Polychlorinated biphenyls modulated tumorigenesis in Sprague Dawley rats: correlation with mixed function oxidase activities and superoxide (O2* ) formation potentials and implied mode of action.
Parallel, chronic (24 months) multidose bioassays of the PCB (polychlorinated biphenyls) Aroclors 1016, 1242, 1254, and 1260 in male and female Sprague-Dawley rats showed sex/Aroclor-dependent increases in hepatic tumors and decreases in extrahepatic tumors. To elucidate the PCB mode of action (MOA) involved, levels of a number of hypothesized mediators were measured in liver specimens collected at 3, 6, 12, 18, and 24 months and screened for correlation with late life hepatotumorigenesis (HT; mostly adenomas). Consistently correlated with HT were (1) tissue accumulations of SigmaPCBs (correlated in both sexes) and of dioxin equivalents (toxic equivalency [TEQ]; correlated in females only); (2) net activities of six groups of mixed function oxidases (MFOs), some PCB-induced, some PCB-repressed, as determined by differential metabolism of PCB congeners; (3) activities of deproteinated, reoxidized hepatic cytosols as catalysts for superoxide (O(2)(*-)) production, such activity having the chemical characteristics of redox-cycling quinones (RCQs), e.g., those derived from the glutathionylated estrogen catechols that were identified in the female rat livers; and (4) increased expression of the indicator of cell proliferation, proliferating cell nuclear antigen. The new findings, along with other recently reported relationships, were indicative of a MOA consisting of (1) SigmaPCB/TEQ accumulation in rat tissues; (2) SigmaPCB/TEQ repression of constitutive MFOs; (3) SigmaPCB/TEQ induction of other MFOs; (4) MFO-mediated formation of RCQs; (5) RCQ-mediated formation of O(2)(*-); (6) O(2)(*-) dismutation to H(2)O(2); and (7) H(2)O(2)-mediated mitotic signaling, resulting in the proliferation of spontaneously or otherwise initiated cells to form hepatic tumors, as in tumor promotion.
Brown
John F
JF
General Electric Company, Fairfield, Connecticut 06431, USA. john.brown@ge.com
Mayes
Brian A
BA
Silkworth
Jay B
JB
Hamilton
Stephen B
SB
D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D002273:Carcinogens; D013481:Superoxides; D011078:Polychlorinated Biphenyls; D005979:Glutathione Peroxidase; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; C025619:steroid 16-beta-hydroxylase; D000410:Alanine Transaminase