Estrogen has been shown to decrease plasma platelet-activating factor (PAF) acetylhydrolase activity, but the precise mechanisms are not known. We examined the effect of estradiol on the secretion of PAF acetylhydrolase by HepG2 cells. In our previous study, we demonstrated the production of this enzyme by HepG2 cells, which we used as an experimental model of normal hepatocytes. 17 beta-Estradiol mildly but consistently inhibited the secretion of PAF acetylhydrolase by HepG2 cells in a concentration-dependent manner. Under basal conditions, HepG2 cells secreted 42.3 pmol/mg cell protein/min PAF acetylhydrolase in 24 hours (mean of 8 dishes), and the presence of 10(-7) mol/L 17 beta-estradiol decreased the secretion to 77% +/- 10.3% of control values (mean +/- SD, n = 8, P < .02). 17 beta-Estradiol treatment affected neither the secretion of apolipoprotein (apo) A-I nor cell-associated PAF acetylhydrolase activity. Electrophoretic separation of [35S]methionine-labeled PAF acetylhydrolase revealed a single band whose molecular weight was approximately 43,000 d. We conclude that estrogen decreases the secretion of PAF acetylhydrolase by the liver, and it may explain, at least in part, the effect of estrogen on plasma PAF acetylhydrolase.