Okadaic acid, cAMP, and selected nutrients inhibit hepatocyte proliferation at different stages in G1: modulation of the cAMP effect by phosphatase inhibitors and nutrients.

The protein phosphatase inhibitor okadaic acid (> 100 nM) caused an abrupt and complete cessation of primary rat hepatocyte cell cycle progression at the restriction point in late G1. A decline in the G1/S transition rate was observed in response to elevated cAMP, excess selected nutrients, and okadaic acid (< 100 nM). Excess nutrients (40 mM glucose +/- 5 mM dihydroxyacetone) acted by imposing an incomplete block in early G1. The cAMP action was potentiated by the phosphatase inhibitor microcystin, which in itself did not affect DNA replication. This suggests that cAMP acted by phosphorylating substrate(s) that is dephosphorylated by a microcystin-sensitive phosphatase. The additive effects of submaximal concentrations of okadaic acid and cAMP analogs indicated that okadaic acid and cAMP acted via different pathways. In conclusion, okadaic acid, cAMP, and excess nutrients, acting through distinct pathways, inhibited hepatocytes in different parts of the G1 phase.