Abstract
Computational models of normal liver function and xenobiotic induced liver damage are increasingly being used to interpret in vitro and in vivo data and as an approach to the de novo prediction of the liver’s response to xenobiotics. The microdosimetry (dose at the level of individual cells) of xenobiotics vary spatially within the liver because of both compound-independent and compound-dependent factors. In this paper, we build model liver lobules to investigate the interplay between vascular structure, blood flow and cellular transport that lead to regional variations in microdosimetry. We then compared simulation results obtained using this complex spatial model with a simpler linear pipe model of a sinusoid and a very simple single box model. We found that variations in diffusive transport, transporter-mediated transport and metabolism, coupled with complex liver sinusoid architecture and blood flow distribution, led to three essential patterns of xenobiotic exposure within the virtual liver lobule: (1) lobular-wise uniform, (2) radially varying and (3) both radially and azimuthally varying. We propose to use these essential patterns of exposure as a reference for selection of model representations when a computational study involves modeling detailed hepatic responses to xenobiotics.
Highlights
The liver’s physiological functions include production of bile, synthesis of clotting factors and hormones, metabolism of nutrients, storage and release of iron, vitamins and glycogen, and detoxification of xenobiotics
The calculated average blood flow velocity with this ΔP is "v 1⁄4 67:5 mm=s in the virtual liver lobule, similar to the value reported by Macphee et al [45]
We explored the effects of different sinusoid anastomotic patterns (Section 2.2 in S1 Text), different lobule sizes (Section 2.3 in S1 Text), and different portal triad (PT)–to–central vein (CV) pressure drops (Section 2.4 in S1 Text) on calculated blood flow distribution in the virtual mouse liver lobules
Summary
As our aim is to explore possible spatial variation in hepatic exposure to the parent xenobiotic, the model has no transport process for the metabolite and the metabolite accumulates in the hepatocytes
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