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12 records – page 1 of 2.

Comparison of the formation of benzo[a]pyrene diolepoxide-DNA adducts in vitro by rat and human microsomes: evidence for the involvement of P-450IA1 and P-450IA2.

https://arctichealth.org/en/permalink/ahliterature65363
Source
J Biochem Toxicol. 1989;4(2):79-86
Publication Type
Article
Date
1989
Author
K. Vähäkangas
H. Raunio
M. Pasanen
P. Sivonen
S S Park
H V Gelboin
O. Pelkonen
Author Affiliation
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Source
J Biochem Toxicol. 1989;4(2):79-86
Date
1989
Language
English
Publication Type
Article
Keywords
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide - analysis
Animals
Antibodies, Monoclonal - diagnostic use
Aryl Hydrocarbon Hydroxylases - metabolism
Comparative Study
Cytochrome P-450 Enzyme System - biosynthesis - metabolism
DNA - analysis
DNA Adducts
Dihydroxydihydrobenzopyrenes - analysis
Enzyme Induction - drug effects
Female
Humans
In Vitro
Isoenzymes - biosynthesis - metabolism
Male
Methylcholanthrene - pharmacology
Microsomes, Liver - enzymology - metabolism
Phenobarbital - pharmacology
Placenta - metabolism
Pregnancy
Rats
Rats, Inbred Strains
Research Support, Non-U.S. Gov't
Species Specificity
Spectrometry, Fluorescence
Abstract
The involvement of cytochrome P-450 isozymes in the activation of benzo[a]pyrene (BP) by human placental and liver microsomes was studied in vitro using monoclonal antibodies (Mab) toward the major 3-methylcholanthrene (MC)-inducible and phenobarbital-inductible rat liver P-450 isozymes (Mab 1-7-1 and Mab 2-66-3, respectively). Microsomes from human placenta and liver and rat liver were incubated with BP and DNA, and BP-diolepoxide-DNA (BPDE-DNA) adducts were measured by synchronous fluorescence spectrophotometry (SFS). The only BP metabolite giving the same fluorescence peak as chemically modified BPDE-DNA was BP-7,8-dihydrodiol. Five (smokers) out of 29 human placentas (smokers and nonsmokers), and five out of nine human livers were able to metabolically activate BP to BPDE-DNA adducts in this system. The Mab 1-7-1 totally inhibited the formation of BPDE-DNA adducts in placental microsomal incubations. Inhibition using rat or human liver microsomes was 50-60% and about 90%, respectively. The Mab 2-66-3 had no effect in any of the microsome types. Adduct formation was inhibited more strongly and at lower concentrations of Mab 1-7-1 compared with the inhibition of AHH activity. This study is a clear indication of the major role of P-450IA1 (P-450c) in human placenta and probably P-450IA2 (P-450d) in human liver in BP activation, while other isozymes also take part in the activation in rat liver. Furthermore, this clearly indicates that AHH activity and BP activation are not necessarily associated.
PubMed ID
2512389 View in PubMed
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CYP2A6: a human coumarin 7-hydroxylase.

