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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
21

Case-only study of interactions between specific genetic polymorphisms and cigarette smoking in the aetiology of Parkinson's disease

Deng, Yifu January 2005 (has links)
The aetiology of Parkinson's disease (PD) is still unclear. Research findings suggest that both environmental and genetic factors may contribute to its development. The interactions between genes and the environment might exist and play a key role. Cigarette smoking was found to be one of the few factors exhibiting a protective effect. If chemical compounds found in cigarette smoke influence PD risk, the difference in the ability of certain individuals in metabolising these substances might alter their susceptibility to the risk of developing PD. Many metabolic enzyme genes exhibit polymorphic traits with alteration of gene function. These might be associated with an altered susceptibility of individuals to PD. Few studies have examined the hypothesis that metabolic enzyme gene polymorphisms might modulate the effect of smoking on PD risk. However, it is crucial to consider these potential interactions when we try to elucidate the aetiology of PD. Even if each factor only contributes a slight variation and influences a small portion of the whole population, non-linear and unpredictable interactions may account for a high proportion of the aetiological fraction. Previous studies have not been strictly designed to examine the interactions between smoking and metabolic enzyme genetic polymorphisms. These studies have not been able to elucidate the extent of the interaction. Therefore, this PhD project attempted to examine whether genetic factors, operating in the phase one and phase two metabolic pathways, interact with smoking to influence the development of PD. This is the first genetic epidemiological study of PD specifically addressing this issue. The research aids in further understanding the aetiology of PD and may be useful for identifying people at higher risk. A case-only design was chosen for this project for two reasons: first, PD is a relatively rare disease and the case-only design is much more efficient at detecting gene-environment interactions; second, the PD cases for the project were recruited over the past few years and represent a prevalence series, for which an appropriate comparison group for the cases is difficult to identify and recruit. In a case-only study, only cases are used to investigate the multiplicative effects of the exposures and susceptible genotypes of interest, while non-case subjects (traditionally controls) are solely used to test the independence between the exposure and the susceptible genotype. Therefore, this approach avoids the challenges of control selection, a major limitation inherent in the case-control approach. This thesis comprised of three independent studies: the first study investigated the interactions between genetic polymorphisms of GSTM1, P1, T1 and Z1 and smoking in PD; the second study examined the interactions between genetic polymorphisms of CYP2E1 and smoking in PD; and the third study examined the interactions between genetic polymorphisms of CYP2D6 and smoking in PD. The first two studies recruited 400 white Caucasian PD cases from both hospital wards and private neurology clinics (230 men and 170 women). The third study further included 142 white Caucasian PD cases newly recruited from the same sources (542 in total, 321 men, and 221 women). The mean age of cases was 67 years with the average onset age at 60 years. GSTM1, GSTP1, GSTT1, GSTZ1 AND CYP2E1 genotyping processes were performed using protocols previously published with minor modification, whereas CYP2D6 genotyping methods were mainly developed by me with assistance from associate supervisor Dr. George Mellick. Reliability and validity of the PCR and RFLP methods were assessed through re-conducting the genotype assays using at least a 10% sample of our DNA samples. The results for all re-assessments were 100% concordant. Crude bivariate analyses were adjusted for potential confounding effects of the variables, including age at onset, gender, family history of PD and pesticide exposures. Among our unaffected, aged subjects (mean age: 63.9 years, sd: 11.4 years), the genotype frequencies at each locus were similar to those reported in other Caucasian populations. The first study showed that the proportion of carriers of the GSTP1-114Val allele (mutant) increased with increasing smoking dose from 0 to > 30 pack-years. Homozygotes of the 114Ala allele (wild-type) decreased with increasing smoking dose (trend test: p=0.02). This trend existed both in male and female cases. This dose-effect relationship was most significant in the group of cases with late-onset PD (i.e., age at onset > 55 years) with the ORicase-only values of 1.88 (95%CI: 0.65-5.48) and 2.63 (95%CI: 1.07-6.49) for > 0-10 and > 10 pack-years, respectively. No similar trend was found among our unaffected, aged subjects (p=0.42). Haplotype analyses revealed significant differences for GSTP1 haplotypes between smoking and non-smoking PD cases (ORicase-only for *C haplotype=2.00 (95%CI: 1.11-3.60), p=0.03). In this case, smoking-exposed PD cases were more likely to posses the *C haplotype defined by A to G base-pair transition at nucleotide +313 and C to T base-pair transition at nucleotide +341 (at amino acid level, valine at both positions 105 and 114). The second study found no difference in CYP2E1 genotype frequencies between PD cases who ever smoked compared to those who never smoked (odds ratio for interaction (ORi) = 1.00 (95% CI: 0.39-2.51, p=0.99)). No CYP2E1 gene-smoking interactions were detected in relation to age at onset of PD. The third study found that among cases without regular pesticide exposures, CYP2D6 PMs who smoked more than 5 pack-years had a later mean age at disease onset (68.6 years) than those with extensive metaboliser phenotypes (EMs) (61.1 years, p=0.02) and non-smokers (60.5 years, p=0.01). Analysis of aged subjects without PD confirmed that neither smoking status nor CYP2D6 PM status was associated with age itself. Our data suggest: 1. smoking exposure is independent of GSTM1, P1, T1, Z1 and CYP2E1 genotypes; 2. smoking may be, to some extent, associated with CYP2D6 genotypes; 3. there are no multiplicative interactive effects linking smoking and GSTM1, T1, Z1 or CYP2E1 genotypes with the risk for PD; 4. there is a multiplicative interactive effect between smoking and GSTP1 haplotype - particularly for genotypes carrying the 114Val allele; and 5. there is a multiplicative interactive effect between smoking and CYP2D6 PMs - particularly for people who ever smoked cigarettes more than 5 pack-years. In general, this thesis provides a model for exploring the gene-smoking interactions in PD. Further studies need to consider the recruitment of a large number of population-based and randomly-selected samples and to pay more attention to measurement of environmental exposures. Further studies also need to examine simultaneously the impact of smoking, pesticide exposures and other potential risk factors on PD. These studies will build evidence for interactions contributing to this common neurological movement disorder.
22

