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Protection of the Cyp1a2(−/−) Null Mouse against Uroporphyria and Hepatic Injury Following Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

https://doi.org/10.1006/taap.2001.9167Get rights and content

Abstract

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the liver of C57BL/6J mice is a model for clinical sporadic porphyria cutanea tarda (PCT). There is massive uroporphyria, inhibition of uroporphyrinogen decarboxylase (UROD) activity, and hepatocellular damage. A variety of evidence implicates the CYP1A2 enzyme as necessary for mouse uroporphyria. Here we report that, 5 weeks after a single oral dose of TCDD (75 μg/kg), Cyp1a2(+/+) wild-type mice showed severe uroporphyria and greater than 90% decreases in UROD activity; in contrast, despite exposure to this potent agent Cyp1a2(−/−) knockout mice displayed absolutely no increases in hepatic porphyrin levels, even after prior iron overload, and no detectable inhibition of UROD activity. Plasma levels of alanine-aminotransferase (ALT) and aspartate aminotransferase (AST)–although elevated in both genotypes after TCDD exposure–were significantly less in Cyp1a2(−/−) than in Cyp1a2(+/+) mice, suggesting that the absence of CYP1A2 also affords partial protection against TCDD-induced liver toxicity. Histological examination confirmed a decrease in hepatocellular damage in TCDD-treated Cyp1a2(−/−) mice; in particular, there was no bile duct damage or proliferation that in the Cyp1a2(+/+) mice might be caused by uroporphyrin. We conclude that CYP1A2 is both necessary and essential for the potent uroporphyrinogenic effects of TCDD in mice, and that CYP1A2 also plays a role in contributing to TCDD-induced hepatocellular injury. This study has implications for both the toxicity assessment of TCDD and the hepatic injury seen in PCT patients.

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      Porphyria cutanea tarda (PCT), the most common human porphyria, is a photosensitive skin disease caused by over-production of hepatic porphyrins, resulting in high urinary concentrations. Biochemically, PCT is characterized by a UROD deficiency that causes uroporphyrinogen III accumulation, although nutritional and/or environmental interactions, such as exposure to AhR agonists, are typically required for disease expression (Smith et al., 2001). In the presence of Fe and CYP1A2, uroporphyrinogen III is oxidized to uroporphomethene, a UROD inhibitor, and finally, uroporphyrin III, a urinary metabolite identified in rodent porphyria models and PCT patients.

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    To whom correspondence should be addressed at MRC Toxicology Unit, Hodgkin Building, University of Leicester, P.O. Box 138, Lancaster Road, Leicester LE1 9HN, UK. Fax: 044–116-252–5616. E-mail: [email protected].

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