| 1. |
- Benhamou, S, et al.
(author)
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Meta- and pooled analyses of the effects of glutathione S-transferase M1 polymorphisms and smoking on lung cancer risk
- 2002
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In: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 23:8, s. 1343-1350
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Journal article (peer-reviewed)abstract
- Susceptibility to lung cancer may in part be attributable to inter-individual variability in metabolic activation or detoxification of tobacco carcinogens. The glutathione S-transferase M1 (GSTM1) genetic polymorphism has been extensively studied in this context; two recent meta-analyses of case-control studies suggested an association between GSTM1 deletion and lung cancer. At least 15 studies have been published after these overviews. We undertook a new meta-analysis to summarize the results of 43 published case-control studies including >18 000 individuals. A slight excess of risk of lung cancer for individuals with the GSTM1 null genotype was found (odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.07-1.27). No evidence of publication bias was found (P = 0.4), however, it is not easy to estimate the extent of such bias and we cannot rule out some degree of publication bias in our results. A pooled analysis of the original data of about 9500 subjects involved in 21 case-control studies from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC) data set was performed to assess the role of GSTM1 genotype as a modifier of the effect of smoking on lung cancer risk with adequate power. Analyses revealed no evidence of increased risk of lung cancer among carriers of the GSTM1 null genotype (age-, gender- and center-adjusted OR = 1.08, 95% CI 0.98-1.18) and no evidence of interaction between GSTM1 genotype and either smoking status or cumulative tobacco consumption.
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| 2. |
- Berg, Tove, et al.
(author)
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Gene expression analysis of membrane transporters and drug-metabolizing enzymes in the lung of healthy and COPD subjects.
- 2014
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In: Pharmacology research & perspectives. - : Wiley. - 2052-1707. ; 2:4, s. e00054-
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Journal article (peer-reviewed)abstract
- This study describes for the first time the expression levels of genes encoding membrane transporters and drug-metabolizing enzymes in the lungs of ex-smoking patients with chronic obstructive pulmonary disease (COPD). Membrane transporters and drug-metabolizing enzymes are key determinants of drug uptake, metabolism, and elimination for systemically administered as well as inhaled drugs, with consequent influence on clinical efficacy and patient safety. In this study, while no difference in gene expression was found between healthy and COPD subjects, we identified a significant regional difference in mRNA expression of both membrane transporters and drug-metabolizing enzymes between central and peripheral tissue in both healthy and COPD subjects. The majority of the differentially expressed genes were higher expressed in the central airways such as the transporters SLC2A1 (GLUT1), SLC28A3 (CNT3), and SLC22A4 (OCTN1) and the drug-metabolizing enzymes GSTZ1, GSTO2, and CYP2F1. Together, this increased knowledge of local pharmacokinetics in diseased and normal lung may improve modeling of clinical outcomes of new chemical entities intended for inhalation therapy delivered to COPD patients. In addition, based on the similarities between COPD and healthy subjects regarding gene expression of membrane transporters and drug-metabolizing enzymes, our results suggest that clinical pharmacological studies in healthy volunteers could be a valid model of COPD patients regarding drug disposition of inhaled drugs in terms of drug metabolism and drug transporters.
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| 3. |
- Nyberg, Lars, et al.
(author)
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A convenient method for local drug administration at predefined sites in the entire gastrointestinal tract : experiences from 13 phase I studies
- 2007
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In: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 30:5, s. 432-440
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Journal article (peer-reviewed)abstract
- For local administration of drugs or enzyme inhibitors in the human gut, a small-bore, smooth tube was introduced through the nose, retrieved from the pharynx, equipped with a firm radio-opaque capsule, and swallowed. Peristalsis moves the capsule to the desired location in the gut where it is anchored before administration via the tube. Drug uptake is followed by plasma sampling. One capsule type is used for solutions, another for solid formulations. With solutions, repeated administrations could be done with the capsule being anchored for 24 h or longer or, alternatively, at several locations along the gut. This communication presents the method and an overview of 13 uptake and enzyme/transporter localization studies. Altogether, 268 intubations were undertaken in a total of 128 subjects. Plasma concentrations found with terbutaline and metoprolol are presented showing that terbutaline has its best uptake in the upper small intestine, whereas metoprolol shows the same bioavailability along the whole gut. Subjects could undertake most of their normal activities while carrying the equipment. No serious adverse events (AEs) occurred. Possibly intubation-related AEs were abdominal pain (n = 8) and constipation (n = 5). In conclusion, the method has been found to be safe, convenient and multifunctional for studies of drug uptake at predetermined gut locations in healthy subjects.
