Gene expression changes in rat liver following exposure to liver growth agents: role of Kupffer cells in xenobiotic-mediated liver growth

Interaction networks: coordinating responses to xenobiotic exposure

“…Kupffer cells activated by peroxisome proliferators are known to release cytokines (Decker, 1990;Rose et al, 1999), and these may then activate hepatocytes proliferation. Such stimulation results in an overall increase in hepatocytes number, concomitantly reducing the density of Kupffer cells in the rat liver (Crunkhorn et al, 2004). This dilution process may well act to reduce the effect of Kupffer cell-released cytokines, by effectively diluting them out, slowing the increase in liver size and causing the cessation of liver growth at approximately twice normal size.…”

“…Following initial xenobiotic induced Kupffer cell activation, a reduction in Kupffer cell number and/or dilution of Kupffer cells due to hepatocyte proliferation occurs. This results in a reduction/dilution in the release of mitogenic cytokines, reduction in the rate of DNA synthesis and cell proliferation, and hence the rate of growth of the liver slows and the liver reaches a maximum size (adapted from Crunkhorn et al, 2004Crunkhorn et al, , © 2003 Elsevier Inc. republished with permission).…”

“…may modify the overall cellular response to xenobiotic exposure (Maglich et al, 2002;Moore et al, 2000b;Swales et al, 2003). Second, intraorgan interaction networks: Most organs are composed of multiple cell types and/or sub-types and the interactions between these are key in determining the overall organ response to xenobiotic exposure (Bojes et al, 1997;Crunkhorn et al, 2004). Third, interorgan interactions are those reactions to a chemical occurring in one organ which then alters the functioning of a second, physically and functionally distinct, organ (Coulson et al, 2003;Wierzbicki et al, 2003).…”

The Evolution of Gene Expression Studies in Drug Safety Assessment

“…These provide an unbiased way for an investigator to identify gene expression changes and include techniques such as differential display (Frueh et al 1996;Garcia-Allan et al 2000;Thai et al 2001) and suppression subtraction hybridization (Crunkhorn et al 2004;Rockett et al 2000).…”

Nuclear receptors: the controlling force in drug metabolism of the liver?

“…However, peroxisome proliferating chemicals are still used today, and in fact human exposure is relatively frequent: How can this be reconciled with the known carcinogenic effects observed in rodents? The use of PPARα null mice demonstrated that the hyperplasia was PPARα-14 dependent (Lee et al 1995), although there is some evident to suggest that PPARα-independent mechanisms may also exist (Crunkhorn et al 2004), and hence the higher levels of PPARα in rodents compared to humans may be responsible for species differences in peroxisome proliferation and cancer (Peters et al 2005), with humans expressing much lower levels (Palmer et al 1998). There has also been shown to be species difference in the effect of PPARα-activation, with increased fatty acid oxidation but not peroxisome proliferation occurring in humans (Choudhury et al 2000).…”