Enzyme profile of rat bile ductular epithelial cells in reference to the resistance phenotype in hepatocarcinogenesis

Abstract

An extensive bile ductular cell hyperplasia with the formation of well-differentiated bile ductules is the most prominent feature of rat liver at 6 to 15 weeks after bile duct ligation. We have improved our previous cell isolation procedure and are now routinely able to obtain from such livers high yields of viable bile ductular epithelial cells. These cells were characterized with respect to their specific activities of gamma-glutamyl transpeptidase and beta-glucuronidase and of select Phase I and Phase II enzymes of biotransformation. At the time of their isolation, only a very small number of the bile ductular epithelial cells were observed to be in DNA synthesis. In addition, in histological sections prepared from intact hyperplastic bile ductular tissue isolates, only the bile ductular epithelial cells exhibited histochemical staining for gamma-glutamyl transpeptidase activity. Typically, greater than 95% of the cells isolated from this tissue were also found to be histochemically positive for gamma-glutamyl transpeptidase activity, and no hepatocytes were seen contaminating this cell population. Biochemically, the isolated bile ductular cells exhibited a gamma-glutamyl transpeptidase specific activity that was 100 times higher than that of hepatocytes isolated at the same time from the bile duct-ligated rats and more than 300 times higher than the specific activity of the enzyme of freshly isolated normal rat hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I and Phase II drug-metabolizing enzymes are expressed and heterogeneously distributed in the biliary epithelium

“…7,32,33 It has become apparent, nevertheless, that BEC are a target for chemical toxicants and carcinogens including methylene FIG. 5.…”

Immunohistochemical demonstration of ?-naphthoflavone-inducible cytochrome P450 1A1/1A2 in rat intrahepatic biliary epithelial cells

“…16,[19][20][21][22][23][24]28,29 The results of the present study demonstrate that CYP1A1/1A2 is present and can be induced within these cells in rat liver by a polycyclic aromatic hydrocarbon such as BNF. Thus, these findings provide an explanation for why intrahepatic biliary epithelial cells are susceptible to damage following their in vivo exposure to 2-acetylaminofluorene and other promutagens and procarcinogens.…”

“…To date, only a very limited number of studies have focused on the presence and activities of xenobiotic-metabolizing enzymes in mammalian intrahepatic biliary epithelial cells, [15][16][17][25][26][27] despite the fact that these cells are targets for a number of xenobiotics that exert their toxicities only after being bioactivated. 16,[19][20][21][22][23][24]28,29 The results of the present study demonstrate that CYP1A1/1A2 is present and can be induced within these cells in rat liver by a polycyclic aromatic hydrocarbon such as BNF.…”

“…6,7,9,10 While the localizations, distributions, and inductions of various phase I and phase II xenobiotic-metabolizing enzymes within parenchymal cells (i.e., hepatocytes) throughout the liver have received considerable attention during the past two decades, [6][7][8][9][11][12][13][14] little is currently known regarding the presence and inducibility of xenobiotic-metabolizing enzymes, particularly phase I enzymes, within intrahepatic biliary epithelial cells and other nonparenchymal liver cells. [15][16][17] Intrahepatic biliary epithelial cells have recently received considerable attention because of their ability to proliferate under certain pathophysiological conditions and because of the possibility that they might serve as the progenitor cell in the liver. [18][19][20][21][22][23][24] Although these cells have been shown to be capable of conjugating various xenobiotics and/or their metabolites with reduced glutathione and uridine 5Ј-phosphate (UDP)-glucuronic acid, they appear to be unable to catalyze cytochrome P450 (CYP)-dependent monooxygenase activities, at least in vitro.…”

“…[18][19][20][21][22][23][24] Although these cells have been shown to be capable of conjugating various xenobiotics and/or their metabolites with reduced glutathione and uridine 5Ј-phosphate (UDP)-glucuronic acid, they appear to be unable to catalyze cytochrome P450 (CYP)-dependent monooxygenase activities, at least in vitro. [15][16][17][25][26][27] Nonetheless, intrahepatic biliary epithelial cells are the targets for certain procarcinogens. 19,21,23,[28][29][30] This suggests that they may contain one or more CYP isoforms, a multigene family of hemecontaining enzymes that plays a major role in bioactivating and detoxicating numerous xenobiotics, 4,5,[31][32][33][34][35] including procarcinogens such as 2-acetylaminofluorene and other aromatic amines.…”