Cyp1a1(-/-) male mice: protection against high-dose TCDD-induced lethality and wasting syndrome, and resistance to intrahepatocyte lipid accumulation and uroporphyria.
To study liver toxicity and uroporphyrin (URO) accumulation and urinary excretion, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent ligand for the aryl hydrocarbon receptor (AHR), is often used as the prototype. In this study, we asked the question how important is the role of CYP1A1 in causing TCDD toxicity. Using a single large intraperitoneal dose of TCDD (200 microg/kg) and following the response over an 8-week period, we found this dose: (a) was lethal in less than 4 weeks to Cyp1a1(+/+) males but not to Cyp1a1(-/-) males or to females of either genotype; (b) caused a wasting syndrome in Cyp1a1(+/+) but not Cyp1a1(-/-) mice; (c) resulted in thymic atrophy, regardless of gender or genotype; (d) decreased spleen size and caused leukocytopenia in males but not females of either genotype; (e) caused hepatocyte hypertrophy in Cyp1a1(+/+) more so than in Cyp1a1(-/-) mice; (f) increased intrahepatocyte lipids and total liver fat content in Cyp1a1(+/+) more than Cyp1a1(-/-) males and females; and (g) caused uroporphyria in Cyp1a1(+/+) males much more than Cyp1a1(+/+) females, or in Cyp1a1(-/-) mice. Contrary to Cyp1a2(-/-) knockout mice that exhibited 15 times less accumulation of TCDD in liver than Cyp1a1/1a2(+/+) wild-type mice, Cyp1a1(-/-) mice did not show this altered TCDD distribution-indicating that CYP1A2 but not CYP1A1 is the major hepatic TCDD-binding "sink". Our data demonstrate that CYP1A1 contributes to high-dose TCDD-induced toxicity, uroporphyria, and lethality.
Uno
Shigeyuki
S
Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
Dalton
Timothy P
TP
Sinclair
Peter R
PR
Gorman
Nadia
N
Wang
Bin
B
Smith
Andrew G
AG
Miller
Marian L
ML
Shertzer
Howard G
HG
Nebert
Daniel W
DW
D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000502:physiology*; D005260:Female; D005838:Genotype; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D013723:Teratogens / Q000633:toxicity*; D014018:Tissue Distribution; D014578:Uroporphyrins / Q000378:metabolism*; D019282:Wasting Syndrome / Q000139:chemically induced* / Q000378:metabolism
D000072317:Polychlorinated Dibenzodioxins; D013723:Teratogens; D014578:Uroporphyrins; D019363:Cytochrome P-450 CYP1A1