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

Tissue expression of drug-metabolizing enzymes influences susceptibility to drugs and carcinogens. Because the biliary epithelium, exposed to bile-borne chemicals, may give rise to drug-induced cholangiopathies and to cholangiocarcinomas, we determined the pattern of expression of drug-metabolizing enzymes in this epithelium. We first demonstrated by blot analyses that biliary epithelial cells (BEC) isolated from human gallbladders display cytochrome P450 (CYP) 1A, 2E1, and 3A, microsomal epoxide hydrolase (mEH), ␣, , and glutathione S-transferase (GST), transcripts and proteins. We also identified CYPassociated steroid 6␤-hydroxylase activity in BEC. CYP and mEH expression was 5-to 20-fold lower in BEC than in autologous hepatocytes, and further differed by a higher ratio of CYP3A5/CYP3A4, and by CYP1A1 predominance over CYP1A2. ␣GST was highly expressed in both hepatocytes and BEC, while GST was restricted to BEC. In approximately 50% of individuals, GST was expressed in hepatocytes and at lower levels in BEC. By using the same antibodies as those used in immunoblots, we could show by immunohistochemistry that CYP2E1, CYP3A, mEH, ␣, , and GST immunoreactivities are expressed and display a heterogeneous distribution in the epithelium lining the entire biliary tract except for small intrahepatic bile ducts that were devoid of CYP3A and ␣GST immunoreactivities. In conclusion, BEC contribute to phase II, and although to a lesser extent than hepatocytes, to phase I biotransformation. The distribution of drug-metabolizing enzymes in BEC suggest that they are heterogeneous in their ability to generate and detoxicate reactive metabolites, which may contribute to specific distributions of cholangiopathies. (HEPATOLOGY 1999;30:1498-1506.)Foreign compounds including procarcinogens and drugs are widely distributed in our environment. The liver is the major organ responsible for their biotransformation into more hydrophilic products, and elimination through bile secretion. Biotransformation results from the activities of phase I and phase II metabolizing enzymes that are mainly, although not exclusively, located within hepatocytes.

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

Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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“…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.…”

Section: Discussionmentioning

confidence: 89%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

“…[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.…”

mentioning

confidence: 99%

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

Shen¹,

Moy²,

Green³

et al. 1998

Hepatology

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Although intrahepatic biliary epithelial cells are targets for certain hepatotoxic chemicals, including some procarcinogens, their ability to monooxygenate, and thereby bioactivate and inactivate xenobiotics, remains to be established. Thus, the present study was undertaken to immunohistochemically determine if cytochrome P450 (CYP) 1A1/ 1A2 is present and can be induced within these nonparenchymal liver cells. Immunoperoxidase and immunofluorescent staining for CYP1A1/1A2 was detected within intrahepatic biliary epithelial cells as well as hepatocytes of control rats and was markedly enhanced in both cell types by ␤-naphthoflavone (BNF). Color confocal laser microscopic analyses of dual immunofluorescent staining for CYP1A1/1A2 and cytokeratins 6 and 9 (56 and 64 kd, respectively) provided unequivocal evidence for the presence and induction of CYP1A1/1A2 within intrahepatic bile duct epithelia. Moreover, microdensitometric analyses of immunoperoxidase staining intensities for CYP1A1/1A2 revealed that intrahepatic biliary epithelial cells of control rats contain 44%, 56%, and 58% as much CYP1A1/1A2 as do centrilobular, midzonal, and periportal hepatocytes, respectively. These analyses further revealed that BNF increased the content of CYP1A1/1A2 in biliary epithelial cells by approximately 120%, while CYP1A1/1A2 levels in centrilobular, midzonal, and periportal hepatocytes were increased by 82%, 159%, and 160%, respectively. The results of this study represent the first in situ demonstration that mammalian intrahepatic biliary epithelial cells contain a CYP isoform, and further that CYP1A1/1A2 can be induced in these cells by BNF. These findings therefore indicate that intrahepatic biliary epithelial cells can oxidatively metabolize xenobiotics in situ and that their ability to bioactivate and inactivate xenobiotics can be significantly enhanced by CYP1A1/1A2 induction.

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Physiology of Cholangiocytes

Tabibian

Masyuk

et al. 2013

Comprehensive Physiology

207

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Cholangiocytes are epithelial cells that line the intra- and extrahepatic ducts of the biliary tree. The main physiologic function of cholangiocytes is modification of hepatocyte-derived bile, an intricate process regulated by hormones, peptides, nucleotides, neurotransmitters, and other molecules through intracellular signaling pathways and cascades. The mechanisms and regulation of bile modification are reviewed herein.

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

Cited by 49 publications

References 31 publications

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

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

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

Physiology of Cholangiocytes

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