Showing papers by "University of Tübingen published in 2008"

Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes

Abstract: Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms Recent reviews have described the range of assays that have been used for this purpose(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi) Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response

Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study

Abstract: Summary Background Mutations in LRRK2 , the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2 -associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2 ? Methods Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2 -associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD. Findings Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2 -associated PD were more benign than those of idiopathic PD. Interpretation Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients. Funding UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.

Electronic nose: current status and future trends.

Abstract: 2.2. New Approaches 707 2.2.1. Optical Sensor Systems 707 2.2.2. Mass Spectrometry 708 2.2.3. Ion Mobility Spectrometry 708 2.2.4. Gas Chromatography 709 2.2.5. Infrared Spectroscopy 709 2.2.6. Use of Substance-Class-Specific Sensors 709 2.3. Combined Technologies 710 3. Companies 710 4. Application Areas 710 4.1. Food and Beverage 712 4.2. Environmental Monitoring 715 4.3. Disease Diagnosis 716 5. Research and Development Trends 718 5.1. Sample Handling 719 5.2. Filters and Analyte Gas Separation 719 5.3. Data Evaluation 720 6. Conclusion 721 7. References 722

The genome of the model beetle and pest Tribolium castaneum.

Abstract: Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.

Identification and characterization of metabolically benign obesity in humans.

Abstract: Background: Obesity represents a risk factor for insulin resistance, type 2 diabetes mellitus, and atherosclerosis. In addition, for any given amount of total body fat, an excess of visceral fat or fat accumulation in the liver and skeletal muscle augments the risk. Conversely, even in obesity, a metabolically benign fat distribution phenotype may exist. Methods: In 314 subjects, we measured total body, visceral, and subcutaneous fat with magnetic resonance (MR) tomography and fat in the liver and skeletal muscle with proton MR spectroscopy. Insulin sensitivity was estimated from oral glucose tolerance test results. Subjects were divided into 4 groups: normal weight (body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], 25.0), overweight (BMI, 25.0-29.9), obese–insulin sensitive (IS) (BMI, 30.0 and placement in the upper quartile of insulin sensitivity), and obese–insulin resistant (IR) (BMI, 30.0 and placement in the lower 3 quartiles of insulin sensitivity). Results: Total body and visceral fat were higher in the overweight and obese groups compared with the normal-weight group (P.05); however, no differences were observed between the obese groups. In contrast, ectopic fat in skeletal muscle (P.001) and particularly the liver (4.3%±0.6% vs 9.5%±0.8%)andtheintima-mediathicknessofthecommon carotidartery(0.54±0.02vs0.59±0.01mm)werelowerand insulin sensitivity was higher (17.4±0.9 vs 7.3±0.3 arbitrary units) in the obese-IS vs the obese-IR group (P.05). Unexpectedly, the obese-IS group had almost identical insulin sensitivity and the intima-media thickness was not statistically different compared with the normal-weight group (18.2±0.9 AU and 0.51±0.02 mm, respectively). Conclusions: A metabolically benign obesity that is not accompanied by insulin resistance and early atherosclerosis exists in humans. Furthermore, ectopic fat in the liver may be more important than visceral fat in the determination of such a beneficial phenotype in obesity.

Simultaneous PET-MRI: a new approach for functional and morphological imaging

Abstract: Noninvasive imaging at the molecular level is an emerging field in biomedical research. This paper introduces a new technology synergizing two leading imaging methodologies: positron emission tomography (PET) and magnetic resonance imaging (MRI). Although the value of PET lies in its high-sensitivity tracking of biomarkers in vivo, it lacks resolving morphology. MRI has lower sensitivity, but produces high soft-tissue contrast and provides spectroscopic information and functional MRI (fMRI). We have developed a three-dimensional animal PET scanner that is built into a 7-T MRI. Our evaluations show that both modalities preserve their functionality, even when operated isochronously. With this combined imaging system, we simultaneously acquired functional and morphological PET-MRI data from living mice. PET-MRI provides a powerful tool for studying biology and pathology in preclinical research and has great potential for clinical applications. Combining fMRI and spectroscopy with PET paves the way for a new perspective in molecular imaging.

Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.

