Bilirubin inhibits protein kinase C activity and protein kinase C-mediated phosphorylation of endogenous substrates in human skin fibroblasts.
The primary target and molecular basis of bilirubin toxicity to cellular function are not known. We have studied the effect of bilirubin on protein kinase C activity in subcellular fractions of human skin fibroblasts and on protein kinase C-mediated phosphorylation of endogenous substrates. Bilirubin inhibited the kinase activity in a concentration-dependent manner: a 50% inhibition was achieved by 45 mumol/l in the homogenate and 75 mumol/l in both the cytosolic and membranous fractions. Inhibition of protein kinase C activity by bilirubin was reversed by increasing the concentrations of activating lipids in both the cytosolic and membranous fractions. Bilirubin-induced inhibition of phosphorylation of endogenous proteins, in both fractions, was noted in the presence of calcium and the activating lipids, but not in the absence of the activators. This inhibition may play a role in the pathogenesis of bilirubin toxicity.
Amit
Y
Y
Department of Neonatology, Hadassah University Hospital, Jerusalem, Israel.
Boneh
A
A
D001663:Bilirubin / Q000633:toxicity*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology* / Q000648:ultrastructure; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*
D011493:Protein Kinase C; D001663:Bilirubin