Localization and Age-Related Changes in Cytochrome P450 Expression in APA Hamster Livers.

Abstract

Abstract:To establish the baseline data, age-related changes and the regional expression of the hepatic P450 isozymes in Syrian hamsters of the APA strain at 3, 6, 12, 18 months old were examined by immunological techniques. Immunohistochemical analysis of liver serial sections revealed that the midzonal and perivenous regions (zones 2 and 3, respectively) were stained with the anti-rat CYP1A1/2, 2B1/2 and 2E1 antibodies. These three antibodies most intensely stained the hepatocytes around the central vein. An anti-rat CYP3A2 staining section had a staining pattern with equally intense reactions in zones 2 and 3. On the other hand, CYP2C6, 2C11 and 4A1 were distributed diffusely throughout the hepatic acinus. There was no age-related difference in the expression pattern of any of the P450 isozymes examined. Total P450 content had a peak at 6 months of age and decreased to 60% of that level thereafter. Western-blot analysis revealed that the peak expressions of the isozymes detected with anti-rat CYP1A1/2, 2C6, 2E1 and 3A2 antibodies were observed in 6-month-old hamsters and declined in older ones. The CYP2B and 2C11 content reached the maximum at the age of 6 months and maintained almost the same level thereafter. The CYP4A level did not change from 3 to 6 months, and then declined to about 40% of the younger level at 12 and 18 months of age. These results suggest that the hepatic P450 isozymes of APA hamsters have region-specific expressions and most isozymes have their peaks of expression at 6 months of age, which differs from the patterns for rat P450.

Direct visualization of functional heterogeneity in hepatobiliary metabolism using 6-CFDA as model compound

“…Here, hepatocytes are non-uniform in their positions and cellular functions. This approach can be used for drug testing and analyzing the effect of hepatic metabolism with age [23] and metabolic diseases in vivo. Our methodlogy may provide additional information in understanding hepatobiliary zonal metabolism when in mouse models of different pathological conditions, and provide valuable insights in clinical medicine.…”

The effects of diabetes with hyperlipidemia on P450 expression in APA hamster livers

“…It is important to note that APA hamsters of SZ3M have developed a renal disorder [34,37], because experimental renal failure has been reported to change drugmetabolizing activity and P450 content in rats [60]. Otherwise, we have reported that the expression levels of most P450 isozymes have their peaks at 6 months of age [6], which corresponds to the age of APA hamsters of SZ3M. The increased level of P450 expression may make the SZ-induced changes of P450 expression level obscure, but further studies are needed to find the cause of these phenomena.…”

“…To easily understand the localization of P450 isozymes, we referred to the method of Bühler [8] and defined the liver acinus as having three zones: the periportal region (zone 1), the midzonal region of the acinus (zone 2), and the perivenous region (zone 3) which contains a few cell layers in the periphery of the central vein (pcv) [6].…”

“…Some P450 isozymes do not exist homogeneously in the liver but have heterogeneous expression [6][7][8][9][10][11]. Such specific localizations of P450 isozymes have become very important, since many potentially toxic factors, such as drugs and carcinogens, are activated to toxic intermediates by each P450 isozyme and damage the liver heterogeneously, especially in the centrilobular region where most P450 isozymes exist abundantly [12].…”