Differences in the expression of xenobiotic-metabolizing enzymes between islets derived from the ventral and dorsal anlage of the pancreas

Standop, Jens; Ulrich, Alexis; Schneider, Matthias; Büchler, Markus W.; Pour, Parviz M.

doi:10.1159/000066093

Cited by 13 publications

(9 citation statements)

References 38 publications

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“…A relationship among exposure to environmental lipophilic chemicals, elevated levels of drug-metabolizing enzymes in the pancreatic exocrine and endocrine cells, and increased incidences of pancreatic cancer and chronic pancreatitis may exist in humans (Foster et al 1993;Standop et al 2002). Future studies of samples from our DLC studies in the rat are aimed at investigating the potential involvement of cytochrome P450 induction in the pathogenesis of the pancreatic acinar pathology.…”

Section: Discussionmentioning

confidence: 99%

Exocrine pancreatic pathology in female Harlan Sprague-Dawley rats after chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds.

Nyska

Jokinen

Brix

et al. 2004

Environ Health Perspect

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Section: Discussionmentioning

confidence: 99%

Exocrine pancreatic pathology in female Harlan Sprague-Dawley rats after chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds.

Nyska

Jokinen

Brix

et al. 2004

Environ Health Perspect

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“…The primary enzyme system involved is made up of numerous P450s. A study was performed with immunochemical detection of CYP1A1, 1A2, 2B6, 2C8/9/19, 2D6, 2E1, 3A4, glutathione S-transferase (GST)-␣, GST-, and GST-, and NADPH P450 oxidoreductase in normal pancreatic tissue specimens (Standop et al, 2002). In all pancreatic regions, most of the enzymes were expressed in islet cells.…”

Section: Applicationmentioning

confidence: 99%

Antibodies as a Probe in Cytochrome P450 Research

Shou

Lu²

2009

Drug Metab Dispos

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ABSTRACT:Cytochrome P450 (P450) is the superfamily of enzymes responsible for biotransformation of endobiotics and xenobiotics. However, their large isoform multiplicity, inducibility, diverse structure, widespread distribution, polymorphic expression, and broad overlapping substrate specificity make it difficult to measure the precise role of each individual P450 to the metabolism of drugs (or carcinogens) and hamper the understanding of the relationship between the genetic/environmental factors that regulate P450 phenotype and the responses of the individual P450s to drugs. The antibodies against P450s have been useful tools for the quantitative determination of expression level and contribution of the epitope-specific P450 to the metabolism of a drug or carcinogen substrate in tissues containing multiple P450 isoforms and for implications in pharmacogenetics and human risk assessment. In particular, the inhibitory antibodies are uniquely suited for reaction phenotyping that helps to predict human pharmacokinetics for clinical drugdrug interaction potential in drug discovery and development.Many enzyme systems exist in the liver and in extrahepatic tissues, such as intestine and kidney, that can contribute to the clearance of drugs from the systemic circulation. Among the various phase I and phase II drug-metabolizing enzymes, the cytochrome P450 (P450) enzymes play a key role in xenobiotic and endobiotic metabolic processing. It has been estimated that approximately two thirds of marketed drugs are metabolized by this enzyme system (Rendic and Di Carlo, 1997;Guengerich, 2003;Williams et al., 2004). In fact, members of three P450 subfamilies (CYP1, CYP2, and CYP3) are largely responsible for the metabolic clearance of drugs and xenobiotics (Rendic and Di Carlo, 1997;Guengerich, 2003;Williams et al., 2004). Multiplicity and overlapping substrate specificity of P450 have greatly complicated efforts at understanding the precise role of individual P450 isoforms in the metabolism of drugs and drug candidates. Therefore, over recent years, a variety of reagents and tools have been developed for in vitro and in vivo studies, and it is now possible to determine which specific P450 isoform(s) is (are) involved in the metabolism of a given compound (Rodrigues, 1999;Rodrigues and Rushmore, 2002;Lu et al., 2003;Williams et al., 2003). Given the importance of fraction of drug metabolized (f m ) in assessing the potential of in vivo drug-drug interaction (DDI), P450 reaction-phenotyping studies are conducted at multiple stages during drug discovery and development. Irrespective of the strategy, information related to P450-mediated metabolism is included in regulatory documents and the absorption, distribution, metabolism, and elimination (ADME) and DDI sections of the product label, where precautions concerning the coadministration of other drugs are listed along with recommendations for dose adjustment (Obach et al., 2006;Huang et al., 2007). Antibodies that are specific to individual P450s can be used to determine P450 pr...

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“…Another extremely important function of the islet cells, not similarly shared by other pancreatic cells, is the defensive strategy provided by drug-metabolizing enzymes. Among the two major groups of drug-metabolizing enzymes in mammals, cytochrome P450 isozymes (CYP) and glutathione S-transferases (GST) [18-22], which are known to be involved in the metabolism of a variety of toxins and carcinogens, were found to be expressed primarily or exclusively in the islet cells of every species that we have investigated, including humans, monkeys, pigs, dogs, guinea pigs, rabbits, rats, hamsters and mouse [19]. This implies a greater involvement of islet cells in the metabolism of xenobiotics within the pancreas.…”

Section: Reviewmentioning

confidence: 99%

“…This implies a greater involvement of islet cells in the metabolism of xenobiotics within the pancreas. Strikingly, in humans, four of the CYP isozymes were expressed exclusively in the PP cells, and two isozymes were expressed in a higher concentration in the PP cells than in the other islet cells [ 22]. Considering the anatomical blood supply of the pancreas, the primary presence of the xenobiotic enzymes in the islets is self explanatory, as in humans and other mammalian species, part of the arterial blood passes through the islets before nourishing the exocrine pancreas [23-27].…”

Section: Reviewmentioning

confidence: 99%

“…This may explain the reason for the initial development of the lesions within the islets. In this context, the expression of CYP2E1 by PP cells, which are frequently present in a large number within the ductal epithelium [22], is noteworthy, because this enzyme is involved in the metabolism of carcinogenic nitrosamines, some of which are present in tobacco smoke [47,48], and suggested to present pancreatic carcinogens. Whether or not this peculiar distribution of carcinogen-metabolizing enzymes in PP cells is the reason for the frequent development of pancreatic cancer in the head of the pancreas [20], is a hypothetical question.…”

Section: Reviewmentioning

confidence: 99%

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2003

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The concept of pancreatic cancer origin is controversial. Acinar, ductal or islet cells have been hypothesized as the cell of origin. The pros and cons of each of these hypotheses are discussed. Based on the world literature and recent observations, pancreatic cells seem to have potential for phenotypical transdifferentiation, i.e ductal-islet, ductal-acinar, acinar-ductal, acinar-islet, isletacinar and islet-ductal cells. Although the possibility is discussed that cancer may arise from either islet, ductal or acinar cells, the circumstances favoring the islet cells as the tumor cell origin include their greater transdifferentiation potency into both pancreatic and extrapancreatic cells, the presence of a variety of carcinogen-metabolizing enzymes, some of which are present exclusively in islet cells and the growth factor-rich environment of islets.

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Differences in the expression of xenobiotic-metabolizing enzymes between islets derived from the ventral and dorsal anlage of the pancreas

Cited by 13 publications

References 38 publications

Exocrine pancreatic pathology in female Harlan Sprague-Dawley rats after chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds.

Exocrine pancreatic pathology in female Harlan Sprague-Dawley rats after chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds.

Antibodies as a Probe in Cytochrome P450 Research

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