Wy-14,643 stimulates hepatic protein kinase C activity.
The mechanism by which hypolipidemic drugs and industrial plasticizers cause hepatic tumors in rodents remains unknown. Protein kinase C is elevated during hepatic cell turnover, and sustained cellular replication has been shown to correlate with an increase in hepatic tumors. Therefore, the effect of [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) on protein kinase C activity was examined. Female Sprague-Dawley rats were given 100 mg/kg Wy-14,643 in olive oil (i.g.), while control rats received equal volumes of oil vehicle. After 24 h, the activity of protein kinase C was estimated in isolated hepatic fractions by measuring the binding of 3H-phorbol-12,13-dibutyrate, a specific ligand for protein kinase C. Administration of Wy-14,643 significantly increased protein kinase C activity nearly 2-fold in microsomal fractions. Thus, it is possible that Wy-14,643 increases cell proliferation and causes tumors by mechanisms involving protein kinase C.
Bojes
H K
HK
Department of Pharmacology, University of North Carolina, Chapel Hill 27599-7365.
Keller
B J
BJ
Thurman
R G
RG
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D011493:Protein Kinase C / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000924:Anticholesteremic Agents; D011743:Pyrimidines; C006253:pirinixic acid; D011493:Protein Kinase C