https://arctichealth.org/en/permalink/ahliterature10471
Source
Toxicology. 2000 Apr 3;144(1-3):139-47
Publication Type
Article
Date
Apr-3-2000
Author
O. Pelkonen
A. Rautio
H. Raunio
M. Pasanen
Author Affiliation
Department of Pharmacology and Toxicology, University of Oulu, PO Box 5000, FIN-90401, Oulu, Finland. olavi.pelkonen@oulu.fi
Source
Toxicology. 2000 Apr 3;144(1-3):139-47
Date
Apr-3-2000
Language
English
Publication Type
Article
Keywords
Anticoagulants - metabolism
Aryl Hydrocarbon Hydroxylases
Coumarins - metabolism
Cytochrome P-450 Enzyme System - antagonists & inhibitors - biosynthesis - metabolism
Humans
Liver - enzymology
Mixed Function Oxygenases - antagonists & inhibitors - biosynthesis - metabolism
Abstract
Coumarin 7-hydroxylation is catalysed by a high-affinity CYP2A6 enzyme in human liver microsomes. CYP2A6 is the only enzyme catalysing this reaction and consequently the formation of 7-hydroxycoumarin can be used as 'an in vitro and in vivo probe' for CYP2A6. CYP2A6 is a major contributor to the oxidative metabolism of nicotine and cotinine, and it also contributes, to a larger or smaller extent, to the metabolism of a few pharmaceuticals (e.g. fadrozole), nitrosamines, other carcinogens (e.g. aflatoxin B1) and a number of coumarin-type alkaloids. CYP2A6 may be inducible by antiepileptic drugs and it is decreased in alcohol-induced severe liver cirrhosis. Several mutated or deleted CYP2A6 alleles have been characterized. Although CYP2A6 represent up to 15% of human microsomes P450 proteins, it is still one of the less well characterised cytochrome P450 enzymes.
PubMed ID
10781881 View in PubMed
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The CYP2A subfamily: function, expression and genetic polymorphism.

https://arctichealth.org/en/permalink/ahliterature20807
Source
IARC Sci Publ. 1999;(148):197-207
Publication Type
Article
Date
1999
Author
H. Raunio
A. Rautio
O. Pelkonen
Author Affiliation
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Source
IARC Sci Publ. 1999;(148):197-207
Date
1999
Language
English
Publication Type
Article
Keywords
Animals
Biotransformation - genetics
Cytochrome P-450 Enzyme System - genetics - physiology
Gene Expression Regulation, Enzymologic - genetics
Genetics, Population
Genotype
Humans
Liver - enzymology
Mice
Neoplasms - enzymology - genetics
Phenotype
Polymorphism, Genetic - genetics
Research Support, Non-U.S. Gov't
Steroid Hydroxylases - genetics - physiology
Abstract
The CYP2A6 gene is one of the three members of the human CYP2A gene subfamily, the others being CYP2A7 and CYP2A13. The CYP2A6 enzyme catalyses the oxidation of several compounds that have clinical or toxicological interest, including pharmaceuticals, procarcinogens, and tobacco smoke constituents. CYP2A6 is expressed mainly in liver, and only trace amounts are found in extrahepatic tissues. Coumarin is a high-affinity substrate for CYP2A6, and a phenotyping test based on coumarin 7-hydroxylation has been developed. Two mutant alleles of the CYP2A6 gene have been found, i.e. CYP2A6*2 and CYP2A6*3. Homozygosity for both mutated alleles appears to confer a poor metabolizer (PM) phenotype, detectable by slow or non-existent 7-hydroxylation of coumarin. Very little is known about the inducibility and regulation of CYP2A6, but studies on the mouse orthologue, CYP2A5, have revealed novel pathways for induction. Since CYP2A6 polymorphism was found fairly recently, nothing is known presently about associations between variant CYP2A6 alleles and diseases or other adverse outcomes of exposure to toxins. Such studies, however, are clearly warranted, given the wide range of procarcinogens and other toxins metabolized by the CYP2A6 enzyme.
PubMed ID
10493259 View in PubMed
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Cytochrome P450 isozyme induction by methyl ethyl ketone and m-xylene in rat liver.

