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.
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 microgram [(3)H]TCDD/kg, 300 microgram [(14)C]4-PeCDF/kg, or 35.8 mg [(14)C]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 (3)H or (14)C 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.
Diliberto
J J
JJ
National Health Effects and Environmental Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, 27711, USA.
Burgin
D E
DE
Birnbaum
L S
LS
D000818:Animals; D001572:Benzofurans / Q000493:pharmacokinetics / Q000652:urine; D001835:Body Weight / Q000187:drug effects; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology*; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics; D000072317:Polychlorinated Dibenzodioxins / Q000493:pharmacokinetics; D014018:Tissue Distribution
D001572:Benzofurans; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D011078:Polychlorinated Biphenyls; D019388:Cytochrome P-450 CYP1A2