Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation.
A physiologically based pharmacokinetic (PBPK) model for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was combined with a five-compartment geometric model of hepatic zonation to predict both total and regional induction of CYP450 proteins within the liver. Three literature studies on TCDD pharmacokinetics and protein induction in female rats were analyzed. In simulating low-dose behavior for mRNA in whole liver and, particularly, in representing immunohistochemical observations, the five-compartment model was more successful than conventional homogeneous one-compartment liver models. The five-compartment liver model was used with the affinity of TCDD for the Ah receptor (AhR) held constant across all the liver (Kb = 0.2 nM). The presumed affinities of the AhR-TCDD complex for TCDD responsive elements in the CYP1A1 (Kd1) and CYP1A2 (Kd2) genes varied between adjacent compartments by a factor of 3. This parameterization leads to predicted 81-fold differences in affinities between the centrilobular and the periportal regions. The affinities used for AhR-TCDD complex binding to TCDD response elements for CYP1A2 in compartment 3 (the midzonal area) ranged from 0.08 to 1.0 nM in the three studies modeled. For CYP1A1 the corresponding dissociation constant in compartment 3 varied from 0.6 to 2.0 nM. In each compartment, the Hill coefficient for induction had to be 4 or greater to match the immunohistochemical results. This multi-compartment liver model is consistent with data on protein and mRNA induction throughout the liver and on the regional distribution of these proteins. No previous model has incorporated regional variations in induction. The PBPK analysis based on the multicompartment liver model suggests that the low-dose behavior for hepatic CYP1A1/CYP1A2 induction by TCDD is highly non-linear.
Andersen
M E
ME
ICF Kaiser Engineers, Research Triangle Park, North Carolina 27709, USA. andersenme@aol.com
Birnbaum
L S
LS
Barton
H A
HA
Eklund
C R
CR
D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008956:Models, Chemical; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000072317:Polychlorinated Dibenzodioxins; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2