https://arctichealth.org/en/permalink/ahliterature12206
Source
Toxicol Appl Pharmacol. 1990 Mar 15;103(1):175-9
Publication Type
Article
Date
Mar-15-1990
Author
H. Raunio
J. Liira
E. Elovaara
V. Riihimäki
O. Pelkonen
Author Affiliation
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Source
Toxicol Appl Pharmacol. 1990 Mar 15;103(1):175-9
Date
Mar-15-1990
Language
English
Publication Type
Article
Keywords
Animals
Butanones - pharmacology
Cytochrome P-450 Enzyme System - biosynthesis
Enzyme Induction - drug effects
Ethanol - pharmacology
Isoenzymes - biosynthesis
Liver - enzymology
Male
Rats
Rats, Inbred Strains
Xylenes - metabolism - pharmacology
Abstract
The rat hepatic cytochrome P450 induction pattern caused by administration of a high peroral dose of methyl ethyl ketone (MEK, 1.4 ml/kg once daily for 3 consecutive days) and m-xylene (1.0 ml/kg X 3) was studied by catalytic activity and immunoblotting techniques. MEK caused a marked increase in the amount of P450 isozymes belonging to the phenobarbital- and ethanol-inducible P450 subfamilies P450IIB and P450IIE, respectively. Catalytic activities linked with these isozymes, pentoxyresorufin O-depentylase (P450IIB), aniline hydroxylase, and N-nitrosodimethylamine N-demethylase (P450IIE), were also increased (18.0-, 5.4-, and 2.4-fold, respectively). The activity of ethoxyresorufin O-deethylase, which is predominantly linked with the polycyclic aromatic hydrocarbon-inducible P450 isozymes, was also increased 2.3-fold without an apparent increase in the amount of the respective P450 protein (P450IA). m-Xylene caused a similar induction pattern with less effect on P450IIE. Simultaneous administration of MEK and m-xylene resulted in an additive or, in the case of pentoxyresorufin O-depentylase, a potentiating effect on P450-linked catalytic activities. These data indicate that MEK and m-xylene elicit a qualitatively similar induction of P450 isozymes, which may play a role in the metabolic interactions of these compounds.
PubMed ID
2315928 View in PubMed
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Cytochrome P4502A6 (CYP2A6) expression in human hepatocellular carcinoma.

https://arctichealth.org/en/permalink/ahliterature21813
Source
Hepatology. 1998 Feb;27(2):427-32
Publication Type
Article
Date
Feb-1998
Author
H. Raunio
R. Juvonen
M. Pasanen
O. Pelkonen
P. Pääkkö
Y. Soini
Author Affiliation
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Source
Hepatology. 1998 Feb;27(2):427-32
Date
Feb-1998
Language
English
Publication Type
Article
Keywords
Animals
Antibodies, Blocking
Aryl Hydrocarbon Hydroxylases
Blotting, Western
Carcinoma, Hepatocellular - enzymology - mortality
Cytochrome P-450 Enzyme System - immunology - metabolism
Dose-Response Relationship, Immunologic
Humans
Immunohistochemistry
Liver Neoplasms - enzymology - mortality
Male
Mice
Mice, Inbred DBA
Microsomes, Liver - enzymology
Mixed Function Oxygenases - immunology - metabolism
Research Support, Non-U.S. Gov't
Survival Rate
Testosterone - metabolism
Abstract
The hepatic cytochrome P4502A6 (CYP2A6) enzyme mediates the oxidative metabolism of several procarcinogens that have liver as their primary target. Mouse models indicate that liver tumors invariably overexpress CYP2A forms, and that inflammation and cirrhosis may regulate the CYP2A expression pattern. In this study, the distribution of the CYP2A6 protein was investigated in a series of 24 human hepatocellular carcinoma (HCC) samples by immunohistochemical analysis. A polyclonal antibody was raised in chicken against CYP2A5, the mouse orthologue of CYP2A6. The antibody was characterized and found to be specific for CYP2A members. In DBA/2 mouse liver, a strong increase of CYP2A5 protein amount, localized in the perivenous region, occurred in response to treatment with pyrazole. In human HCC samples, overexpression of CYP2A6 protein was associated with the presence of chronic inflammation and cirrhosis. CYP2A6 protein was observed in 9 of 16 (56%) of samples with non-neoplastic hepatocytes and in 10 of 24 (42%) HCC samples. The staining for CYP2A6 protein was very heterogeneous in tumor cells, suggesting that increased expression of CYP2A6 occurred in a distinct subpopulation of neoplastic cells. In Kaplan-Meyer survival analysis, there was a tendency toward a more favorable prognosis in patients with CYP2A6-positive tumors in comparison with patients with CYP2A6-negative tumors. These data suggest that, in human HCC, in contrast to mouse liver tumors, CYP2A6 overexpression is not an invariable phenotype.
PubMed ID
9462641 View in PubMed
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Distribution of cytochrome P4501A (CYP1A) in the tissues of Baltic ringed and grey seals.

