The effect of dose on 2,3,7,8-TCDD tissue distribution, metabolism and elimination in CYP1A2 (-/-) knockout and C57BL/6N parental strains of mice

Journal Article · Sun Nov 15 00:00:00 EST 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.08.009· OSTI ID:21344793

Hakk, Heldur ^[1]; Diliberto, Janet J ^[2]; Birnbaum, Linda S ^[3]

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1. USDA-ARS Biosciences Research Laboratory, P.O. Box 5674, Fargo, ND (United States)
2. US-EPA ORD, National Health Effects and Environmental Research Laboratory, Experimental Toxicology Division, Research Triangle Park, NC (United States)
3. National Institute of Environmental Health Sciences and National Toxicology Program, Research Triangle Park, NC (United States)

Numerous metabolism studies have demonstrated that the toxic contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is poorly metabolized. A hallmark feature of TCDD exposure is induction of hepatic CYP1A2 and subsequent sequestration leading to high liver-to-fat concentration ratios. This study was initiated to determine whether TCDD was inherently poorly metabolized or unavailable for metabolism because of sequestration to CYP1A2. [{sup 3}H]TCDD was administered as a single, oral dose (0.1 and 10 mug/kg) to 12 male C57BL/6N mice or 12 CYP1A2 (-/-) mice. At 96 h, less than 5% of the dose was eliminated in the urine of all groups, and TCDD detected in urine was bound to mouse major urinary protein (mMUP). Feces were the major elimination pathway (24-31% of dose), and fecal extracts and non-extractables were quantitated by HPLC for metabolites. No great differences in urinary or fecal elimination (% dose) were observed between the high and low dose treatments. TCDD concentrations were the highest in adipose tissue for CYP1A2 knockout mice but in liver for C57BL/6N mice supporting the role of hepatic CYP1A2 in the sequestration of TCDD. Overall metabolism between parental and knockout strains showed no statistical differences at either the high or low doses. The data suggested that metabolism of TCDD is inherently slow, due principally to CYP1A1, and that hepatic CYP1A2 is not an active participant in the metabolism of TCDD in male mice. Rather, CYP1A2 governs the pharmacokinetics of TCDD by making it unavailable for hepatic CYP1A1 through sequestration and attenuating extrahepatic tissue disposition.

• OSTI ID: 21344793
• Journal Information: Toxicology and Applied Pharmacology, Vol. 241, Issue 1; Other Information: DOI: 10.1016/j.taap.2009.08.009; PII: S0041-008X(09)00345-7; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADIPOSE TISSUE
DIOXIN
DOSES
FECES
KNOCK-OUT REACTIONS
LIVER
METABOLISM
METABOLITES
MICE
ORGANIC CHLORINE COMPOUNDS
STRAINS
TISSUE DISTRIBUTION
TOXICITY
TRITIUM
ANIMAL TISSUES
ANIMALS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BODY
CONNECTIVE TISSUE
DIGESTIVE SYSTEM
DIRECT REACTIONS
DISTRIBUTION
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROGEN ISOTOPES
ISOTOPES
LIGHT NUCLEI
MAMMALS
MATERIALS
NUCLEAR REACTIONS
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
RADIOISOTOPES
RODENTS
VERTEBRATES
WASTES
YEARS LIVING RADIOISOTOPES