Uroporphyria and hepatic carcinogenesis induced by polychlorinated biphenyls–iron interaction: Absence in the Cyp1a2(− /− ) knockout mouse

• Published in: Biochemical and biophysical research communications 2005-05, Vol.331 (1), p.147-152
• Main Authors: Greaves, Peter, Clothier, Bruce, Davies, Reginald, Higginson, Fiona M., Edwards, Richard E., Dalton, Timothy P., Nebert, Daniel W., Smith, Andrew G.
• Format: Article
• Language: English
• Subjects: Animals; Carcinogenesis; Cyp1a2(− /− ) mice; Cytochrome P-450 CYP1A2 - genetics; Cytochrome P-450 CYP1A2 - metabolism; Drug Synergism; Environmental Pollutants - toxicity; Humans; Iron; Iron - toxicity; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - enzymology; Mice; Mice, Inbred C57BL; Mice, Knockout; PCBs; Polychlorinated Biphenyls - toxicity; Porphyria; Porphyrias, Hepatic - chemically induced; Porphyrias, Hepatic - enzymology; Porphyrias, Hepatic - pathology; Rats; Uroporphyrins - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.03.136

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 (100 ppm) of Cyp1a2(+/+) wild-type mice caused hepatic uroporphyria, which was strongly increased by iron–dextran (800 mg 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.