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Alteration of the Ability of Liver Microsomes to Activate N-2-Fluorenylacetamide to a Mutagen of Salmonella typhimurium during Hepatocarcinogenesis¹

Department of Anatomic and Research Pathology, M. D. Anderson Hospital and Tumor Institute, The University of Texas System Cancer Center, Texas Medical Center, Houston, Texas 77030

Male Sprague-Dawley rats were exposed to an intermittent carcinogenic regimen of 2-fluorenylacetamide, which evokes discrete morphological and biological alterations in the hepatocytes. At weekly intervals the postmitochondrial (S9) and postmicrosomal fractions of the exposed livers were isolated and incubated with N-2-fluorenylacetamide or N-hydroxy-2-fluorenylacetamide, respectively, by the method of Ames to mutate Salmonella typhimurium TA1538. During the early exposure S9 from N-2-fluorenylacetamide-fed rats produced more mutants than did controls, reaching a maximum of 300% at 4 weeks. Although this activity remained elevated throughout the next several weeks, it was in decline. Throughout most of the remainder of the feeding regimen, the S9 activity was severely depressed. The diminished ability of the microsomal system to activate the parent compound to a mutagenizing form was striking when hepatic nodules were separately tested and compared with surrounding parenchyma or normal controls. Throughout this same period of exposure, the activity of the postmicrosomal fraction was near that of controls.

The decrease of S9 activity was accompanied by a concomitant decline in microsomal protein. These findings would tend to fit with recently reported results that indicate a decline in drug-metabolizing activity during chemical hepatocarcinogenesis by demonstrating that the capacity of these cells to produce mutagen is similarly reduced.

¹ Supported by NIH Grant CA 20657.

² To whom requests for reprints should be addressed.

Received 12/19/77. Accepted 4/27/78.