https://arctichealth.org/en/permalink/ahliterature71887
Source
Mar Environ Res. 2001 Jun;51(5):465-85
Publication Type
Article
Date
Jun-2001
Author
O M Hyyti
M. Nyman
M L Willis
H. Raunio
O. Pelkonen
Author Affiliation
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Source
Mar Environ Res. 2001 Jun;51(5):465-85
Date
Jun-2001
Language
English
Publication Type
Article
Keywords
Animals
Animals, Wild
Biological Markers - analysis
Cytochrome P-450 CYP1A1 - analysis - biosynthesis
Environmental Exposure
Female
Gene Expression Regulation
Health status
Hydrocarbons, Chlorinated
Immunohistochemistry
Insecticides - adverse effects
Liver - enzymology
Male
Research Support, Non-U.S. Gov't
Seals, Earless - physiology
Tissue Distribution
Abstract
Information about the expression of CYP1A in wildlife species is essential for understanding the impact of organochlorine exposure on the health status of an exposed population. Therefore, we aimed at characterising a putative CYP1A enzyme expression in both hepatic and extrahepatic tissues of ringed and grey seals from the Baltic Sea and from less polluted waters. The cellular localisation of CYP1A was identified using a monoclonal antibody against scup P4501A1 (MAb 1-12-3). Immunohistochemical staining showed the highest level of CYP1A expression in liver hepatocytes, and the second highest level in the endothelial cells of capillaries and larger blood vessels in the liver and other organs. The most frequent and strongest staining was found in Baltic ringed seals. Although CYP1A-positive staining was observed in only a few tissues in the other seal populations, it was more intense in Baltic grey seals than in Canadian grey seals. The CYP1A enzyme activity, expressed as ethoxyresorufin O-deethylation (EROD), followed a similar tissue distribution and geographical pattern as the immunohistochemistry with clearly elevated EROD activities in most tissues of both Baltic seal populations. Immunochemical characterisation by immunoblotting confirmed the presence and elevation pattern of a putative CYP1A protein in ringed and grey seals, supporting our findings using other methods. The evenly distributed elevation of CYP1A expression among most of the tissues examined indicates that Baltic seals are exposed to CYP1A inducing agents affecting the whole body. This may result in an increased or decreased toxic potential of foreign substances, which may ultimately determine the biological effects of the contaminants.
PubMed ID
11488512 View in PubMed
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Expression of P-glycoprotein in hepatocellular carcinoma: a potential marker of prognosis.

https://arctichealth.org/en/permalink/ahliterature22613
Source
J Clin Pathol. 1996 Jun;49(6):470-3
Publication Type
Article
Date
Jun-1996
Author
Y. Soini
N. Virkajärvi
H. Raunio
P. Pääkkö
Author Affiliation
Department of Pathology, University of Oulu, Finland.
Source
J Clin Pathol. 1996 Jun;49(6):470-3
Date
Jun-1996
Language
English
Publication Type
Article
Keywords
Carcinoma, Hepatocellular - chemistry - drug therapy
Cell Division - genetics
Comparative Study
Disease-Free Survival
Drug Resistance, Multiple - genetics
Female
Gene Expression
Humans
Immunohistochemistry
Liver Neoplasms - chemistry - drug therapy
Male
Mitomycin - therapeutic use
P-Glycoprotein - analysis - genetics
Prognosis
Proliferating Cell Nuclear Antigen - analysis
Research Support, Non-U.S. Gov't
Tumor Markers, Biological - analysis - genetics
Tumor Suppressor Protein p53 - analysis
Abstract
AIMS: (1) To investigate the immunohistochemical expression of the multidrug resistance gene (MDR1) product P-glycoprotein in histological samples from 31 hepatocellular carcinomas (HCCs); and (2) to correlate the results with cell proliferation, p53 expression, the disease-free interval, and cumulative patient survival. METHODS: C219 (a monoclonal antibody), CM-1 (a polyclonal rabbit anti-human antibody) and PC10 (a monoclonal mouse anti-human antibody) were used to detect expression of P-glycoprotein, p53 and proliferating cell nuclear antigen (PCNA), respectively, by means of the avidin-biotin peroxidase method. RESULTS: Membrane bound positivity for P-glycoprotein was observed in 20 (65%) of the 31 HCCs. Cytoplasmic globular positivity was also seen in some cases. There were no significant associations between expression of P-glycoprotein and cell proliferation (determined by PCNA immunoexpression and the mitotic count), or p53 expression. Patients with P-glycoprotein positive tumours had a shorter disease-free interval than those with P-glycoprotein negative tumours, and also had a shorter survival time. There was no difference in survival between P-glycoprotein positive patients who had or had not received chemotherapy, suggesting that chemotherapy (mainly mitomycin-C) did not affect survival in these patients. CONCLUSIONS: Expression of P-glycoprotein in HCCs is associated with a shorter disease-free interval and shorter survival time. As expression of P-glycoprotein was not associated with cell proliferation or expression of p53, its effect on disease progression and survival seems to be independent of these factors.
PubMed ID
8763260 View in PubMed
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Expression of xenobiotic-metabolizing CYPs in human pulmonary tissue.

