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Prostaglandin synthase catalyzed metabolic activation of p-phenetidine and acetaminophen by microsomes isolated from rabbit and human kidney.

R. Larsson,D. Ross,T. Berlin,L. Olsson,P. Moldéus

Published 1985 in Journal of Pharmacology and Experimental Therapeutics

ABSTRACT

The metabolism of p-phenetidine in microsomes from rabbit kidney and the metabolism of acetaminophen and p-phenetidine in human kidney microsomes to protein binding metabolites were examined. Microsomal preparations from rabbit kidney medulla catalyzed the irreversible arachidonic acid-dependent binding of p-[14C]phenetidine to tissue protein. This was not observed in similar preparations from kidney cortex or if the microsomal protein was denatured. The Km (60 microM) of the binding reaction indicated that the enzymatic processes responsible for the binding have very high affinity for p-phenetidine. Indomethacin inhibited the binding to medullary microsomal protein whereas the inclusion of catalase and superoxide dismutase did not affect protein binding. Linolenic acid hydroperoxide was very effective in supporting binding whereas tertiary butylhydroperoxide and H2O2 were less effective. The binding in the presence of hydroperoxides was not sensitive to indomethacin or metyrapone. The binding ratio of 14C-ring to 14C-ethyl labeled p-phenetidine using rabbit kidney medulla microsomal protein was 2:1 suggesting that the binding species may be p-phenetidine quinone-imine and quinone-diimine dimers which have been shown previously to be products of the peroxidatic oxidation of p-phenetidine. The inclusion of reduced glutathione in incubations containing p-[14C] phenetidine, rabbit kidney medulla microsomes and arachidonic acid resulted in a decrease in radioactivity bound to protein and an increase in radioactivity in the aqueous phase after extraction. Thin-layer chromatography of the aqueous phase revealed the presence of reduced glutathione conjugates of the previously identified reactive dimers of p-phenetidine.(ABSTRACT TRUNCATED AT 250 WORDS)

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