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| 4. |
- Seidegård, Janeric, 1949-
(author)
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Microsomal epoxide hydrolase : characterization, induction, and in vitro modulation, of the catalytic activity
- 1982
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Doctoral thesis (other academic/artistic)abstract
- Microsomal epoxide hydrolase has been characterized, mainly in the fiver and lung of the rat.A reported radiometric assay using 3H-styrene 7,8-oxide as substrate has been modified by purifying the substrate before use, decreasing the incubation volume, and prolonging the incubation time. These changes resulted in av 75-150-fold enhancement in sensitivity.Rat lung microsomal epoxide hydrolase has been characterized using this modified assay procedure. The lung enzyme is similar to the liver microsomal epoxide hydrolase in a number of ways, including its high pH optimum (approximately 9.0) and the effects of alcohols, 1,1,1-trichloropropene 2,3-oxide and cyclohexene oxide. However, the specific activity of the lung microsomal enzyme is 10 times lower than the corresponding liver activity. Furthermore, treatment of rats with phenobarbital increases the specific activity of liver microsomal epoxide hydrolase about 3-fold without affecting the lung enzyme.The transverse topology of liver microsomal epoxide hydrolase has been investigated using proteases and non-penetrating reagents and the results suggest that microsomal epoxide hydrolase may be buried deeply in the membrane of the endoplasmic reticulum. The possibility of complex formation between microsomal epoxide hydrolase and the benzpyrene monooxygenase system was investigated by further subfractionation of the liver microsomes from both non-treated and 3-methylcholanthrene-treated animals. The conclusion drawn was that there may exist such a complex in control rat liver microsomes, but not after induction.Induction of microsomal epoxide hydrolase activity, other drug-metabolizing enzymes and related enzymes whith trans-stilbene oxide was characterized. Daily injections of 400 mg/kg body weight for 5 days resulted in the maximal induction, which was 220 % for cytochrome P-450,720 % for microsomal epoxide hydrolase, and 300-400 % for cytosolic glutathione S-transferase(s). Induction with metabolites and structural anologues of trans-stilbene oxide was used to determine the structural features necessary for induction.Benzil was found to be a potent activator (500-600 %) of microsomal epoxide hydrolase in vitro and the nature of this activation was characterized. The effects of benzil and 3 other activakrs of microsomal epoxide hydrolase - viz, metyrapone, chaicone epoxide, and clotrimazole-were examined using different substrates, microsomes from different species (rat, mouse, rabbit, and man), purified rat liver microsomal epoxide hydrolase, and the purified enzyme incorporated into phospholipid vesicles. The main conclusions were that these substances activate only when styrene 7.8-oxide is used as the substrate and that the phospholipids of the membrande play an important role in the activation process.
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| 5. |
- Smits, KM, et al.
(author)
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Association of metabolic gene polymorphisms with tobacco consumption in healthy controls
- 2004
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 110:2, s. 266-270
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Journal article (peer-reviewed)abstract
- Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20,938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYPIAI, GSTMI, GSTTI, NAT2 and GSTPI. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected.
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| 6. |
- Smits, KM, et al.
(author)
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Interaction between smoking, GSTM1 deletion and colorectal cancer: results from the GSEC study
- 2003
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In: Biomarkers. - : Informa UK Limited. - 1366-5804 .- 1354-750X. ; 8:3-4, s. 299-310
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Journal article (peer-reviewed)abstract
- Cigarette smoking has inconsistently been associated with an increased risk of colorectal cancer. One of the enzymes responsible for the detoxification of the carcinogenic compounds present in tobacco smoke is glutathione S-transferase-mu (GST-mu). The gene that codes for this enzyme is GSTM1. In this study, we evaluated the associations and interaction between GSTM1 deletion, smoking behaviour and the development of colorectal cancer. We performed a pooled analysis within the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). We selected six studies on colorectal cancer, including 1130 cases and 2519 controls, and restricted our analyses to Caucasians because the number of patients from other races was too limited. In addition we performed a meta-analysis including the studies from the GSEC database and other studies identified on MEDLINE on the same subject. The prevalence of the GSTM1 null genotype was within the range reported in other studies: 51.8% of the cases had the GSTM1 null genotype versus 56.6% of the controls. No significant association between the GSTM1 null genotype and colorectal cancer was found (odds ratio 0.92, 95% confidence interval 0.73-1.14). Our results suggest a possible positive association between lack of the GST-mu enzyme and colorectal cancer for non-smoking women (odds ratio 1.47, 95% confidence interval 0.80-2.70). There was no interaction between the effects of smoking and GSTM1 genotype on colorectal cancer risk in men and women (chi(2) = 0.007, p = 0.97). Our findings do not support an association between the GSTM1 null genotype and colorectal cancer. In addition, we did not find any modification of the smoking-induced colorectal cancer risk by GSTM1 genotype.
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| 7. |
- Taioli, E, et al.
