Rat liver endothelial and Kupffer cell-mediated mutagenicity of polycyclic aromatic hydrocarbons and aflatoxin B1.
The ability of isolated rat liver endothelial and Kupffer cells to activate benzo(a)pyrene (BP), trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (DDBP), trans-1,2-dihydroxy-1,2-dihydrochrysene (DDCH), and aflatoxin B1 (AFB1) to mutagenic metabolites was assessed by means of a cell-mediated bacterial mutagenicity assay and compared with the ability of parenchymal cells to activate these compounds. Endothelial and Kupffer cells from untreated rats were able to activate AFB1 and DDBP; DDBP was activated even in the absence of an NADPH-generating system. Pretreating the animals with Aroclor 1254 strongly enhanced the mutagenicity of the dihydrodiol, whereas the mutagenicity of AFB1 showed a slight increase. BP and DDCH were only activated by endothelial and Kupffer cells isolated from Aroclor 1254-pretreated rats. Parenchymal cells from untreated animals activated all four carcinogens tested; Aroclor 1254 enhanced the parenchymal cell-mediated mutagenicity of BP and DDCH but did not affect that of DDBP and clearly reduced that of AFB1. The reduced mutagenicity of AFB1 correlates with the decrease in the amount of 2 alpha-hydroxytestosterone formed when testosterone was incubated with parenchymal cell microsomes from Aroclor 1254-pretreated rats (compared with microsomes from untreated animals): the formation of 2 alpha-hydroxytestosterone is specifically catalyzed by cytochrome P-450h, a hemoprotein thought to be involved in the activation of AFB1. These results show that not only rat liver parenchymal cells, but also endothelial and Kupffer cells, activate several carcinogens to mutagenic metabolites.
Steinberg
P
P
Institute of Toxicology, University of Mainz, Federal Republic of Germany.
Schlemper
B
B
Molitor
E
E
Platt
K L
KL
Seidel
A
A
Oesch
F
F
D016604:Aflatoxin B1; D000348:Aflatoxins / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009153:Mutagens / Q000493:pharmacokinetics*; D011083:Polycyclic Compounds / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013739:Testosterone / Q000378:metabolism
D000348:Aflatoxins; D009153:Mutagens; D011083:Polycyclic Compounds; D013739:Testosterone; D016604:Aflatoxin B1