Effects of CYP1A2 on Disposition of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, 2,3,4,7,8-Pentachlorodibenzofuran, and 2,2′,4,4′,5,5′-Hexachlorobiphenyl in CYP1A2 Knockout and Parental (C57BL/6N and 129/Sv) Strains of Mice

doi:10.1006/taap.1999.8720

Toxicology and Applied Pharmacology

Volume 159, Issue 1, 15 August 1999, Pages 52-64

https://doi.org/10.1006/taap.1999.8720 Get rights and content

Abstract

TCDD is the prototype and most potent member of the highly lipophilic polyhalogenated aromatic hydrocarbons (PHAHs), which are persistent and ubiquitous environmental contaminants. In both acute and subchronic animal studies, there is a specific accumulation of TCDD in liver greater than in adipose tissue. The inducible hepatic binding protein responsible for this hepatic sequestration of TCDD and its congeners has been shown by our laboratory to be CYP1A2 (J. J. Diliberto, D. Burgin, and L. S. Birnbaum, 1997, Biochem. Biophys. Res. Commun. 236, 431–433). The present study was conducted using knockout (KO) mice lacking expression of CYP1A2 (CYP1A2−/−) in order to investigate the role of CYP1A2 gene on the disposition of TCDD, 4-PeCDF (a dioxin-like PHAH), and PCB 153 (a nondioxin-like PCB) in KO (CYP1A2−/−) mice and age-matched parental mice strains (C57BL/6N: CYP1A2+/+, Ah^b/b and 129/Sv: CYP1A2+/+, Ah^d/d). Mice were dosed (25 μg [³H]TCDD/kg, 300 μg [¹⁴C]4-PeCDF/kg, or 35.8 mg [¹⁴C]PCB 153/kg bw in a corn oil vehicle) orally and terminated after 4 days. Residues of administered compounds in collected tissues and daily excreta were quantitated using ³H or ¹⁴C activity. Results demonstrated differential effects in disposition for the various treatments within the three genetically different groups of mice. In KO mice, TCDD, 4-PeCDF, and PCB 153 had very little hepatic localization of chemical, and the major depot was adipose tissue. In contrast, parental strains demonstrated hepatic sequestration of TCDD and 4-PeCDF, whereas disposition of PCB 153 in parental strains was similar to that in KO mice. Another difference between KO mice and parental strains was the enhanced urinary excretion of 4-PeCDF. This study demonstrates the importance of CYP1A2 in pharmacokinetic behavior and mechanistic issues for TCDD and related compounds.

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^☆: This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. Approval does not signify that the contents necessarily reflect the view and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

²: To whom correspondence and reprint requests should be addressed at MD-74, PKB/ETD/NHEERL, U.S. EPA, Research Triangle Park, NC 27711.

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Regular ArticleEffects of CYP1A2 on Disposition of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, 2,3,4,7,8-Pentachlorodibenzofuran, and 2,2′,4,4′,5,5′-Hexachlorobiphenyl in CYP1A2 Knockout and Parental (C57BL/6N and 129/Sv) Strains of Mice☆

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Pharmacokinetics and biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin: 1. Dose-dependent tissue distribution and induction of hepatic ethoxyresorufin O-deethylase in rats following a single injection

Arch. Toxicol.

Regular Article
Effects of CYP1A2 on Disposition of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, 2,3,4,7,8-Pentachlorodibenzofuran, and 2,2′,4,4′,5,5′-Hexachlorobiphenyl in CYP1A2 Knockout and Parental (C57BL/6N and 129/Sv) Strains of Mice☆