Regulation and polymorphism of CYP2A6, CYP2B6 and CYP2E1 : functional and clinical aspects /

Wang, Jue, January 2006 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.
23

Probing the PCB metabolome: metabolism of chiral and non-chiral polychlorinated biphenyls to chiral hydroxylated metabolites in humans and rats

Uwimana, Eric 01 December 2018 (has links)
Polychlorinated biphenyls (PCBs) continue to pose a health concern because of their predominance in the diet and air as well as in environmental samples and humans. PCB congeners with 3 or 4 chlorine substituents in ortho position have been associated with neurodevelopmental disorders. Hydroxylated metabolites (OH-PCBs) of these PCBs are also potentially toxic to the developing brain. Metabolism studies have mainly focused on animal models. However, preliminary data from this dissertation work have revealed PCB metabolism differences between laboratory animal models and humans in terms of metabolite profiles, chiral signatures. More concerning, biotransformation of chiral PCBs is poorly investigated in humans. The objective of this dissertation research was to study the biotransformation of chiral and prochiral PCBs to chiral hydroxylated metabolites in humans and rats and to identify individual human P450 enzymes involved in the metabolism of these PCBs. I chose chiral PCB congeners 2,2',3,4',6-pentachlorobiphenyl (PCB 91); 2,2',3,5',6-pentachlorobiphenyl (PCB 95), 2,2',3,3',4,6'-hexachlorobiphenyl (PCB 132) and 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) for this investigation because they are environmentally relevant and their metabolism has been studied in rodents and other laboratory animal species (Kania-Korwel et al., 2016a). Prochiral PCB congeners 2,2′,4,6′-tetrachlorobiphenyl (PCB 51) and 2,2′,4,5,6′-pentachlorobiphenyl (PCB 102) were selected because their considerable presence in technical PCB mixtures. To test the hypothesis that P450 enzyme and species differences mediate the congener-specific enantioselective metabolism of chiral PCBs to hydroxylated metabolites, I sought to establish structure-metabolism relationships by studying the enantioselective metabolism of structurally diverse chiral PCBs by human liver microsomes (HLMs). Racemic PCB 91, PCB 95 and PCB 132 were incubated in vitro with pooled or individual donor HLMs at 37 °C, and levels and chiral signatures of the parent PCB and its hydroxylated metabolites were determined by high-resolution gas chromatography equipped with time-of-flight mass spectrometry (GC/TOF-MS) or electron capture detection (GC-ECD). Hydroxylated metabolites formed were identified and metabolic schemes for these PCBs proposed. I found inter-individual differences in the formation of OH-PCBs by individual donor HLMs. Comparison of the metabolite profiles of PCB 91, PCB 95, PCB 132 and PCB 136 (PCB 136 metabolism by HLMs was investigated by other researchers) revealed congener-specific differences in the oxidation of PCBs by human cytochrome P450 enzymes. PCB 91 and PCB 132 were mainly hydroxylated in meta position, with the 1,2-shift metabolites being the major metabolites formed from both PCB congeners by HLMs. In contrast, PCB 95 and PCB 136 were primarily hydroxylated in the para position. Moreover, we determined human P450 isoforms involved in the metabolism of neurotoxic PCBs using in silico and in vitro approaches. In silico predictions suggested that chiral PCBs are metabolized by CYP1A2, CYP2A6, CYP2B6, CYP2E1, and CYP3A4. Experimentally we found that CYP2A6, CYP2B6 and to a minor extent CYP2E1 were the enzymes involved in the metabolism of these chiral PCBS. We also investigated nonchiral sources of chiral OH-PCBs by studying the P450- and species-dependent biotransformation of prochiral PCB 51 and PCB 102 to chiral OH-PCB metabolites. Prochiral PCB 51 and PCB 102 were incubated with liver microsomes prepared from male Sprague-Dawley rats pretreated with various inducers of P450 enzymes including phenobarbital (PB), dexamethasone (DEX), isoniazid (INH), β-naphthoflavone (BNF), clofibric acid (CFA) or corn oil (CO); and untreated male cynomolgus monkeys, Hartley albino guinea pigs, New Zealand rabbits, golden Syrian hamsters; and untreated female Beagle dogs. PCB 51 and PCB 102 were metabolized to 2,2',4,6'-tetrachlorobiphenyl-3'-ol (OH-PCB 51) and 2,2',4,5,6'-pentachlorobiphenyl-3'-ol (OH-PCB 102), respectively. The formation of both metabolites was P450 isoforms- and species-dependent. Moreover, OH-PCB 51 and OH-PCB 102 were chiral and were formed enantioselectively in all microsomes investigated. Taken together, my findings demonstrate (1) considerable inter-individual variability in the congener-specific metabolism of PCBs to OH-PCBs; (2) the enantioselective formation of OH-PCBs by human CYP2A6, CYP2B6, and CYP2E1; and (3) that chiral PCB metabolites are formed enantioselectively from prochiral PCB congeners. Interestingly, the metabolism of PCBs by CYP2A6 appears to involve arene oxide intermediates, as suggested by the formation of 1,2-shift products as major metabolites of PCB 91 and PCB 132. In contrast, 1,2-shift products are minor PCB metabolites formed in rodents. Therefore extrapolation of hepatic metabolism across species may not be consistent and these differences should be considered in future toxicity and risk assessment studies.
24

