Immunochemical detection of liver protein adducts of the nonsteroidal antiinflammatory drug diclofenac.
Serious idiosyncratic hepatic injury has been associated with the use of many nonsteroidal antiinflammatory drugs, including the widely prescribed agent diclofenac. In order to investigate the possibility that covalent protein adducts of reactive metabolites of diclofenac might be responsible for the hepatotoxicity produced by this drug, we have developed a polyclonal antibody that can recognize such adducts in tissues. Immunoblotting revealed that protein adducts of reactive metabolites of diclofenac of 50, 70, 110, and 140 kDa were formed in the livers of mice treated with diclofenac. In the future, it will be determined whether these adducts can cause hepatotoxicity by either a hypersensitivity or metabolic mechanism. Similar approaches may be used to study the protein adducts and mechanisms of hepatotoxicity of other nonsteroidal antiinflammatory drugs.
Pumford
N R
NR
Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Myers
T G
TG
Davila
J C
JC
Highet
R J
RJ
Pohl
L R
LR
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology; D004008:Diclofenac / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism*; D004342:Drug Hypersensitivity / Q000378:metabolism; D005260:Female; D006433:Hemocyanins / Q000276:immunology; D015151:Immunoblotting; D008099:Liver / Q000276:immunology / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D011506:Proteins / Q000276:immunology / Q000378:metabolism*; D011817:Rabbits
D011506:Proteins; D004008:Diclofenac; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin; D008239:Lysine