Abstract
Aryl sulfotransferase (AST) IV catalyzes the 3'-phosphoadenosine-5'-phosphosulfate-dependent formation of sulfuric acid esters of a wide range of phenols, benzylic alcohols, hydroxamic acids, catecholamines, tyrosine carboxylesters, and peptides with N-terminal tyrosines. The objective of this investigation was to determine whether aryl carboxylic acids could act either as substrates or inhibitors for AST IV. These studies were conducted with AST IV that was purified to homogeneity from male Sprague-Dawley rats. Although none of the carboxylic acids tested were substrates for AST IV, they did competitively inhibit the enzyme with 1-naphthalenemethanol as substrate at pH 7.0. 1-Naphthoic acid, 2-naphthoic acid, and salicylic acid were particularly effective inhibitors of the sulfotransferase. The distance of the carboxyl group from the aromatic ring influenced the inhibitory capability of the carboxylic acids examined. The Kis for 1-naphthylacetic acid and 2-naphthylacetic acid as inhibitors of AST IV-catalyzed sulfation of 1-naphthalenemethanol were approximately 10-fold higher than those of the corresponding naphthoic acids. A substituted 2-naphthylacetic acid derivative, naproxen, also inhibited the aryl sulfotransferase. Preliminary studies indicate that aryl carboxylic acids also inhibit sulfation of phenols catalyzed by AST IV. 2-Naphthoic acid inhibited the sulfation of 2-naphthol catalyzed by AST IV at pH 5.5 with a Ki of 260 microM. In addition to these results with the homogeneous sulfotransferase, inhibition of aryl sulfotransferase activity by carboxylic acids was also observed in rat hepatic 100,000 g supernatant fractions. Thus, aryl carboxylic acids represent a new class of inhibitors for AST IV.
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