Kinetics of interaction of 2-acetylaminofluorene with normal liver and carcinogen-induced hepatocyte nodules in vivo and in vitro.

This study examines the initial uptake and subcellular distribution of the carcinogen [14C]-2-acetylaminofluorene in liver nodules and normal liver. The route of administration of the carcinogen was intravenously through a peripheral branch of the superior mesenteric vein, intragastrically or intraperitoneally. Tissue distribution was initially dependent on blood flow, but the retention after 5 minutes varied between different tissues according to tissue affinity, high in liver, fat and muscle, low in kidney and brain. The major fraction was retained in the liver. In vitro experiments demonstrated that total levels of [14C]-2-acetylaminofluorene were 8-fold lower in hepatocytes from liver nodules compared with normal liver. The 2-acetylaminofluorene was bound more avidly to 12 to 15 kilodalton cytosolic proteins than to 40 to 50 kilodalton proteins in normal liver and this binding was much less in hepatocyte nodules. The subcellular distribution indicated that the microsomal fractions had a greater specificity than mitochondria, homogenate, or cytosol. This specificity was not due to the lipid content of the fractions. Microsomal fractions from liver nodules had 2-fold less [14C]-2-acetylaminofluorene bound than from normal liver. The carcinogen was bound in cytosolic proteins with a peak 90 minutes after intravenous injection, as compared with a peak for microsomes at 10 minutes. These results lend further support for the concept that the biochemical properties in liver nodules minimize the metabolism of xenobiotics in vivo.