Alcoholic Liver Disease: From CYP2E1 to CYP2A5

Leung, Tung M., Lu, Yongke 01 August 2017 (has links)
This article reviews recent studies on CYP2E1-mediated alcoholic liver injury, the induction of CYP2A5 by alcohol and the mechanism for this upregulation, especially the permissive role of CYP2E1 in the induction of CYP2A5 by alcohol and the CYP2E1-ROS-Nrf2 pathway, and protective effects of CYP2A5 against ethanol-induced oxidative liver injury. Ethanol can induce CYP2E1, an active generator of reactive oxygen species (ROS), and CYP2E1 is a contributing factor for alcoholinduced oxidative liver injury. CYP2A5, another isoform of cytochrome P450, can also be induced by ethanol. Chronic feeding of ethanol to wild type mice increased CYP2A5 catalytic activity, protein and mRNA levels as compared to pair-fed controls. This induction was blunted in CYP2E1 knockout (cyp2e1 -/- ) mice but was restored when human CYP2E1 was reintroduced and expressed in cyp2e1 -/- mice. Ethanol-induced CYP2E1 co-localized with CYP2A5 and preceded the elevation of CYP2A5. The antioxidants N-acetyl cysteine and vitamin C lowered the alcohol elevation of ROS and blunted the alcohol induction of CYP2A5, but not CYP2E1, suggesting ROS play a novel role in the crosstalk between CYP2E1 and CYP2A5. The antioxidants blocked the activation of Nrf2, a transcription factor known to upregulate expression of CYP2A5. When alcohol-induced liver injury was enhanced in Nrf2 knockout (Nrf2 -/- ) mice, alcohol elevation of CYP2A5 but not CYP2E1 was also lower in Nrf2 -/- mice. CYP2A5 knockout (cyp2a5 -/- ) mice exhibited an enhanced alcoholic liver injury compared with WT mice as indicated by serum ALT, steatosis and necroinflammation. Alcohol-induced hyperglycemia were observed in cyp2a5 -/- mice but not in WT mice.
25

Investigação molecular e epidemiológica de genes do metabolismo de xenobióticos em pacientes com câncer colorretal esporádico

Fernandes, Glaucia Maria de Mendonça 12 December 2013 (has links)
Made available in DSpace on 2016-01-26T12:51:47Z (GMT). No. of bitstreams: 1 glauciamariamfernandes_dissert.pdf: 1922219 bytes, checksum: f00f507bdc9bcdc1daa422a7965c5c41 (MD5) Previous issue date: 2013-12-12 / Fundação de Amparo a Pesquisa do Estado de São Paulo / Introduction: The xenobiotics are exogenous substances to the organism, as N-nitrosamines, heterocyclic amines (HAs) and polycyclic aromatic hydrocarbons (PAHs), can which result in DNA adducts formation. Polymorphisms in genes involved in the metabolism of xenobiotics could contribute to this process and modulate the development of cancer. Objectives: To investigate the CYP1A1*2A (rs4646903), CYP1A1*2C (rs1048943), CYP2E1*5B (rs2031920), CYP1E1*6 (rs6413432), Tyr113His EPHX1 (rs1051740) and His139Arg EPHX1 (rs2234922) polymorphisms related to the metabolism of xenobiotics, the risk of sporadic colorectal (SCRC) cancer, the interaction of these polymorphisms with lifestyle (smoking and drinking) and clinical and histopathological parameters and to evaluate the association of SCRC with socio-demographic factors. Methods: A case-control study was conducted in 641 subjects in the Brazilian population (241 patients with colorectal cancer and 400 controls (individuals without a history of cancer). Real-Time PCR and PCR-RFLP was performed for genotyping. Statistical analysis was performed using the chi-square tet and multiple logistic regression binary. Results: The results showed statistically significant differences between the case and control groups for age greater than 50 years (OR=8.21, 95%CI=5.49-12.28, p<0.01) and male gender (OR=0.50, 95%CI=0.32-0.87, p<0.01) The analysis of polymorphisms revealed an association between the alleles polymorphic CYP2E1*5B (OR=2.84, 95%CI=1.78-4.52, p<0.01, additive model) and CYP2E1*6 (OR=2.78, 95%CI=1.91-4.06, p<0.01, additive model) and the SCRC. Tumor size, lymph node involvement and disease primary site were not associated with polymorphisms. Conclusion: The CYP2E1*5B and CYP2E1*6 polymorphisms are involved in the risk of SCRC and individuals with age &#8805; 50 years are more susceptible to this tumor type, of males are less susceptible. / Introducão: Os xenobióticos são substâncias exógenas ao organismo, tais como as N-nitrosaminas, aminas heterocíclicas (HAs) e hidrocarbonetos policíclicos aromáticos (HPAs), que podem formar adutos de DNA. Polimorfismos em genes envolvidos no metabolismo dos xenobióticos podem contribuir com este processo e, consequentemente, modular o desenvolvimento de câncer. Objetivos: Investigar os polimorfismos CYP1A1*2A (rs 4646903), CYP1A1*2C (rs1048943), CYP2E1*5B (rs 2031920), CYP1E1*6 (rs 6413432), EPHX1 Tyr113His (rs1051740) e EPHX1 His139Arg (rs2234922), relacionados com o metabolismo dos xenobióticos, no risco de câncer de colorretal esporádico (CCRE), a interação desses polimorfismos com os hábitos de vida (tabagismo e etilismo) e parâmetros clínico-histopatológicos e avaliar a associação do CCRE com os fatores sócio-demográficos. Os Métodos: Um estudo caso-controle foi realizado em 641 indivíduos da população brasileira (241 pacientes com câncer de coloretal e 400 controles (indivíduos sem histórico de câncer). As técnicas de PCR em Tempo Real e PCR-RFLP foram realizadas para a genotipagem dos polimorfismos. A análise estatística utilizou os testes de Qui-Quadrado e Regressão Logística Múltipla Binária. Resultados: Os resultados mostraram diferenças estatisticamente significantes entre os grupos caso e controle para idade superior a 50 anos (OR=8,21; IC95%=5,49-12,28, p<0,01) e gênero masculino (OR=0,50; IC95%=0,32-0,87, p<0,01). A análise dos polimorfismos revelou associação entre os alelos polimórficos CYP2E1*5B (OR=2,84; IC95%=1,78-4,52; p<0,01, modelo aditivo) e CYP2E1*6 (OR=2,78; IC95%=1,91-4,06, p<0,01, modelo aditivo) e o CCRE. O tamanho do tumor, envolvimento de linfonodos e sítio primário da doença não foram associados com os polimorfismos. Conclusão: Os polimorfismos CYP2E1*5B e CYP2E1*6 estão envolvidos no risco de CCRE e indivíduos com idade superior ou igual a 50 anos são mais suscetíveis a este tipo tumoral, enquanto aqueles do gênero masculino são menos suscetíveis.
26

