Cyp1a1(-/-) male mice: protection against high-dose TCDD-induced lethality and wasting syndrome, and resistance to intrahepatocyte lipid accumulation and uroporphyria.

Abstract

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.

• Authors: Shigeyuki Uno, Timothy P Dalton, Peter R Sinclair, Nadia Gorman, Bin Wang, Andrew G Smith, Marian L Miller, Howard G Shertzer, Daniel W Nebert
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 196 Issue 3 Pg. 410-21 (May 01 2004) ISSN: 0041-008X [Print] United States
• PMID: 15094312 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Polychlorinated Dibenzodioxins
• Teratogens
• Uroporphyrins
• Cytochrome P-450 CYP1A1

Topics

• Animals
• Cytochrome P-450 CYP1A1 (genetics, physiology)
• Female
• Genotype
• Liver (drug effects, enzymology, metabolism)
• Male
• Mice
• Polychlorinated Dibenzodioxins (antagonists & inhibitors, pharmacokinetics, toxicity)
• Teratogens (toxicity)
• Tissue Distribution
• Uroporphyrins (metabolism)
• Wasting Syndrome (chemically induced, metabolism)