Suramin, a protein kinase C inhibitor, impairs hepatic regeneration.
Previously we have shown that partial hepatectomy (PH) or exposure of the liver to the mitogen prolactin induces activation of hepatic protein kinase C (PKC). Here, we used suramin, an antitrypanosomal and chemotherapeutic drug which inhibits that enzyme, as a probe of PKC signal transduction in the regenerative response after PH in the rat. Suramin was administered i.p. in nonhepatotoxic doses of 20 to 160 mg/kg 14 days prior to PH. Three measures of hepatic DNA synthesis or cell division, thymidine kinase activity, [3H]thymidine incorporation, and mitotic index were inhibited in a dose-dependent fashion. Baseline PKC activity, in both the cytosolic and particulate fractions, was unchanged by suramin. After PH, PKC activation, signalled by an increase in activity in the particulate fraction, was observed in control rats at 30 and 60 min. However, rats which had previously received suramin demonstrated dose-dependent inhibition of PKC activation. Suramin is known to also disrupt the binding of certain growth factors to their receptors. But if inhibition of PKC activation were conferred by interference with growth factor-receptor binding by suramin, then the generation of diacylglycerol, the second messenger for PKC activation, should likewise be impaired. However, we observed that the diacylglycerol mass generated at 15, 30, and 45 min after PH was not altered by suramin pretreatment. We conclude that the diminution in DNA synthesis after PH by suramin is likely the consequence of direct inhibition of PKC, suggesting that PKC activation is an important, perhaps obligatory, signal transduction event in liver regeneration.
Daller
J A
JA
Department of Surgery, University of Arizona, Tuscon 85724.
Buckley
A R
AR
Van Hook
F W
FW
Buckley
D J
DJ
Putnam
C W
CW
D000818:Animals; D004261:DNA Replication / Q000187:drug effects; D003864:Depression, Chemical; D004075:Diglycerides / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008940:Mitotic Index / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013498:Suramin / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000032:analysis
D004075:Diglycerides; D013498:Suramin; D013937:Thymidine Kinase; D011493:Protein Kinase C