Effects Of Benzene On Liver, Kidney And Lung Cyp1a, Cyp2b4, Cyp2e1 And Cyp3a6 Mrna, Protein Level, And Drug Metabolizing Enzyme Activities And Toxicity In Diabetic Rabbits

Arslan, Sevki 01 March 2008 (has links) (PDF)
The effects of diabetes on cytochrome P450 dependent drug metabolizing enzymes have not to be clarified yet. The most widely used animals in these studies have been rats, and information regarding the effects of diabetes on cytochrome P450 dependent procarcinogen/carcinogen metabolism in rabbits is limited. In the present study, we investigated, for the first time, the influence of benzene on liver, kidney and lung microsomal cytochrome P450 dependent drug metabolizing enzyme activities, protein and mRNA levels in diabetic and non-diabetic rabbits. Male New Zealand rabbits were made diabetic by a single dose of alloxan treatment in this study. AST, ALT and LDH enzyme activities in the blood serum and lipid peroxidation in liver microsomes were found to increase in diabetic, benzene treated and benzene treated diabetic rabbits. Besides these, CYP2E1 dependent NDMA N-demethylase and p-nitrophenol hydroxylase activities and CYP2E1 protein level were found to increase in liver and kidney of diabetic and benzene-treated rabbits. The combined effects of benzene and diabetes on these activities and protein level were found to be additive. Although diabetes caused induction of pulmonary CYP2E1 protein level and associated enzyme activities, benzene treatment of rabbits resulted in no change in enzyme activities and protein level in lung. The level of mRNA was investigated by Real-Time PCR. Accordingly, hepatic CYP2E1 mRNA level was increased 6.71-, 10.53- and 12.93-fold in diabetic, benzene treated and benzene treated diabetic rabbits with respect to the control animals. Similarly, renal CYP2E1 mRNA level was found in increase in these rabbits. In addition to CYP2E1, CYP3A6 associated enzyme activity, erythromycin N-demethylase, CYP3A6 protein and mRNA level were found to increase in diabetic rabbit liver and lung. Unlike diabetes, benzene treatment caused suppression of CYP3A6 protein and inhibition of associated enzyme activity in liver. There was no significant change in the erythromycin N-demethylase activity and CYP3A6 level of liver and lung as a result of benzene treatment of diabetic rabbits. Moreover, diabetes induced CYP1A2 protein and mRNA level and CYP1A associated enzyme activities in the rabbit liver. On the other hand, benzene caused statistically insignificant decreases in CYP1A dependent enzyme activities and CYP1A2 protein level in liver. CYP1A associated enzyme activities, CYP1A2 protein and mRNA levels were not changed in the liver of benzene treated diabetics. The results of the present work indicate that both diabetes and benzene stimulate metabolic activation toxic chemicals metabolized by CYP2E1 such as NDMA and benzene by inducing CYP2E1 which results in the formation of increased amounts of reactive metabolites. Application of benzene to diabetic rabbits further elevates expression and activities of the CYP2E1. As a result of additive induction of the CYP2E1 in benzene treated diabetics, further increase the risk of hepatotoxicity produced by toxins may be observed when compared to the separate treatments. This may in turn further potentiate the risk of organ toxicity and mutagenesis in liver and kidney of these subjects. As in the case of CYP2E1, the risk of carcinogenesis due to induction of CYP1A may be increased in diabetic subjects. Moreover, in diabetic and benzene exposed subjects, alteration of drug clearance and clinical drug toxicity may be observed due to induction or suppression of CYP3A.
27

