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 polyh alogenated aromatic hydrocarbons (PHAHs), which are persistent and ubiquito us 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 (CYP1AZ-/-) in order to inv estigate the role of CYP1A2 gene on the disposition of TCDD, 4-PeCDF (a dio xin-like PHAH), and PCB 153 (a nondiosin-like PCB) in KO (CYP1A2-/-) mice a nd age-matched parental mice strains (C57BL/6N: CYP1A2+/+, Ah(b/b) and 129/ Sv: CYP1A2+/+, Ah(d/d)). Mice were dosed (25 mu g [H-3]TCDD/kg 300 mu g [C- 14]4-PeCDF/kg, or 35.8 mg [C-14]PCB 153/kg bw in a corn oil vehicle) orally and terminated after 4 days. Residues of administered compounds in collect ed tissues and daily excreta were quantitated using H-3 or C-14 activity. R esults demonstrated differential effects in disposition for the various tre atments 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 dem onstrated hepatic sequestration of TCDD and 4-PeCDF, whereas disposition of PCB 153 in parental strains was similar to that in KO mice. Another differ ence between KO mice and parental strains was the enhanced urinary excretio n of 4-PeCDF. This study demonstrates the importance of CYP1A2 in pharmacok inetic behavior and mechanistic issues for TCDD and related compounds. (C) 1999 Academic Press.