https://arctichealth.org/en/permalink/ahliterature20891
Source
Exp Toxicol Pathol. 1999 Jul;51(4-5):412-7
Publication Type
Article
Date
Jul-1999
Author
H. Raunio
J. Hakkola
J. Hukkanen
A. Lassila
K. Päivärinta
O. Pelkonen
S. Anttila
R. Piipari
A. Boobis
R J Edwards
Author Affiliation
Department of Pharmacology and Toxicology, University of Oulu, Finland. hannu.raunio@oulu.fi
Source
Exp Toxicol Pathol. 1999 Jul;51(4-5):412-7
Date
Jul-1999
Language
English
Publication Type
Article
Keywords
Cells, Cultured
Cytochrome P-450 Enzyme System - metabolism
Humans
Liver - enzymology
Lung - enzymology
Models, Biological
Research Support, Non-U.S. Gov't
Xenobiotics - metabolism
Abstract
The pattern of expression of individual cytochrome P450 (CYP) forms participating in the metabolism of xenobiotics is being increasingly well characterised in the human pulmonary tissue. Recent studies using methods having increased sensitivity and specificity, such as the reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, have revealed constitutive and inducible expression of several CYP forms in different cell types of the human lung. These studies have revealed the presence of mRNA of several procarcinogen-activating CYP forms in whole lung tissue and alveolar macrophages, including CYP1A1, CYP2B6/7, CYP2E1, and CYP3A5. The results of several studies on CYP2D6 expression have yielded contradictory results. Immunohistochemical analysis shows that CYP3A5 protein is present in all lung samples studied, and is localized in the ciliated and mucous cells of the bronchial wall, bronchial glands, bronchiolar ciliated and terminal cuboidal epithelium, type I and type II alveolar epithelium, vascular and capillary endothelium, and alveolar macrophages. Also CYP3A4 protein is found in some cell types in a minority (about 20%) of lung samples. Primary cultures of freshly isolated broncho-alveolar macrophages as well as a continuously growing bronchial carcinoma cell line (A-549) are being used for CYP induction studies in our laboratory. The results indicate that CYP1 family members are inducible in these cells by polycyclic aromatic hydrocarbon (PAH) inducers, and that CYP3A5, but not CYP3A4, is present constitutively. The results of these studies indicate that several different xenobiotic-metabolizing CYPs are present in the human lung and lung-derived cell lines, possibly contributing to in situ activation of pulmonary procarcinogens. Interindividual differences in the expression of these CYPs may contribute to the risk of developing lung cancer and possibly other pulmonary diseases initiated by agents that require metabolic activation.
PubMed ID
10445407 View in PubMed
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12 records – page 1 of 2.