Regional Hepatic CYP1A1 and CYP1A2 Induction with 2,3,7,8-Tetrachlorodibenzo-p-dioxin Evaluated with a Multicompartment Geometric Model of Hepatic Zonation

Andersen, Melvin E.; Birnbaum, Linda S.; Barton, Hugh A.; Eklund, Christopher

doi:10.1006/taap.1996.8067

Cited by 89 publications

(35 citation statements)

References 24 publications

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“…All these timedependent processes, including synthesis of specific messenger-RNA or specific proteins, can be modeled with approaches that realistically incorporate our knowledge of the chemistry and biology of the overall response of the tissue or organism. More recent PBPK models for TCDD (Kohn et al, 1993;Andersen et al, 1993Andersen et al, , 1997 have elaborated on this initial model to include increasing biological detail in relation to DNA binding, mRNA induction and protein synthesis for the induced gene products.…”

Section: A Pbpk Model For Dioxin */Early Approachesmentioning

confidence: 99%

Toxicokinetic modeling and its applications in chemical risk assessment

Andersen

2003

Toxicology Letters

158

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Section: A Pbpk Model For Dioxin */Early Approachesmentioning

confidence: 99%

Toxicokinetic modeling and its applications in chemical risk assessment

Andersen

2003

Toxicology Letters

158

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“…As dose increases, more of the cells in the liver become induced and the region of induced cells progresses toward the periportal area of the liver acinus (Figure 3). Andersen et al modeled regional enzyme induction using a semiempirical induction model (Andersen et al 1997a) that could represent the differential induction throughout the liver ( Figure 5 The pattern of immunohistochemical staining for CYP1A1 protein is consistent with a switch that induces a change from a normal phenotype to an AhR-responding phenotype over a narrow range of dose. In the context of the topic of this article, this AhR-agonist PCB has altered the molecular circuitry of these hepatocytes, leading to activation of a cellular switch.…”

Section: An Example With Tumor Promotionmentioning

confidence: 99%

“…The induction of individual cells appears to occur almost in an all-or-none fashion. Cells are either induced or remain in a basal state (Andersen et al 1997a;Tritscher et al 1992). This response, a concerted response of a cell to the receptor-ligand complex, is not yet well understood.…”

Section: An Example With Tumor Promotionmentioning

confidence: 99%

Molecular circuits, biological switches, and nonlinear dose-response relationships.

Andersen

Yang

French

et al. 2002

Environ Health Perspect

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Signaling motifs (nuclear transcriptional receptors, kinase/phosphatase cascades, G-coupled protein receptors, etc.) have composite dose-response behaviors in relation to concentrations of protein receptors and endogenous signaling molecules. "Molecular circuits" include the biological components and their interactions that comprise the workings of these signaling motifs. Many of these molecular circuits have nonlinear dose-response behaviors for endogenous ligands and for exogenous toxicants, acting as switches with "all-or-none" responses over a narrow range of concentration. In turn, these biological switches regulate large-scale cellular processes, e.g., commitment to cell division, cell differentiation, and phenotypic alterations. Biologically based dose-response (BBDR) models accounting for these biological switches would improve risk assessment for many nonlinear processes in toxicology. These BBDR models must account for normal control of the signaling motifs and for perturbations by toxic compounds. We describe several of these biological switches, current tools available for constructing BBDR models of these processes, and the potential value of these models in risk assessment.

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“…A schematic representation of the surfaces of hexagonal acinar structures within the liver in the geometric liver model used to predict regional induction characteristics with TCDD. The most recent physiologically based pharmacokinetic (PBPK) models for TCDD subdivide the liver acinus into five compartments based on concentric regions within the acinus (25,26). This geometric model (Al allows prediction of regional induction (1) by assuming different binding characteristics of TCDD with DNA response elements in each region.…”

Section: Models Ofregional Inductionmentioning

confidence: 99%

“…These pharmacokinetic and gene induction models recently were extended to consider regional effects together with the observation of the sharp boundary between induced and noninduced regions (25,26 Figure 2. A schematic representation of the surfaces of hexagonal acinar structures within the liver in the geometric liver model used to predict regional induction characteristics with TCDD.…”

Section: Models Ofregional Inductionmentioning

confidence: 99%

The use of biochemical and molecular parameters to estimate dose-response relationships at low levels of exposure.

Andersen¹,

Barton²

1998

Environ Health Perspect

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Biomarkers based on alterations in molecular and biochemical parameters may be useful in chemical risk assessment for establishing the presence of an exposure, ranking relative risks among exposed individuals, and estimating risks at low levels of exposure. Because it is unlikely that the relation between toxic responses and the degree of alteration in the biomarker is equivalent at all doses, quantification of risks at low levels is not necessarily more accurate using these biomarkers for extrapolation. The application of response biomarkers for risk evaluation at low levels of exposure is discussed in relation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound that causes induction of cytochromes CYP1 Al and CYP1A2 in liver and other tissues. CYP1A1 induction in liver increases monotonically with TCDD dosage; however, several of the dose-response curves for hepatic effects of TCDD are U-shaped. The U-shaped dose-response curve for hepatic tumor promotion appears to result because the integrated toxicologic response depends on multiple underlying processes-mitosuppression, toxicity, and cell proliferation-each of which has a different dose-response relationship with respect to TCDD. Although dose-response relationships for the biomarkers are not expected to duplicate the complex shapes seen with the integrated responses, measurements and pharmacodynamic modeling of the changes in these molecular and biochemical parameters can still be useful for obtaining an upperbound risk estimate at low levels of exposure. Environ Health Perspect 106 (Suppl 1:349-355 (1998). http.//ehpnetl.niehs.nih.gov/docs/1998/Suppl-1/349-355andersen/abstract.html

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Regional Hepatic CYP1A1 and CYP1A2 Induction with 2,3,7,8-Tetrachlorodibenzo-p-dioxin Evaluated with a Multicompartment Geometric Model of Hepatic Zonation

Cited by 89 publications

References 24 publications

Toxicokinetic modeling and its applications in chemical risk assessment

Toxicokinetic modeling and its applications in chemical risk assessment

Molecular circuits, biological switches, and nonlinear dose-response relationships.

The use of biochemical and molecular parameters to estimate dose-response relationships at low levels of exposure.

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