Metabolism of ethanol by rat hepatocytes results in generation of a lipid chemotactic factor: studies using a cell-free system and role of oxygen-derived free radicals.
We have reported that liver cells metabolizing ethanol release a lipid that has chemotactic activity for human polymorphonuclear leukocytes. The purpose of the present study was to investigate the role of ethanol and of oxygen-derived free radicals in generation of this activity. A cell-free, ethanol-metabolizing system consisting of rat liver cytosol was found to generate a polar lipid which possessed a chemotactic activity identical to the activity from intact cells. The importance of acetaldehyde in this process was established by the findings that (i) an inhibitor of the metabolism of ethanol to acetaldehyde, 4-methylpyrazole, blocked production of the chemotactic lipid; (ii) acetaldehyde could substitute for ethanol; and (iii) cytosol alone incubated with ethanol in the absence of mitochondrial acetaldehyde metabolism generated the activity. Acetaldehyde can serve as a substrate for cytosolic oxidases in reactions that generate radicals (e.g., superoxide anion) which have been shown to attack unsaturated lipids to yield lipid hydroperoxides. When scavengers of oxygen-derived free radicals (superoxide dismutase, catalase, and dimethylsulfoxide) were added to the ethanol-metabolizing system they prevented generation of the activity. The data are consistent with a mechanism of chemotactic factor generation by ethanol-metabolizing liver cytosol in which acetaldehyde causes formation of oxygen-derived free radicals that attack unsaturated cytosolic lipid to generate a polar chemotactic compound.
Roll
F J
FJ
Department of Medicine, University of California, San Francisco.
Alexander
M A
MA
Cua
D
D
Swanson
W
W
Perez
H D
HD
D000818:Animals; D002374:Catalase / Q000494:pharmacology; D002474:Cell-Free System; D002630:Chemotactic Factors / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism*; D005609:Free Radicals; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000494:pharmacology
D002630:Chemotactic Factors; D005609:Free Radicals; D000431:Ethanol; D008353:Mannitol; D002374:Catalase; D013482:Superoxide Dismutase; D010100:Oxygen