Exposure of
iron-loaded C57BL/10ScSn mice to the
polychlorinated biphenyls (
PCBs) mixture
Aroclor 1254 in the diet (0.01%) for 5 weeks caused massive
hepatic porphyria far greater than occurred with
PCBs alone. This regime eventually causes
hepatocellular carcinoma. Hepatic microsomal ethoxy-, pentoxy-, and
benzyloxyresorufin dealkylase activities (respectively
EROD,
PROD, and
BROD) catalyzed primarily by
cytochrome P4501A1 and 2B
isoenzymes were markedly induced after 2 weeks of diet (when no
porphyria had developed) but showed little effect of
iron.
EROD activity in the nuclear membrane was also induced by the
PCBs as was
CYP1A1 protein when shown by immunoblotting. Nuclear dealkylase activities of
PCBs-treated mice were considerably less than microsomal activities but were stimulated by
iron pretreatment. The mechanism of the
iron-enhanced toxicity may be due to oxidative damage associated with chronic induction of
CYP1A1 isoforms.
Lucigenin-enhanced chemiluminescence (CL) by microsomes and nuclear membranes was used as a method to estimate their potential to form
reactive oxygen species. Despite CL being induced by
PCBs it was less with microsomes from
iron-treated mice. In a comparison of a variety of inducers of microsomal
cytochrome P450 there was no correlation between inducer, uroporphyrogenic agent, and intensity of CL. On the other hand, cytosolic
glutathione S-transferase (GST) activities with
1-chloro-2,4-dinitrobenzene and
1,2-dichloro-4-nitrobenzene (DCNB) as substrates, were also induced by the
PCBs mixture, the induction with DCNB being synergistically potentiated by
iron pretreatment. Complementary results were observed by immunocytochemistry using anti alpha-GST antibody. In contrast, total
glutathione peroxidase activity and
selenium-dependent
glutathione peroxidase activity were depressed by
PCBs but particularly in mice also administered
iron. The results illustrate that
PCBs not only induce
CYP1A1 in microsomes but also in the nuclear membrane, which may be of significance in the mechanism of the
iron-enhanced carcinogenicity of these chemicals. The
iron-enhanced induction of GST with accompanying depletion of
glutathione peroxidase provides evidence for oxidative processes induced in vivo by the
PCBs.