Molecular Pharmacology, Vol 13, 625-633, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Studies on the Microsomal Formation of Arylating Metabolites of Acetaminophen and Phenacetin

¹ Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20014

A chemically reactive metabolite of phenacetin is formed by a cytochrome P-450 in hamster liver microsomes by a mechanism that is different from the generation of the chemically reactive metabolite from acetaminophen. The V_max of covalent binding of phenacetin exceeds that of acetaminophen, showing that phenacetin is not first deethylated to acetaminophen, which is then activated. Previous treatment with 3-methylcholanthrene increases the V_max of covalent binding for acetaminophen but decreases the V_max of covalent binding for phenacetin, even though it increases the V_max of deethylation of phenacetin to acetaminophen. Previous treatment with phenobarbital increases the V_max of covalent binding for phenacetin without increasing the same parameter for acetaminophen. Addition of sodium fluoride (0.1 M) increases the rate of covalent binding for acetaminophen but decreases it for phenacetin. When covalent binding is prevented by trapping the reactive metabolites with glutathione during incubations carried out under ¹⁸O₂ atmospheres, reductive cleavage by Raney nickel of the glutathione conjugates formed from either phenacetin or acetaminophen yields acetaminophen; however, the acetaminophen from the phenacetin-glutathione incubations contains about 50% ¹⁸O in position 4, whereas the acetaminophen from the acetaminophen-glutathione incubations contains virtually no ¹⁸O. These findings are consistent with the hypothesis that acetaminophen is converted to N-hydroxyacetaminophen, which dehydrates to yield the arylating species, acetimidoquinone, whereas the reactive species from phenacetin arises by epoxidation.

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