Tissue-level modeling of xenobiotic metabolism in liver: An emerging tool for enabling clinical translational research

Abstract

This review summarizes some of the recent developments and identifies critical challenges associated with in vitro and in silico representations of the liver and assesses the translational potential of these models in the quest of rationalizing the process of evaluating drug efficacy and toxicity. It discusses a wide range of research efforts that have produced, during recent years, quantitative descriptions and conceptual as well as computational models of hepatic processes such as biotransport and biotransformation, intra- and intercellular signal transduction, detoxification, etc. The above mentioned research efforts cover multiple scales of biological organization, from molecule-molecule interactions to reaction network and cellular and histological dynamics, and have resulted in a rapidly evolving knowledge base for a "systems biology of the liver." Virtual organ/organism formulations represent integrative implementations of particular elements of this knowledge base, usually oriented toward the study of specific biological endpoints, and provide frameworks for translating the systems biology concepts into computational tools for quantitative prediction of responses to stressors and hypothesis generation for experimental design.

Figure 1

Typical structure of a generalized PBPK model ⁹⁴ (figure adapted and used with kind permission of Springer Science and Business Media).

Figure 2

Zonation effects.

Figure 3

Structure of the liver's lobules (taken from http://www.niaaa.nih.gov/Resources/GraphicsGallery/Liver/lobulep295.htm and Ref. 95).

Figure 4

Multicompartment liver model incorporating the effects of zonation on metabolic reactions (figure adapted from Ref. 43).

Figure 5

Framework illustrating interactions between in silico and in vitro liver model (figure adapted from Yan et al. ⁵⁰ ).

Figure 6

Pharmacogenomic/toxicogenomic regulation and signaling of phase I and phase II metabolizing enzymes participating in hepatic metabolic and detoxification processes for xenobiotics (figure adapted from Rushmore and Kong ⁸¹ ).

Figure 7

Schematic representation of various factors contributing to heterogeneity in toxicokinetics and toxicodynamics of xenobiotics in the liver ⁸⁵ .