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Modulation of Hepatic mRNA Translation Activity and Specific Expression of Arylsulfotransferase IV during Acetylaminofluorene-induced Rat Hepatocarcinogenesis¹

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

Enzymatic sulfation of N-hydroxylated arylamines by mammalian hepatic cytosol sulfotransferases (AST; EC 2.8.2.1) is an important metabolic step which generates ultimate carcinogens. The metabolic activity of AST IV, the putative isozymic form of AST primarily responsible for catalyzing N-hydroxy-2-acetylaminofluorene sulfation, is modulated during 2-acetylaminofluorene (AAF)-induced rat hepatocarcinogenesis.

To characterize the molecular mechanisms regulating the differential expression of AST IV, we have assessed polyadenylated mRNA derived from the livers of Sprague-Dawley rats undergoing different stages of AAF hepatocarcinogenesis for general in vitro translation capacity and specific expression of AST IV and albumin. Following 1 and 3 cycles of a cyclical feeding regimen (3 weeks 0.05% AAF, then 1 week basal diet), the mRNA capacity for translation was lowered and the expression of AST IV and albumin was down-regulated about 2-fold each but recovered to normal levels when treated rats were subsequently placed on basal diet for 3 continuous weeks. Cytosolic albumin levels were determined by Western blot analysis to be lowered about 1.5–2-fold.

In contrast, however, mRNA from rats on basal diets for 3 weeks subsequent to cycle 5 of the feeding regimen recovered only about 50% of the capacity for AST IV expression, although overall translation capacity and albumin expression returned to normal levels. This pattern of reversible expression, followed by irreversible expression of AST IV at early and late stages of AAF hepatocarcinogenesis, respectively, provides the first evidence correlating the modulation of hepatic mRNA capacity for AST IV expression with differential cytosolic AST IV activity in the AAF hepatocarcinogenesis model. The results further suggest that during early stages in hepatocarcinogenesis modulation of mRNA protein synthesis functions may be a critical factor in AAF-mediated lowering of AST IV expression, while other persistent genetic lesions are likely playing a more significant role at the late stages of the carcinogenic process leading to neoplastic transformation of initiated hepatocytes.

¹ To whom requests for reprints should be addressed, at Biochemical Pharmacology Section, Biomedical Division, The Samuel Roberts Noble Foundation, Inc., P. O. Box 2180, Ardmore, OK 73402.

² Preliminary reports of this work were presented to the 81st Annual Meeting of the American Association for Cancer Research, Washington, DC, 1990.

Received 6/14/90. Accepted 11/ 1/90.