Induction of drug‐metabolizing enzymes in human pancreatic cancer and chronic pancreatitis

Foster, John R.; Idle, Jeffrey R.; Hardwick, James P.; Bars, R.; Scott, Patrick; Braganza, Joan M.

doi:10.1002/path.1711690412

Cited by 105 publications

(65 citation statements)

References 25 publications

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“…The more frequently immunostained CYP-enzymes in chronic pancreatitis were predominantly located in islet cells, suggesting that islet cells are an important target of alcohol-related toxicity. Our results, thus, contrast with that of Foster et al (4), claiming the acinar cells as the prime target. The discrepancies could be related to regional differences in the etiology of the disease (ie, alcohol consumption (in our case) versus occupational exposure to xenobiotics (in Foster's case)).…”

Section: Discussioncontrasting

confidence: 99%

Differences in Immunohistochemical Expression of Xenobiotic-Metabolizing Enzymes Between Normal Pancreas, Chronic Pancreatitis and Pancreatic Cancer

Standop

Schneider²,

Ulrich³

et al. 2003

Toxicol Pathol

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Metabolic activation of many toxins, carcinogens, drugs, and anti-cancer agents is governed by the cytochrome P450 (CYP) drug-metabolizing enzyme system. To help elucidate the role of this enzyme system in the pathogenesis of chronic inflammatory and malignant pancreatic diseases, we compared the immunohistochemical expression pattern of 8 CYP-enzymes in 24 normal, 20 chronic pancreatitis, and 21 pancreatic cancer specimens using antibodies to CYP 1A1, 1A2, 2B6, 2C8/9/19, 2D6, 2E1, and 3A4, and the NADPH cytochrome P450 oxido-reductase (NA-OR). Compared to the normal pancreas, a higher frequency of immunopositivity for CYP 1A2, 2B6, 2C8/9/19, 2D6, and NA-OR was found in chronic pancreatitis, and of all CYPs but 1A2 in pancreatic cancer. On the other hand, CYP 1A1 and 2E1 antibody staining was less frequently observed in chronic pancreatitis. In all specimens with pancreatic polypeptide (PP)-rich regions (pancreas head), more islet cells than ductal and acinar cells were immunopositive. Moreover, the immunoreactivity of islet cells from PP-rich specimens with anti-CYP antibodies was consistently more frequent and intense than in islet cells from PP-poor areas (body and tail). Immunoreactivity for xenobiotic-metabolizing enzymes was frequently observed in the normal pancreas, chronic pancreatitis, and pancreatic cancer, and displayed differences of its frequency and intensity between the 3 groups. Considering immunohistochemical evidence of enzyme expression and pancreatic blood supply together, islet cells appear to be an important and possible early site of CYP-enzyme induction in pancreatic diseases.Keywords. Cytochrome P450; drug metabolism; islets of Langerhans; pancreatic polypeptide. INTRODUCTIONCytochrome P450 (CYPs) mono-oxygenases are important enzymes in the oxidative, peroxidative, and reductive metabolism of endogenous and exogenous compounds (28). CYP-enzymes function not only in the detoxification of a wide range of xenobiotics, including drugs, environmental pollutants, and dietary products, but also in the metabolic activation of carcinogens and they are most likely involved in the initiation, promotion, and progression of chronic inflammatory and malignant diseases (3,6,9). The activity of these phase I xenobiotic-metabolizing enzymes results in the formation of either more reactive compounds or substrates for conjugation by phase II xenobiotic-metabolizing enzymes. Moreover, specific CYP-enzymes have recently been shown to be involved in the metabolism of several anti-cancer agents (8-10). Therefore, information regarding the localization and distribution of CYP-enzymes in healthy and diseased tissues are helpful for understanding the susceptibility of the tissue to diseases and for developing therapeutic or preventive methods.Glutathione S-transferases (GST), on the other hand, belong to the large family of phase II xenobiotic-metabolizing enzymes that catalyze the conjugation of the CYP-generated

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Section: Discussioncontrasting

confidence: 99%

Differences in Immunohistochemical Expression of Xenobiotic-Metabolizing Enzymes Between Normal Pancreas, Chronic Pancreatitis and Pancreatic Cancer

Standop

Schneider²,

Ulrich³

et al. 2003

Toxicol Pathol

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“…important mechanisms involved in host defence against xenobiotic chemicals and endogenous toxins. Xenobiotically or endogenously mediated cellular injury might play a role in the etiology of CP [37][38][39]. In the present study we investigated the possible association between CP and genetic polymorphisms in three UGT1A isoenzymes that are associated with changes in enzyme activity and function and are potentially expressed in pancreatic tissue [20,[25][26][27]30,31].…”

