title: Protection of the Cyp1a2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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 microg/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.
authors.affiliation: MRC Toxicology Unit, Leicester University, Leicester, LEI 9HN, United Kingdom. ags5@le.ac.uk
authors.forename: A G
authors.initials: AG
authors.lastname: Smith
authors.forename: B
authors.initials: B
authors.lastname: Clothier
authors.forename: P
authors.initials: P
authors.lastname: Carthew
authors.forename: N L
authors.initials: NL
authors.lastname: Childs
authors.forename: P R
authors.initials: PR
authors.lastname: Sinclair
authors.forename: D W
authors.initials: DW
authors.lastname: Nebert
authors.forename: T P
authors.initials: TP
authors.lastname: Dalton
mesh_terms: D000818:Animals; D001284:Atrophy / Q000139:chemically induced; D003433:Crosses, Genetic; D019388:Cytochrome P-450 CYP1A2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D017094:Porphyrias, Hepatic / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D014575:Uroporphyrinogen Decarboxylase / Q000378:metabolism; D014578:Uroporphyrins / Q000378:metabolism / Q000652:urine*
chemical_list: D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D014578:Uroporphyrins; D019388:Cytochrome P-450 CYP1A2; D014575:Uroporphyrinogen Decarboxylase