VR
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004357:Drug Synergism; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D014176:Protein Biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011929:Razoxane / Q000008:administration & dosage / Q000633:toxicity*; D012709:Serum Albumin / Q000032:analysis
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D012709:Serum Albumin; D011929:Razoxane; D004317:Doxorubicin; D001219:Aspartate Aminotransferases; D000469:Alkaline Phosphatase