Distribution and induction of aflatoxin B1-9a-hydroxylase activity in rat liver parenchymal and non-parenchymal cells.
Chronic administration of aflatoxin B1 (AFB1) to rats gives rise to hepatocellular and cholangiocellular carcinomas without affecting Kupffer and endothelial cells. The enzymatic conversion of AFB1 to AFB1-8,9-epoxide is the critical step in the activation of the myocotoxin, while the conversion of AFB1 to aflatoxin M1 (AFM1), catalyzed by the AFB1-9a-hydroxylase, is considered to be a detoxication route for the toxin. In the present study the distribution and inducibility of AFB1-9a-hydroxylase were analyzed in microsomes derived from freshly isolated liver parenchymal (PC) and nonparenchymal cells (i.e. Kupffer + endothelial cells, NPC). AFB1-9a-hydroxylase activity was clearly measurable in NPC and similar to that of PC. In NPC the rate of formation of AFM1 was higher (when incubating with 16 microM AFB1) than or similar (with 128 microM AFB1) to that of AFB1-8,9-epoxide, while in PC it was significantly lower. Taken together, these results suggest that the AFB1-9a-hydroxylase activity might be particularly important in NPC to protect these cells from AFB1 by converting it to a significantly less mutagenic metabolite and by reducing the amount of AFB1 available for epoxidation. Furthermore, it is shown that AFB1-9a-hydroxylase activity is inducible by phenobarbital (only in PC), 3-methylcholanthrene, isosafrole and Aroclor 1254, thus indicating that in rat liver the conversion of AFB1 to AFM1 is catalyzed by members of the cytochrome 1A and 2B families.
Gemechu-Hatewu
M
M
Institute of Toxicology, University of Mainz, Germany.
Platt
K L
KL
Oesch
F
F
Steinberg
P
P
D000818:Animals; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D004790:Enzyme Induction; D007728:Kupffer Cells / Q000166:cytology / Q000201:enzymology; D008099:Liver / Q000166:cytology* / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006899:Mixed Function Oxygenases; C019623:aflatoxin B1 hydroxylase