(author)
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Polymorphisms in CYP1A1, GSTM1, GSTT1 and lung cancer below the age of 45 years
- 2003
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In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 1464-3685 .- 0300-5771. ; 32:1, s. 60-63
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Journal article (peer-reviewed)abstract
- Background A genetic component of early-onset lung cancer has been suggested. The role of metabolic gene polymorphisms has never been studied in young lung cancer cases. Phase 1 and Phase 2 gene polymorphisms are involved in tobacco carcinogens' metabolism and therefore in lung cancer risk. Methods The effect of metabolic gene polymorphisms on lung cancer at young ages was studied by pooling data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database. All primary lung cancer cases of both sexes who were Caucasian and less than or equal to45 years of age at diagnosis, and the corresponding controls were selected. We obtained 261 cases and 1452 controls. Results There was a marginally significant association between lung cancer and GST1 null genotype (OR = 1.2; 95% Cl: 1.0-1.6), and a significant association between lung cancer and the homozygous CYP1A1 Msp1 variant allele (CYP1A1*2A and *2B) genotype (OR = 4.7 95% Cl: 1.2-19.0). When data were stratified by smoking status, the association between CYP1A1 genotype and lung cancer was confined to never smokers. Conclusions These results suggest that metabolic genetic factors play a role in lung cancer developing at young ages.
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| 8. |
- Tuvesson, Helen, et al.
(author)
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Cytochrome P450 3A4 is the major enzyme responsible for the metabolism of laquinimod, a novel immunomodulator
- 2005
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In: Drug Metabolism and Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-009X .- 0090-9556. ; 33:6, s. 866-872
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Journal article (peer-reviewed)abstract
- In the present study, the involvement of cytochrome P450 enzyme( s) in the primary metabolism of laquinimod, a new orally active immunomodulator, has been investigated in human liver microsomes. Hydroxylated and dealkylated metabolites were formed. The metabolite formation exhibited single enzyme Michaelis-Menten kinetics with apparent K-M in the range of 0.09 to 1.9 mM and V-max from 22 to 120 pmol/mg/min. A strong correlation between the formation rate of metabolites and 6β-hydroxylation of testosterone was obtained within a panel of liver microsomes from 15 individuals (r(2) = 0.6 to 0.94). Moreover, ketoconazole and troleandomycin, specific inhibitors of CYP3A4 metabolism, demonstrated a significant inhibition of laquinimod metabolism. Furthermore, in incubations with recombinant CYP3A4, all the primary metabolites were formed. In vitro interaction studies with CYP3A4 substrates and possible concomitant medication demonstrated that laquinimod inhibits the metabolism of ethinyl estradiol with an IC50 value of about 150 μ M, which is high above the plasma level of laquinimod after clinically relevant doses. Ketoconazole, troleandomycin, erythromycin, prednisolone, and ethinyl estradiol inhibited the metabolism of laquinimod, and IC50 values of 0.2, 11, 24, 87, and 235 μ M, respectively, were calculated. In conclusion, the present study demonstrates that laquinimod is a low affinity substrate for CYP3A4 in human liver microsomes. The likelihood for in vivo effects of laquinimod on the metabolism of other CYP3A4 substrates is minor. However, inhibitory effects on the metabolism of laquinimod by potent and specific inhibitors of CYP3A4, such as ketoconazole, are anticipated and should be considered in the continued clinical program for laquinimod.
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| 9. |
- Wallström, Peter, et al.
(author)
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Antibodies against 5-Hydroxymethyl-2'-deoxyuridine Are Associated with Lifestyle Factors and GSTM1 Genotype: A Report from the Malmö Diet and Cancer Cohort.
- 2003
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In: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755. ; 12:5, s. 444-451
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Journal article (peer-reviewed)abstract
- Plasma autoantibodies (aAbs) against the oxidized DNA base derivative 5-hydroxymethyl-2'-deoxyuridine (5-HMdU) are potential biomarkers of cancer risk and oxidative stress. We examined their association with a number of cancer risk factors: smoking, alcohol habits, body fatness, and absence of the glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) in a sample from the population-based Malmö Diet and Cancer cohort (Sweden). This was a cross-sectional study of 264 men and 280 women, 46–67 years of age. Anti-5-HMdU aAb concentration was determined by an ELISA. Data on tobacco exposure were collected through a questionnaire. Alcohol consumption was estimated by a modified diet history method. Body fatness was assessed by a bioimpedance method. The absence or presence of genes coding for GSTM1 and GSTT1 was determined in granulocyte DNA by a multiplex PCR technique. aAb titers were significantly greater in those with high alcohol consumption. Current smokers lacking GSTM1, particularly men, had greater aAb titers compared with nonsmokers or persons expressing GSTM1. Body fatness was inversely associated with antibody titers in men. GSTT1 genotype was not associated with aAb titers. Overall, women had higher aAb titers than men. Adjustment for potential confounders (history of chronic diseases, anti-inflammatory medication, and season of blood sampling) did not change the results. Our study shows that a high alcohol consumption, smoking in combination with lack of GSTM1, and low body fatness (in men) is associated with high titers of anti-5-HMdU aAbs in this population.
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