Abstract: Summary Background Cutaneous squamous-cell carcinomas (SCC) are among the most common cancers capable of metastasis. Current Tumour Node Metastasis (TNM) staging includes horizontal tumour size, involvement of extradermal structures, and degree of differentiation. The aim of this study was to prospectively analyse the key factors predicting metastasis and local recurrence in cutaneous SCC. Methods We assessed prospectively investigated potential risk factors for metastasis or local recurrence of SCC, previously suggested by retrospective studies and small case series, in 615 white patients. Between Jan 1, 1990, and Dec 31, 2001, all patients underwent surgery for cutaneous SCC with complete histological examination of the three-dimensional excision margins (3D-histology) in one centre. Univariate and multivariate analysis included tumour thickness, horizontal size, body site, histological differentiation, desmoplastic growth, history of multiple SCC, and immunosuppression. Primary endpoints were time to metastasis and time to local recurrence, defined as the time from date of diagnosis of the primary tumour to the date of diagnosis of metastasis or local recurrence, respectively. Findings 653 patients were enrolled in the study. 38 patients were lost to follow-up leaving 615 assessable patients (median age 73 years [range 27–98]). During a median follow-up period of 43 months (range 1–165), 26 (4%) of 615 patients developed metastases and 20 patients developed local recurrence (3%). Tumours 2·0 mm or less in thickness did not metastasise. Metastases occurred in 12 (4%) of 318 tumours between 2·1 mm and 6·0 mm in thickness, and in 14 (16%) of 90 tumours with a thickness greater than 6·0 mm. On multivariate analysis, key prognostic factors for metastasis were increased tumour thickness (hazard ratio 4·79 [95% CI 2·22–10·36]; p Interpretation Only SCC greater than 2·0 mm in thickness are associated with a significant risk of metastasis. Tumours greater than 6·0 mm are associated with a high risk of metastasis and local recurrence. Desmoplastic growth is an independent risk factor for local recurrence. Studies should assess the role of follow-up visits and sentinel-lymph-node biopsy in high-risk patients. Funding This study was supported by the German Research Foundation/Sonderforschungsbereich 685 and Deutsche Krebshilfe (MR), the intramural Angewandte Klinische Forschung fellowship (203-1-0) from the University Medical School, Eberhard Karls University Tuebingen (KDB), and the ‘Sudwestdeutsche Tumorzentrum'—Comprehensive Cancer Centre Tubingen (KDB, MR, HB).

Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg.

Abstract: A b s t r ac t BACKGROUND Drug-eluting stents reduce restenosis in coronary arteries, but clinical trials have failed to prove their efficacy in peripheral arteries. We investigated the use of paclitaxel-coated angioplasty balloons and paclitaxel dissolved in the angiographic contrast medium during angioplasty of the leg. METHODS In a small, multicenter trial, we randomly assigned 154 patients with stenosis or occlusion of a femoropopliteal artery to treatment with standard balloon catheters coated with paclitaxel, uncoated balloons with paclitaxel dissolved in the contrast medium, or uncoated balloons without paclitaxel (control). The primary end point was late lumen loss at 6 months. RESULTS The mean (±SD) age of the patients was 68±8 years, 24% were smokers, and 49% had diabetes. Twenty-seven percent of the lesions were total occlusions, and 36% were restenotic lesions. The mean lesion length was 7.4±6.5 cm. There were no significant differences in baseline characteristics between the groups. There were no adverse events attributable to the paclitaxel-coated balloons. At 6 months, the mean late lumen loss was 1.7±1.8 mm in the control group, as compared with 0.4±1.2 mm (P<0.001) in the group treated with paclitaxel-coated balloons and 2.2±1.6 mm (P = 0.11) in the group treated with paclitaxel in the contrast medium. The rate of revascularization of target lesions at 6 months was 20 of 54 (37%) in the control group, 2 of 48 (4%) in the group treated with paclitaxel-coated balloons (P<0.001 vs. control), and 15 of 52 (29%) in the group treated with paclitaxel in the contrast medium (P = 0.41 vs. control); at 24 months, the rates increased to 28 of 54 (52%), 7 of 48 (15%), and 21 of 52 (40%), respectively. CONCLUSIONS Use of paclitaxel-coated angioplasty balloons during percutaneous treatment of femoropopliteal disease is associated with significant reductions in late lumen loss and target-lesion revascularization. No significant benefit is seen with the use of a paclitaxel-containing contrast medium. (ClinicalTrials.gov number, NCT00156624.)

Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma

Abstract: The incidence of venous thromboembolism (VTE) is more than 1%omicron annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-Weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with <= 1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.

