Toxicological Sciences, Vol 52, 9-19, Copyright © 1999 by Society of Toxicology
MJ Santostefano, VM Richardson, NJ Walker, J Blanton, KO Lindros, GW Lucier, SK Alcasey and LS Birnbaum
Dose-response relationships for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
suggest a differential sensitivity of liver cell types to the induction of
cytochrome P450 gene expression, and that the induction of hepatic protein
CYP1A2 causes sequestration of TCDD. In addition, immunolocalization of
hepatic CYP1A1/1B1/1A2 proteins is not uniform after exposure to TCDD. The
mechanism for the regio-specific induction of hepatic P450s by TCDD is
unknown, but may involve the differential distribution of participants in
the AhR-mediated pathway and/or regional P450 isozymes, as well as,
non-uniform distribution/sequestration of TCDD. Therefore, this study
examined the effects of TCDD in unfractionated, centrilobular and
periportal hepatocytes isolated from female Sprague-Dawley rats acutely
exposed (3 days) to a single oral dose of 0.01-10.0 microg [3H]TCDD/kg. A
dose- dependent increase in concentration of TCDD was accompanied by a
dose- dependent increase in CYP1A1, CYP1A2, and CYP1B1 mRNA expression and
associated enzymes in all liver-cell populations. Centrilobular hepatocytes
showed a 2.7- to 4.5-fold higher concentration of TCDD as compared to the
periportal hepatocytes at doses up to 0.3 microg TCDD/kg. Centrilobular
hepatocytes also exhibited an elevated MROD activity as compared to the
periportal hepatocytes at doses up to 0.3 microg TCDD/kg. Furthermore,
centrilobular hepatocytes showed an elevated concentration of induced
CYP1A2 and CYP1B1 mRNA as compared to periportal hepatocytes within the
0.01- and 0.3-microg TCDD/kg- treatment groups. This is the first study to
demonstrate that a dose- dependent difference in distribution of TCDD
exists between centrilobular and periportal cells that might be related to
regional differences in P450 induction.
ARTICLES
Dose-dependent localization of TCDD in isolated centrilobular and periportal hepatocytes
Curriculum in Toxicology, University of North Carolina, Chapel Hill, USA. santostefano.michael@epamail.epa.gov
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