12-O-Tetradecanoylphorbol-13-acetate activates the synthesis of phosphatidylethanol in animal cells exposed to ethanol

Abstract

Tumor-promoting phorbol esters acutely activate a pathway in lymphocytes leading to the synthesis and accumulation of phosphatidylethanol, using exogenous ethanol as a precursor. This product is a representative of a unique class of acidic glycerophospholipids in which the head group is a primary alcohol. The formation of this lipid, in response to different phorbol ester derivatives, correlates with their activity as tumor promoters and inducers of growth changes in a variety of animal cells. Since phosphatidylethanol represents an unusual metabolite of ethanol, it is proposed that studies of its synthesis and biological functions may also provide new perspectives on the biology of alcohol addiction as well as the role of this biological pathway in tumor promotion.

Synthesis of phosphatidylethanol--a potential marker for adult males at risk for alcoholism.

“…The remarkable responsiveness of the system to phorbol esters, implying that protein kinase C is a major regulator of this pathway, points to a need to assess the role of certain nutrients, growth factors, drugs, and hormones (i.e., agents that mediate their effects through protein kinase C) in alcoholism. This view is also supported by the observation that bryostatin and teleocidin, also activators of protein kinase C, can stimulate this pathway in other cell systems (2,3).…”

“…The enzymatic pathway for phosphatidylethanol synthesis appears widespread in animal tissues with significant TPAinduced responses being observed in bovine lymphocytes, human peripheral lymphocytes, human mammary cells, human colon cancer cells, and HL-60 cells (2,3). The in vivo production of phosphatidylethanol in kidney, liver, and brain tissues has also been reported independently by Alling et al (6) for rats receiving toxic doses of ethanol.…”

“…These products were subsequently characterized to be glycerolphospholipids in which the typical head group (i.e., choline, ethanolamine, inositol, or serine) had been replaced by ethanol (2) (Fig. 1) Our finding that the pathway for phosphatidylethanol synthesis could be activated by TPA in human lymphocytes from peripheral blood has opened the way to exploring whether the ability of human subjects to synthesize this unique metabolite of ethanol correlates in any way with the individual's dependency on alcohol.…”

“…These products were subsequently characterized to be glycerolphospholipids in which the typical head group (i.e., choline, ethanolamine, inositol, or serine) had been replaced by ethanol (2) (Fig. 1).…”

“…The formation of this class of acidic lipids, phosphatidylethanols, depended on both the treatment of the cells with an active phorbol ester (or another activator of protein kinase C) and the presence of exogenous ethanol in the culture medium (2,3). Recent studies of Pai et al (4) and Tettenborn and Mueller (5) have also shown conclusively that the observed phosphatidylethanols are formed by a transphosphatidylation reaction that is catalyzed by membrane-associated phospholipase D; this involves an exchange of ethanol for choline of preexisting phosphatidylcholine (Fig.…”