Previously we have shown that partial hepatectomy (PH) or exposure of
the liver to the mitogen prolactin induces activation of hepatic prote
in kinase C (PKC). Here, we used suramin, an antitrypanosomal and chem
otherapeutic drug which inhibits that enzyme, as a probe of PKC signal
transduction in the regenerative response after PH in the rat. Surami
n 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 divi
sion, thymidine kinase activity, [H-3]thymidine incorporation, and mit
otic index were inhibited in a dose-dependent fashion, Baseline PKC ac
tivity, in both the cytosolic and particulate fractions, was unchanged
by suramin. After PH, PKC activation, signalled by an increase in act
ivity in the particulate fraction, was observed in control rats at 30
and 60 min. However, rats which had previously received suramin demons
trated dose-dependent inhibition of PKC activation. Suramin is known t
o also disrupt the binding of certain growth factors to their receptor
s. 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 likew
ise be impaired. However, we observed that the diacylglycerol mass gen
erated at 15, 30, and 45 min after PH was not altered by suramin pretr
eatment. We conclude that the diminution in DNA synthesis after PH by
suramin is likely the consequence of direct inhibition of PKC, suggest
ing that PKC activation is an important, perhaps obligatory, signal tr
ansduction event in liver regeneration.