Intralobular distribution and quantitation of cytochrome P-450 enzymes in human liver as a function of age

Abstract

We have used immunohistochemical, immunoblotting and messenger RNA blotting approaches to study the distribution and quantitation of three cytochrome P-450 enzymes, namely P-450 IA2, P-450 IIC and P-450 IIIA and, for comparison, epoxide hydrolase and NADPH-cytochrome P-450 reductase in human liver. Age-related changes in both the amounts and the intralobular distributions of these enzymes were demonstrated, and the enzymes differ in these regards: In fetal liver, P-450 IA2 and P-450 IIC were very low, when present at all, whereas P-450 IIIA, epoxide hydrolase and the reductase were already abundant and found in all the hepatocytes. During the postnatal period, P-450 IIC dramatically increased and was observed in all hepatocytes, the centrilobular ones being more intensely stained. P-450 IIIA was restricted to centrilobular and midzonal hepatocytes in normal adult liver. P-450 IA2 showed this same intralobular distribution; however, its presence was detected only several weeks or months after birth as judged both by immunohistochemical and immunoblotting techniques. Epoxide hydrolase and NADPH-cytochrome P-450 reductase were easily visualized in all hepatocytes regardless of the age of the donor; in child and adult livers, centrilobular hepatocytes were more intensely stained. Immunoreactive protein contents and corresponding messenger RNA levels correlated well with immunohistochemical observations. No major modification was seen in fibrotic liver, whereas both positive and negative cells were observed in cirrhotic liver nodules for all enzymes studied.

The WNT/β-Catenin Pathway Is a Transcriptional Regulator ofCYP2E1,CYP1A2,and Aryl Hydrocarbon Receptor Gene Expression in Primary Human Hepatocytes

“…On the other hand, our results indicate that, despite its centrilobular expression in vivo (Ratanasavanh et al, 1991), CYP3A4 transcriptional regulation in PHHs is independent of b-catenin and APC expression and/or stimulation. This is in agreement with the finding that in early Ctnnb1 2/2 mice, Cyp3a11 mRNA expression is not affected (Sekine et al, 2006), while Cyp3a is slightly induced in male mice (Braeuning et al, 2009).…”

Cell-type-specific expression of rat steroid 5 alpha-reductase isozymes.

“…(i) The concentration of the enzyme in hepatocytes surrounding the portal triad would facilitate catabolism of circulating testosterone and other steroids since the direction of blood flow in the organ is from portal triad to central vein. We note, however, that the distributions of some drug-inactivating cytochrome P-450 enzymes are exactly opposite (i.e., central vein >> portal triad hepatocytes) from that seen for the Sa-reductase type 1 isozyme (29). (ii) The type 1 isozyme distribution may reflect the developmental lineage of hepatocytes, since precursor stem cells cluster around the portal triad and more terminally differentiated cells around the central vein (30).…”

Immunohistological Analysis of Glutathione Transferase A4 Distribution in Several Human Tissues Using a Specific Polyclonal Antibody

“…GSTA4 staining was frequently more intense in periportal than in centrilobular normal hepatocytes. By contrast, cytochromes P450 are usually more expressed in centrilobular parenchymal cells (Ratanasavanh et al 1991), and other GST alpha enzymes do not exhibit heterogeneous intralobular location (Hiley et al 1988). The preferential periportal expression of GSTA4 could be related to higher peroxidase activity in this lobular area, in agreement with the role of this isozyme in detoxification of lipid peroxidation products such as hydroxyalkenals (Kera et al 1987).…”