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.
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. [(3)H]TCDD was administered as a single, oral dose (0.1 and 10 microg/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.
Hakk
Heldur
H
USDA-ARS Biosciences Research Laboratory, P.O. Box 5674, Fargo, ND, USA.
Diliberto
Janet J
JJ
Birnbaum
Linda S
LS
D000273:Adipose Tissue / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011506:Proteins / Q000378:metabolism; D014018:Tissue Distribution
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D011506:Proteins; C035737:major urinary proteins; D019388:Cytochrome P-450 CYP1A2