Vol. 288, Issue 1, 254-259, January 1999

Peroxisomes Are Involved in the Swift Increase in Alcohol Metabolism¹

Blair U. Bradford, Nobuyuki Enomoto, Kenichi Ikejima, Michelle L. Rose, Heidi K. Bojes, Donald T. Forman and Ronald G. Thurman

Laboratory of Hepatobiology and Toxicology, Department of Pharmacology (B.U.B., N.E., K.I., M.L.R., H.K.B., R.G.T.), and Department of Pathology and Laboratory Medicine (D.T.F.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

The purpose of this study was to determine whether catalase-dependent alcohol metabolism is activated by alcohol (i.e., swift increase in alcohol metabolism). When ethanol or the selective substrate for catalase, methanol, was given (5.0 g/kg) in vivo 2 to 3 h before liver perfusion, methanol and oxygen metabolism were increased significantly. This increase was blocked when the specific Kupffer cell toxicant GdCl₃ was administered 24 h before perfusion. These data support the hypothesis that catalase-dependent alcohol metabolism is activated by acute alcohol and that Kupffer cells are involved. Ethanol treatment in vivo increased ketogenesis from endogenous fatty acids nearly 3-fold and increased plasma triglycerides and hepatic acyl CoA synthetase activity; all increases were blocked by GdCl₃. These findings support the hypothesis that ethanol increases H₂O₂ supply for catalase-dependent alcohol metabolism by increasing fatty acid supply. Infusion of oleate stimulated oxygen uptake 1.5-fold and methanol metabolism 4-fold, but these parameters were not altered by GdCl₃. Moreover, the effects of ethanol treatment were blocked by the cyclooxygenase inhibitor indomethacin, and prostaglandin E₂ (PGE₂) was increased more than 200% in media from cultured Kupffer cells from rats treated with ethanol in vivo. Furthermore, lipoprotein lipase activity in retroperitoneal fat pads, which is known to be inhibited by PGE₂, was reduced 70% by ethanol. These data are consistent with the hypothesis that Kupffer cells play a key role in activation of catalase-dependent alcohol metabolism, most likely by producing mediators (e.g., PGE₂) that inhibit lipoprotein lipase, increase the supply of fatty acids to the liver, and increase generation of H₂O₂ via peroxisomal -oxidation.