The auxin influx carrier LAX3 promotes lateral root emergence

Abstract: Lateral roots originate deep within the parental root from a small number of founder cells at the periphery of vascular tissues and must emerge through intervening layers of tissues We describe how the hormone auxin, which originates from the developing lateral root, acts as a local inductive signal which re-programmes adjacent cells Auxin induces the expression of a previously uncharacterized auxin influx carrier LAX3 in cortical and epidermal cells directly overlaying new primordia Increased LAX3 activity reinforces the auxin-dependent induction of a selection of cell-wall-remodelling enzymes, which are likely to promote cell separation in advance of developing lateral root primordia

Epidemiology of melanoma and nonmelanoma skin cancer--the role of sunlight.

Abstract: Melanoma and nonmelanoma skin cancer (NMSC) are now the most common types of cancer in white populations. Both tumor entities show an increasing incidence rate worldwide but a stable or decreasing mortality rate.1,2 The rising incidence rates of NMSC are probably caused by a combination of increased sun exposure or exposure to ultraviolet (UV) light, increased outdoor activities, changes in clothing style, increased longevity, ozone depletion, genetics and in some cases, immune suppression. A dose-dependent increase in the risk of squamous cell carcinoma (SCC) of the skin was found associated with exposure to Psoralen and UVA irradiation. An intensive UV exposure in childhood and adolescence was causative for the development of basal cell carcinoma (BCC) whereas for the aetiology of SCC a chronic UV exposure in the earlier decades was accused.

Energy Spectrum of Cosmic-Ray Electrons at TeV Energies

Abstract: The very large collection area of ground-based gamma-ray telescopes gives them a substantial advantage over balloon/satellite based instruments in the detection of very-high-energy (>600 GeV) cosmic-ray electrons. Here we present the electron spectrum derived from data taken with the H.E.S.S. system of imaging atmospheric Cherenkov telescopes. In this measurement, the first of this type, we are able to extend the measurement of the electron spectrum beyond the range accessible to direct measurements. We find evidence for a substantial steepening in the energy spectrum above 600 GeV compared to lower energies.

EULAR recommendations for the management of Behçet disease

Abstract: Objectives: To develop evidence-based European League Against Rheumatism (EULAR) recommendations for the management of Behcet disease (BD) supplemented where necessary by expert opinion. Methods: The multidisciplinary expert committee, a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), consisted of nine rheumatologists (one who was also a clinical epidemiologist and one also a Rehabilitation Medicine doctor), three ophthalmologists, one internist, one dermatologist and one neurologist, representing six European countries plus Tunisia and Korea. A patient representative was also present. Problem areas and related keywords for systematic literature research were identified. Systematic literature research was performed using Medline and the Cochrane Library databases from 1966 through to December 2006. A total of 40 initial statements were generated based on the systematic literature research. These yielded the final recommendations devel- oped from two blind Delphi rounds of voting. Results: Nine recommendations were developed for the management of different aspects of BD. The strength of each recommendation was determined by the level of evidence and the experts' opinions. The level of agreement for each recommendation was determined using a visual analogue scale for the whole committee and for each individual aspect by the subgroups, who consider themselves experts in that field of BD. There was excellent concordance between the level of agreement of the whole group and the ''experts in the field''. Conclusion: Recommendations related to the eye, skin- mucosa disease and arthritis are mainly evidence based, but recommendations on vascular disease, neurological and gastrointestinal involvement are based largely on expert opinion and uncontrolled evidence from open trials and observational studies. The need for further properly designed controlled clinical trials is apparent.

Wnt/β-catenin signaling controls development of the blood–brain barrier

Abstract: The blood–brain barrier (BBB) is confined to the endothelium of brain capillaries and is indispensable for fluid homeostasis and neuronal function. In this study, we show that endothelial Wnt/β-catenin (β-cat) signaling regulates induction and maintenance of BBB characteristics during embryonic and postnatal development. Endothelial specific stabilization of β-cat in vivo enhances barrier maturation, whereas inactivation of β-cat causes significant down-regulation of claudin3 (Cldn3), up-regulation of plamalemma vesicle-associated protein, and BBB breakdown. Stabilization of β-cat in primary brain endothelial cells (ECs) in vitro by N-terminal truncation or Wnt3a treatment increases Cldn3 expression, BBB-type tight junction formation, and a BBB characteristic gene signature. Loss of β-cat or inhibition of its signaling abrogates this effect. Furthermore, stabilization of β-cat also increased Cldn3 and barrier properties in nonbrain-derived ECs. These findings may open new therapeutic avenues to modulate endothelial barrier function and to limit the devastating effects of BBB breakdown.

