Uroporphyria and hepatic carcinogenesis induced by polychlorinated biphenyls-iron interaction: absence in the Cyp1a2(-/-) knockout mouse.
Aryl hydrocarbon receptor ligands, such as polychlorinated biphenyls (PCBs), cause inhibition of the heme biosynthesis enzyme, uroporphyrinogen decarboxylase; this leads to uroporphyria and hepatic tumors, which are markedly enhanced by iron overload in C57BL/10 and C57BL/6 strains of mice. Cyp1a2(-/-) knockout mice were used to compare the effects of CYP1A2 expression on uroporphyria and liver carcinogenesis. PCBs in the diet (100ppm) of Cyp1a2(+/+) wild-type mice caused hepatic uroporphyria, which was strongly increased by iron-dextran (800mg Fe/kg). In contrast, uroporphyria was not detected in Cyp1a2(-/-) knockout mice, although expression of CYP1A1 and CYP2B10 was greatly induced. After 57 weeks on this diet, hepatic preneoplastic foci and tumors were seen in the Cyp1a2(+/+) mice; numbers and severity were enhanced by iron. No foci or tumors were detected in Cyp1a2(-/-) mice, although evidence for other forms of liver injury was observed. Our findings suggest a link not only between CYP1A2, iron metabolism, and the induction of uroporphyria by PCBs, but also with subsequent hepatocarcinogenesis.
Greaves
Peter
P
MRC Toxicology Unit, University of Leicester, Leicester, UK.
Clothier
Bruce
B
Davies
Reginald
R
Higginson
Fiona M
FM
Edwards
Richard E
RE
Dalton
Timothy P
TP
Nebert
Daniel W
DW
Smith
Andrew G
AG
D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D007501:Iron / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D017094:Porphyrias, Hepatic / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D014578:Uroporphyrins / Q000378:metabolism
D004785:Environmental Pollutants; D014578:Uroporphyrins; D011078:Polychlorinated Biphenyls; D007501:Iron; D019388:Cytochrome P-450 CYP1A2