Section: Discussionmentioning

confidence: 99%

Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis

Verlaan

Morsche

Pap³

et al. 2004

Pharmacogenetics

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aObjectives Chronic pancreatitis (CP) is associated with alcohol abuse, smoking and other dietary or environmental factors. UDP-glucuronosyltransferases (UGTs) are phase II detoxifying enzymes responsible for glucuronidation of various exogenous and endogenous compounds. Genetic variations, resulting in variable rates of glucuronidation, are of toxicological and physiological importance and are frequently associated with diseases. Recently, a genetic polymorphism in UGT1A7 was possibly associated with an increased risk for CP. We investigated whether polymorphisms in the genes for UGT1A1, UGT1A6 and UGT1A8 modified the risk for CP.Methods DNA samples were obtained from 258 adult CP patients with alcoholic (n 153), hereditary (n 25) or idiopathic (n 80) origin. DNA from 140 healthy controls was analyzed for comparison. Patients and controls were all of Caucasian origin. Genetic polymorphisms in UGTs were determined by PCR, eventually followed by restriction-fragment-length-polymorphism analyses in all subjects.Results The distribution of the various alleles of UGT1A1, UGT1A6 and UGT1A8 did not differ between CP patients and healthy controls.Conclusion These data suggest that genetic polymorphisms in UGT1A1, UGT1A6 and in UGT1A8 do not predispose to the development of CP in Caucasians.

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“…There is some evidence to indicate that individual forms of P450 are expressed in tumours, and previous studies have shown increased expression of individual forms of P450 in different types of malignant tumour (Foster et al, 1993;Murray et al, 1993;Kivisto et al, 1995b;Nakajima et al, 1996), including tumours of the oesophagus (Murray et al, 1994) and colon (McKay et al, 1993). In this study, we have investigated the expression of P450 in stomach cancer and compared it with normal stomach and different types of intestinal metaplasia, the major precursor lesion of stomach cancer.…”

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confidence: 92%

Enhanced expression of cytochrome P450 in stomach cancer

Murray

Taylor²,

Burke³

et al. 1998

Br J Cancer

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Summary The cytochromes P450 have a central role in the oxidative activation and detoxification of a wide range of xenobiotics, including many carcinogens and several anti-cancer drugs. Thus the cytochrome P450 enzyme system has important roles in both tumour development and influencing the response of tumours to chemotherapy. Stomach cancer is one of the commonest tumours of the alimentary tract and environmental factors, including dietary factors, have been implicated in the development of this tumour. This type of tumour has a poor prognosis and responds poorly to current therapies. In this study, the presence and cellular localization of several major forms of P450, CYPl A, CYP2E1 and CYP3A have been investigated in stomach cancer and compared with their expression in normal stomach. There was enhanced expression of CYP1 A and CYP3A in stomach cancer with CYP1 A present in 51% and CYP3A present in 28% of cases. In contrast, no P450 was identified in normal stomach. The presence of CYPlA and CYP3A in stomach cancer provides further evidence for the enhanced expression of specific forms of cytochrome P450 in tumours and may be important therapeutically for the development of anticancer drugs that are activated by these forms of P450.Keywords: cytochrome P450; neoplasm; stomach Stomach cancer is one of the commonest cancers of the alimentary tract and has a relatively poor prognosis with limited response to current modes of therapy (Thompson et al, 1993). Environmental factors, particularly dietary factors, are considered to be important in the aetiology and pathogenesis of this type of tumour. The current model for development of stomach cancer proposes that this type of tumour develops from normal stomach through different types of intestinal metaplasia (Correa, 1988).The cytochromes P450 (P450) are a multi-gene family (Nelson et al, 1996) of constitutive and inducible haem-containing enzymes with a critical role in the metabolism of a diverse range of xenobiotics, including many potential carcinogens (Shimada and Guengerich, 1991;Gonzalez and Gelboin, 1994; RobertsThomson et al, 1995) and various anti-cancer drugs (Kivisto et al, 1995a). Thus, the P450s are considered to have a central role in chemical carcinogenesis and are involved in tumour initiation and promotion as they can activate or deactivate most carcinogens (Gonzalez and Gelboin, 1994). Furthermore the P450s can influence the response of established tumours to anti-cancer drugs by metabolizing these drugs both in normal tissues and in tumour cells. In addition, P450s may have a role in cell regulation, in view of their involvement in the metabolism of physiological chemicals active in inter-and intracellular signalling, including steroid hormones, eicosanoids and fatty acids (Capdevila et al, 1992).The liver is the major normal tissue that expresses P450, while specific forms of P450 are expressed in several different normal extra-hepatic tissues, including small intestine, kidney and lung (Schwartzman et al, 1990;Kaminsky and Fasco, 1992; Shima...

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Induction of drug‐metabolizing enzymes in human pancreatic cancer and chronic pancreatitis

Cited by 105 publications

References 25 publications

Differences in Immunohistochemical Expression of Xenobiotic-Metabolizing Enzymes Between Normal Pancreas, Chronic Pancreatitis and Pancreatic Cancer

Differences in Immunohistochemical Expression of Xenobiotic-Metabolizing Enzymes Between Normal Pancreas, Chronic Pancreatitis and Pancreatic Cancer

Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis

Enhanced expression of cytochrome P450 in stomach cancer

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