A multicompartment geometric model of the liver in relation to regional induction of cytochrome P450s

Toxicology and Applied Pharmacology
Melvin E AndersenL S Birnbaum

Abstract

A geometric, multicompartment model of the liver was developed to examine regional protein induction and to provide model output suitable for predicting the degree of induction in both the whole liver and in specific regions. The model was based on functional hexagonal arrays within the liver. A geometric representation was used to divide these functional units into five zones: a concentric periportal zone, a fenestrated periportal region that interconnects among multiple functional units, and three concentric centrilobular areas, referred to, respectively, as zones 1 through 5. The surface areas (and volumes for hexagonal cylinders) of these live zones were, respectively, 13.5, 25.2, 33.9, 20.3, and 6.8% of the total liver. The pharmacokinetic model for induction had dissociation constants (Kd) and Hill constants (n) for interactions of transcriptional activator-ligand complexes with response elements on DNA. Estimates of regional induction were converted to color intensities to "paint" the two-dimensional liver for a visual comparison with immunohistochemical observations. To obtain sharp moving boundaries of induced areas with increasing dose (as noted in various experiments), n values in each subcompartment must be large. T...Continue Reading

References

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Citations

Mar 14, 2003·Environmental Health Perspectives·Melvin E AndersenJames E Dennison
Sep 13, 2006·Environmental Health Perspectives·Weihsueh A ChiuMarina V Evans
Apr 28, 2010·PLoS Computational Biology·John Wambaugh, Imran Shah
Jan 22, 2005·Risk Analysis : an Official Publication of the Society for Risk Analysis·Leona H ClarkHugh A Barton
Aug 13, 2005·Biological Reviews of the Cambridge Philosophical Society·Jean-François Ponge
May 7, 2010·Clinical and Translational Science·Marianthi G LerapetritouLoannis P Androulakis
Jul 24, 2008·Dose-response : a Publication of International Hormesis Society·Nigel J Walker, Jae-Ho Yang
Mar 1, 2004·Environmental Toxicology and Pharmacology·Melvin E Andersen, James E Dennison
Sep 17, 2016·PloS One·James P SlukaJames A Glazier
Mar 12, 2004·Toxicological Sciences : an Official Journal of the Society of Toxicology·C Tenley FrenchMelvin E Andersen
Sep 21, 2002·Journal of Biochemical and Molecular Toxicology·Atsushi TakatoriYasuhiro Yoshikawa
Dec 31, 2009·Bulletin of Mathematical Biology·Cammey C ManningHien T Tran
Jul 8, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Y LiuJ V Bruckner
Mar 7, 2009·Chemical Reviews·Stefan Balaz
Jun 1, 1997·Regulatory Toxicology and Pharmacology : RTP·H A Barton, M E Andersen

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