DISTRIBUTION AND INDUCTION OF AFLATOXIN B-1-9A-HYDROXYLASE ACTIVITY IN RAT-LIVER PARENCHYMAL AND NONPARENCHYMAL CELLS

Chronic administration of aflatoxin B-1 (AFB(1)) to rats gives rise to hepatocellular and cholangiocellular carcinomas without affecting Kup ffer and endothelial cells. The enzymatic conversion of AFB(1) to AFB( 1)-8,9-epoxide is the critical step in the activation of the mycotoxin , while the conversion of AFB(1) to aflatoxin M(1) (AFM(1)), catalyzed by the AFB(1)-9a-hydroxylase, is considered to be a detoxication rout e for the toxin. In the present study the distribution and inducibilit y of AFB(1)-9a-hydroxylase were analyzed in microsomes derived from fr eshly isolated liver parenchymal (PC) and nonparenchymal cells (i.e. K upffer + endothelial cells, NPC). AFB(1)-9a-hydroxylase activity was c learly measurable in NPC and similar to that of PC. In NPC the rate of formation of AFM(1) was higher (when incubating with 16 mu M AFB(1)) than or similar (with 128 mu M AFB(1)) to that of AFB(1)-8,9-epoxide, while in PC it was significantly lower. Taken together, these results suggest that the AFB(1)-9a-hydroxylase activity might be particularly important in NPC to protect these cells from AFB(1) by converting it t o a significantly less mutagenic metabolite and by reducing the amount of AFB(1) available for epoxidation. Furthermore, it is shown that AF B(1)-9a-hydroxylase activity is inducible by phenobarbital (only in PC ), 3-methylcholanthrene, isosafrole and Aroclor 1254, thus indicating that in rat liver the conversion of AFB(1) to AFM(1) is catalyzed by m embers of the cytochrome 1A and 2B families.