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2-Acetylaminofluorene-mediated Alteration in the Level of Liver Arylsulfotransferase IV during Rat Hepatocarcinogenesis

The Samuel Roberts Noble Foundation, Inc., Ardmore, Oklahoma 73402

Rat liver cytosolic sulfotransferase activity forms the highly reactive sulfuric acid ester of N-hydroxy-2-acetylaminofluorene (N-OH-2AAF), an ultimate carcinogen in 2-acetylaminofluorene (2AAF) hepatocarcinogenesis. A previous report demonstrated that 2AAF-induced liver hyperplastic nodules displayed a persistent loss of cytosolic N-OH-2AAF sulfotransferase activity following a hepatocarcinogenesis-producing regimen of 2AAF administration. As an initial step in examining the mechanism responsible for lowering N-OH-2AAF sulfotransferase activity, a monospecific polyclonal antibody to aryl sulfotransferase IV (AST IV) was produced and used in the assessment of AST IV as a candidate enzyme for liver cytosolic N-OH-2AAF sulfotransferase activity. Studies comparing the levels of N-OH-2AAF sulfotransferase activity of highly purified AST IV and rat liver cytosols with corresponding immunochemical analysis of AST IV contents demonstrated that there was sufficient AST IV activity in liver cytosols to indicate that it was the primary enzyme catalyzing cytosolic N-OH-2AAF sulfation. A subsequent immunochemical survey of nine extrahepatic tissues showed no detectable AST IV content and indicated that AST IV expression may be tissue specific. An immunochemical comparison of AST IV levels in control liver cytosols (high in sulfotransferase activity) with cytosols from 2AAF-derived hyperplastic nodules (low in sulfotransferase activity) or liver tumors (no sulfotransferase activity) showed low or no detectable levels, respectively, of AST IV. In addition, an immunochemical analysis of four rat hepatoma cell lines showed they contained no detectable levels of AST IV. These results suggested a strong correlation existed between a decrease in AST IV expression and tumor development. When the liver cytosols of rats taken from early, intermediate, and late stages of 2AAF carcinogenesis were analyzed for the development of a persistent loss of N-OH-2AAF sulfotransferase activity, a parallel loss of cytosolic N-OH-2AAF sulfotransferase activity and AST IV content was observed in rats which had proceeded from a stage of low risk to high risk for liver cancer. These findings indicated that (a) AST IV, a liver-specific enzyme, was the principle enzyme comprising cytosolic N-OH-2AAF sulfotransferase activity and (b) the decrease in sulfotransferase activity in nodules and tumors resulted from a decrease in the level of AST IV expression. Furthermore, it is suggested that a persistent decrease in AST IV expression may reflect a role for AST IV as part of a resistance phenotype in which transforming liver cells are able to escape the cytotoxic effects of highly reactive 2AAF metabolites and progress to cancer.

¹ To whom requests for reprints should be addressed.

Received 9/19/89. Revised 5/10/90.

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