TY - JOUR T1 - Studies on the Microsomal Formation of Arylating Metabolites of Acetaminophen and Phenacetin JF - Molecular Pharmacology JO - Mol Pharmacol SP - 625 LP - 633 VL - 13 IS - 4 AU - JACK A. HINSON AU - SIDNEY D. NELSON AU - JERRY R. MITCHELL Y1 - 1977/07/01 UR - http://molpharm.aspetjournals.org/content/13/4/625.abstract N2 - 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 Vmax 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 Vmax of covalent binding for acetaminophen but decreases the Vmax of covalent binding for phenacetin, even though it increases the Vmax of deethylation of phenacetin to acetaminophen. Previous treatment with phenobarbital increases the Vmax 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. ER -