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© 1990 Oxford University Press

research-article

Self-catalyzed irreversible inactivation of rat hepatic aryl sulfotransferase IV by Nhydroxy-2-acetylaminofluorene

Bonnie L.K. Mangold, Joy Erickson, Caroline Lohr, Denis J. McCann and James B. Mangold

Medicinal Chemistry and Pharmacognosy Section, School of Pharmacy, University of Connecticut Storrs, CT 06269-2092, USA

Rat hepatic aryl sulfotransferase IV catalyzes the sulfonation of the hepatocarcinogen, N-hydroxy-2-acetylaminofluorene. The resulting reactive N-O-sulfate ester is believed to be the ultimate carcinogenic species responsible for the induction of hepatic neoplasia. Previous studies have shown that dietary administration of either 2-acetylaminofluorene or N-hydroxy-2-acetylamlnofluorene to rats is accompanied by a rapid decline in hepatic aryl sulfotransferase activity in vivo. In the present study, preincubation of purified rat hepatic aryl sulfotransferase IV with N-hydroxy-2-acetylamino-fluorene resulted in rapid, time-dependent enzyme inactivation. This in vitro inactivation was not reversed by dialysis or gel filtration, Inclusion of excess nucleophile, methionine, resulted in considerable but not complete protection from inactivation. The inactivation was PAPS dependent and blocked by the sulfotransferase inhibitor, pentachlorophenol. The above observations and the apparent pseudo first-order kinetics observed suggest that the inactivation was in part mechanism based. Mechanism-based inactivation of the aryl sulfotransferases has not been previously reported. Further-more, the results of the present study indicate that the previously reported in vivo decline in rat hepatic aryl sulfotransferase activity may be attributable in part to enzyme inactivation by its own reactive product.


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 J. Biol. Chem.Home page
C. C. Kiehlbauch, Y. F. Lam, and D. P. Ringer
Homodimeric and Heterodimeric Aryl Sulfotransferases Catalyze the Sulfuric Acid Esterification of N-Hydroxy-2-acetylaminofluorene
J. Biol. Chem., August 11, 1995; 270(32): 18941 - 18947.
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