Association Of The Cyp2e1, Fmo3, Nqo1, Gst And Nos3 Genetic Polymorphisms With Ischemic Stroke Risk In Turkish Population

Ozcelik, Aysun 01 December 2011 (has links) (PDF)
Stroke, a major cause of death and disability, is described as interruption or severe reduction of blood flow in cerebral arteries. Oxidative stress plays an important role in the pathogenesis of atherosclerosis and carotid atherosclerosis is a risk factor for stroke. Combination of multiple environmental and genetic risk factors is thought to increase susceptibility to the development of this disease. Therefore, investigation of the polymorphisms of drug metabolizing enzymes is of crucial importance to determine the molecular etiology of the disease. The main objective of this study was to investigate the possible association between polymorphisms of enzymes causing oxidative stress (CYP2E1, FMO3 and NOS3) and enzymes protecting against oxidative stress (GST and NQO1), and the pathogenesis of atherosclerosis and ischemic stroke risk. The study population consisted of 245 unrelated ischemic stroke patients and 145 healthy control subjects. There was no statistically difference between the patient and control groups in terms of age and gender. Hypertension, diabetes, smoking and obesity were found to be at least 2 times more common in stroke patients than controls. While total cholesterol, triglyceride and LDL-cholesterol level were higher in stroke patients, HDL-cholesterol level was lower in stroke patients when compared to controls. In the case-control analyses for the risk of ischemic stroke, CYP2E1*5B mutant allele, *5B was found to be associated with the development of disease (Odds Ratio / OR=7.876, 95%CI=1.025-60.525, P=0.019). In addition, significant difference was observed between stroke patients and controls with respect to CYP2E1*5B genotype distribution (OR=0.869, 95%CI=1.044-62.339, P=0.017). On the other hand, in the NQO1*2 polymorphism, together with NQO1 heterozygote (*1*2), NQO1 homozygote mutant (*2*2) genotype was found protective against ischemic stroke (OR=0.627, 95%CI=0.414-0.950, P=0.027). The risk of hypertensive individuals having stroke was highest in the FMO3 472GA group (OR=6.110, P=0.000). In diabetics, GSTP1 313AG genotype was found to be the highest risk factor for stroke (OR=3.808 P=0.001). On the other hand, NQO1 *1*2 heterozygote genotype was associated with 5 times increased risk for stroke in smokers (OR=5.000, P=0.000). In addition GSTM1 present genotype constituted 8 times increased stroke risk in obese individuals (OR=8.068, P=0.001). Logistic regression analysis revealed that hypertension, diabetes mellitus, obesity and smoking were significant risk factors for stroke. On the other hand, HDL-cholesterol and having NQO1 *1*2 heterozygote genotype were found to be protective factors against stroke.
28

Molecular basis for the anti-inflammatory properties of chlomethiazole /

Simi, Anastasia, January 2003 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.
29

Qualitative and Quantitative Assessment of Cytochromes P450 mRNA in Human : Studies in the Liver, Blood and Gastrointestinal Mucosa

