Role of the Drug-Metabolizing Enzyme CYP during Mouse Liver Development

Abstract

The drug-metabolizing enzyme CYP is mainly involved in the metabolism of various substances in the liver, such as drugs, endogenous substances, and carcinogens. Recent reports have also revealed that CYP1B1 plays a major role in the developmental process. Because the level of CYP expression is markedly high in the liver, we hypothesize that CYP plays a role in the developmental process of the liver. To verify this hypothesis, we analyzed the expression patterns of various CYP molecular species and their functions during the differentiation of embryonic stem cells (ES cells) into hepatocytes and the developmental process in mice. The results demonstrated that CYP2R1 and CYP26A1 are expressed at an earlier stage of the differentiation of ES cells into hepatocytes than hepatoblast-specific markers. Additionally, during the development of the mouse liver, CYP2R1 and CYP26A1 were mostly up-regulated during the stage when hepatoblasts appeared. In addition, when CYP2R1 and CYP26A1 expressions were forced in ES cells and liver of adult mice, they differentiated into hepatoblast marker positive cells. These results suggest that CYP2R1 and CYP26A1 may play a major role in hepatoblast cell differentiation during the development of the liver.Key words embryonic stem cell; liver; CYP; hepatoblast The mature liver contains a variety of cell types, such as hepatocytes, sinusoidal endothelial cells, bile duct epithelial cells, stellate cells and Kupffer cells. The hepatocyte account for 80% of the volume of the liver and play a major role in liver functions, such as metabolism and excretion of drugs. Additionally, the fetal liver is known to act as a hematopoietic organ.The expression of CYP is significantly up-regulated in the liver, and CYP converts fat-soluble drugs into a water-soluble state so that they can be easily excreted. In addition to drug metabolism, CYP is also known to be involved in the oxidative metabolism of endogenous substances, including steroids, bile acid, hormones, and eicosanoids. To date, 58 types of CYP molecular species have been identified in humans, and 108 types have been identified in mice.1-3) As the CYP molecular species share high amino acid sequence homology in several substrate-recognition sites, in addition to the abovementioned functions of CYP, it may also play a major role in development and differentiation in the body. Because CYP begins to be expressed close to the time of hematopoiesis initiation during the fetal stage and CYP requires heme for its structure, CYP is considered to be involved in the development of the liver during the fetal stage. Moreover, it has been reported that the metabolites of endogenous substances and the intermediate metabolites of chemical substances have an effect on the development of individuals and on homeostasis.4-6) Therefore, CYP, which transiently appears during the process of development, is thought to possibly play an important role in the development of the liver.It has been reported that the knockout of either the CYP26A1 gene in mice causes abn...

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

“…7) In this study, we investigated whether the transient, high expression of CYP26A1 and CYP2R1 also occurred during differentiation from undifferentiated cells to hepatoblasts, using another differentiation system.…”

“…4,6) We previously demonstrated that in both the induction of differentiation of embryonic stem (ES) cells into hepatocytes experiments and the fetal mice experiments, the expressions of CYP2R1 and CYP26A1 were induced prior to the expression of DLK1, a hepatoblast marker. 7) We suggested that CYP2R1 and CYP26A1 may play a role in hepatoblast cell differentiation during the development of the liver.…”

“…4,6) We previously demonstrated that in both the induction of differentiation of embryonic stem (ES) cells into hepatocytes experiments and the fetal mice experiments, the expressions of CYP2R1 and CYP26A1 were induced prior to the expression of DLK1, a hepatoblast marker. 7) We suggested that CYP2R1 and CYP26A1 may play a role in hepatoblast cell differentiation during the development of the liver.In this study, we considered whether CYP2R1 and CYP26A1 involved in differentiation from an undifferentiated cell, such as oval cells into hepatoblast in drug-induced hepatitis. This study investigated the roles of CYP2R1 and CYP26A1 in oval cell-mediated liver regeneration by analyzing the expression patterns of these CYPs following partial hepatectomy in mice with DDC-induced liver injury.…”

Maternal and Fetal Pharmacokinetic Analysis of Cannabidiol during Pregnancy in Mice

“…The CBD levels of the fetal brain were similar to those of other organs. We also report that the CYP3A family involved in CBD metabolism is rarely expressed in the fetal liver during this period (Ochiai et al, 2016;Kitaoka et al, 2018a;Kitaoka et al, 2018b). Therefore, we felt the need to measure CBD levels in the liver.…”

“…Concerning metabolism, CBD is oxidized in the adult liver by cytochrome P450 (CYP) 3A at the 6β, 2′, and 4′ positions (Jiang et al, 2011;Ujvary and Hanus, 2016). However, the metabolic activity of CYP3A is significantly lower in the fetal liver than in the adult liver (Ochiai et al, 2016;Kitaoka et al, 2018a;Kitaoka et al, 2018b). Therefore, it is considered that CBD is distributed throughout the entire fetal body with little metabolism in the liver.…”