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. Cypla2((-/-)) 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 ill 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 or uroporphyria by PCBs, but also with subsequent hepatocarcinogenesis. © 2005 Elsevier Inc. All rights reserved.