Thörn, Mari January 2005 (has links)
<p>Drugs and other foreign compounds must often be metabolised before they can be excreted from the body. One enzyme system that is responsible for this is the cytochrome P450 gene family (CYP). In this thesis, new sensitive molecular techniques have been used to study the human gene expression of some CYP enzymes, as well as the P-glycoprotein transporter (P-gp). The aim was to evaluate whether tissues other than the liver, e.g. the blood, could be used to assess an individual's drug metabolic capacity. Another aim was to investigate the gene expression in relation to the liver transplant process and a third aim was to evaluate the expression in gastrointestinal mucosa in both normal and inflamed mucosa.</p><p>We evaluated the CYP gene expression in paired specimens of liver and blood but found no correlation in the expression patterns of these two tissues. Instead, we found the opposite pattern, where, for example, CYP1B1 had the highest expression in the blood but the lowest in the liver and CYP2E1 was the enzyme with the highest expression in the liver. In an investigation of the expression of four different CYP enzymes and P-gp in liver transplants before and during the first year after transplantation, we found that the levels of all the CYP enzymes but not P-gp increased with time. We also found that the expression of CYP3A4 was inversely related to the normalised plasma levels of the immunosuppressive drugs cyclosporine and tacrolimus.</p><p>In the gastrointestinal tract, CYP2E1 was the enzyme with the highest mRNA expression compared with CYP3A4, CYP3A5 and the transporter P-gp. CYP3A4 has its highest expression in the duodenum compared with the expression in the stomach and the colon. CYP3A5 is expressed at a higher level than CYP3A4 in the colon. P-gp expression levels increase through the gastrointestinal tract to the left colon. Gene expression levels of CYP2E1 and CYP3A4 decrease in severely inflamed rectal mucosa. </p><p>In conclusion, this is a sensitive method for studying gene activity in a clinical situation, even though at this point we are not able to use blood or gastrointestinal mucosa as “surrogate” tissue to estimate an individual’s drug metabolic capacity. The studies in liver transplants and gastrointestinal mucosa are unique in that the gene expression is investigated during a clinical course of events.</p>
30

Qualitative and Quantitative Assessment of Cytochromes P450 mRNA in Human : Studies in the Liver, Blood and Gastrointestinal Mucosa

Thörn, Mari January 2005 (has links)
Drugs and other foreign compounds must often be metabolised before they can be excreted from the body. One enzyme system that is responsible for this is the cytochrome P450 gene family (CYP). In this thesis, new sensitive molecular techniques have been used to study the human gene expression of some CYP enzymes, as well as the P-glycoprotein transporter (P-gp). The aim was to evaluate whether tissues other than the liver, e.g. the blood, could be used to assess an individual's drug metabolic capacity. Another aim was to investigate the gene expression in relation to the liver transplant process and a third aim was to evaluate the expression in gastrointestinal mucosa in both normal and inflamed mucosa. We evaluated the CYP gene expression in paired specimens of liver and blood but found no correlation in the expression patterns of these two tissues. Instead, we found the opposite pattern, where, for example, CYP1B1 had the highest expression in the blood but the lowest in the liver and CYP2E1 was the enzyme with the highest expression in the liver. In an investigation of the expression of four different CYP enzymes and P-gp in liver transplants before and during the first year after transplantation, we found that the levels of all the CYP enzymes but not P-gp increased with time. We also found that the expression of CYP3A4 was inversely related to the normalised plasma levels of the immunosuppressive drugs cyclosporine and tacrolimus. In the gastrointestinal tract, CYP2E1 was the enzyme with the highest mRNA expression compared with CYP3A4, CYP3A5 and the transporter P-gp. CYP3A4 has its highest expression in the duodenum compared with the expression in the stomach and the colon. CYP3A5 is expressed at a higher level than CYP3A4 in the colon. P-gp expression levels increase through the gastrointestinal tract to the left colon. Gene expression levels of CYP2E1 and CYP3A4 decrease in severely inflamed rectal mucosa. In conclusion, this is a sensitive method for studying gene activity in a clinical situation, even though at this point we are not able to use blood or gastrointestinal mucosa as “surrogate” tissue to estimate an individual’s drug metabolic capacity. The studies in liver transplants and gastrointestinal mucosa are unique in that the gene expression is investigated during a clinical course of events.

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