Analysis of CYP2R1 and CYP26A1 Expression Patterns in Regeneration in Mice with Liver Injury

Abstract

Cytochrome P450 enzymes (CYPs) are involved in the metabolism of various substances in the liver and small intestine and show markedly higher expression levels in the liver compared to other organs. The liver exhibits a remarkable capacity to regenerate. After excision of 70% of the liver, the organ can regenerate to its original size in approximately 1 week. Unlike the normal liver, in the injured liver, hepatic stem cells known as oval cells are considered to play an important role in regeneration. However, the role of CYPs in liver regeneration remains unclear. In the present study, we investigated the role of CYPs in the regeneration of injured liver. Liver injury was induced by 4-week repeated doses of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) in the diet. Next, both DDC-fed mice and control diet (containing no DDC)-fed mice were subjected to 70% hepatectomy, and the hepatic gene expression patterns measured during regeneration were analyzed. Mice with DDC-induced liver injury expressed the oval cell markers cytokeratin 19 (CK19) and epithelial cell adhesion molecule (EpCAM), and partial hepatectomy increased the expression levels of CYP2R1 and CYP26A1 as well as the hepatoblast marker alpha-fetoprotein (AFP) in these mice. The results of this study suggest that CYP2R1 and CYP26A1 are important in the differentiation of oval cells into hepatoblastlike cells in the injured liver. Key words injured liver CYP26A1; CYP2R1; liver regenerationThe adult liver consists of hepatic parenchymal cells (hepatocytes), hepatic sinusoidal endothelial cells, biliary epithelial cells, stellate cells, and Kupffer cells. Hepatic parenchymal cells occupy approximately 80% of the liver volume and play important roles in various liver functions, including nutrient storage, detoxification, metabolism, and excretion. The fetal liver, in contrast, is the major site of hematopoiesis.The liver has the highest regenerative capacity of any organ in the body. After excision of 70% of the liver, the remnant liver regenerates to its original size in approximately 1 week through the hypertrophy or proliferation of the remaining tissue. Two major mechanisms have been proposed for liver generation: hypertrophy and proliferation of hepatocytes and differentiation of undifferentiated cells into hepatocytes.1) In the first mechanism, in a normal liver that has undergone partial hepatectomy, the remaining hepatocytes retain the potential for hypertrophy and proliferation for liver regeneration. In the second mechanism, in a liver that has been injured by drugs, the proliferative capacity of hepatocytes is reduced, and thus the hypertrophy or proliferation of hepatocytes is unlikely. 1)Instead, some biliary epithelial cells dedifferentiate, likely into undifferentiated oval cells, which then proliferate and differentiate into hepatocytes to contribute to liver regeneration.In rats in which hepatocyte proliferation is inhibited by 2-acethylaminofluorene, partial hepatectomy or administration of carbon tetrachloride results in the emergence of...