Learning and Classification of Malware Behavior

Abstract: Malicious software in form of Internet worms, computer viruses, and Trojan horses poses a major threat to the security of networked systems. The diversity and amount of its variants severely undermine the effectiveness of classical signature-based detection. Yet variants of malware families share typical behavioral patternsreflecting its origin and purpose. We aim to exploit these shared patterns for classification of malware and propose a method for learning and discrimination of malware behavior. Our method proceeds in three stages: (a) behavior of collected malware is monitored in a sandbox environment, (b) based on a corpus of malware labeled by an anti-virus scanner a malware behavior classifieris trained using learning techniques and (c) discriminative features of the behavior models are ranked for explanation of classification decisions. Experiments with different heterogeneous test data collected over several months using honeypots demonstrate the effectiveness of our method, especially in detecting novelinstances of malware families previously not recognized by commercial anti-virus software.

Simultaneous Assessment of Soil Microbial Community Structure and Function through Analysis of the Meta-Transcriptome

Abstract: Background Soil ecosystems harbor the most complex prokaryotic and eukaryotic microbial communities on Earth. Experimental approaches studying these systems usually focus on either the soil community's taxonomic structure or its functional characteristics. Many methods target DNA as marker molecule and use PCR for amplification. Methodology/Principal Findings Here we apply an RNA-centered meta-transcriptomic approach to simultaneously obtain information on both structure and function of a soil community. Total community RNA is random reversely transcribed into cDNA without any PCR or cloning step. Direct pyrosequencing produces large numbers of cDNA rRNA-tags; these are taxonomically profiled in a binning approach using the MEGAN software and two specifically compiled rRNA reference databases containing small and large subunit rRNA sequences. The pyrosequencing also produces mRNA-tags; these provide a sequence-based transcriptome of the community. One soil dataset of 258,411 RNA-tags of ∼98 bp length contained 193,219 rRNA-tags with valid taxonomic information, together with 21,133 mRNA-tags. Quantitative information about the relative abundance of organisms from all three domains of life and from different trophic levels was obtained in a single experiment. Less frequent taxa, such as soil Crenarchaeota, were well represented in the data set. These were identified by more than 2,000 rRNA-tags; furthermore, their activity in situ was revealed through the presence of mRNA-tags specific for enzymes involved in ammonia oxidation and CO2 fixation. Conclusions/Significance This approach could be widely applied in microbial ecology by efficiently linking community structure and function in a single experiment while avoiding biases inherent in other methods.

Development of word reading fluency and spelling in a consistent orthography: An 8-year follow-up.

Abstract: In a longitudinal study, development of word reading fluency and spelling were followed for almost 8 years. In a group of 115 students (65 girls, 50 boys) acquiring the phonologically transparent German orthography, prediction measures (letter knowledge, phonological short-term memory, phonological awareness, rapid automatized naming, and nonverbal IQ) were assessed at the beginning of Grade 1; reading fluency and spelling were tested at the end of Grade 1 as well as in Grades 4 and 8. Reading accuracy was close to ceiling in all reading assessments, such that reading fluency was not heavily influenced by differences in reading accuracy. High stability was observed for word reading fluency development. Of the dysfluent readers in Grade 1, 70% were still poor readers in Grade 8. For spelling, children who at the end of Grade 1 still had problems translating spoken words into phonologically plausible letter sequences developed problems with orthographic spelling later on. The strongest specific predictors were rapid automatized naming for reading fluency and phonological awareness for spelling. Word recognition speed was a relevant and highly stable indicator of reading skills and the only indicator that discriminated reading skill levels in consistent orthographies. Its long-term development was more strongly influenced by early naming speed than by phonological awareness.

OpenMS – An open-source software framework for mass spectrometry

Abstract: Mass spectrometry is an essential analytical technique for high-throughput analysis in proteomics and metabolomics. The development of new separation techniques, precise mass analyzers and experimental protocols is a very active field of research. This leads to more complex experimental setups yielding ever increasing amounts of data. Consequently, analysis of the data is currently often the bottleneck for experimental studies. Although software tools for many data analysis tasks are available today, they are often hard to combine with each other or not flexible enough to allow for rapid prototyping of a new analysis workflow. We present OpenMS, a software framework for rapid application development in mass spectrometry. OpenMS has been designed to be portable, easy-to-use and robust while offering a rich functionality ranging from basic data structures to sophisticated algorithms for data analysis. This has already been demonstrated in several studies. OpenMS is available under the Lesser GNU Public License (LGPL) from the project website at http://www.openms.de .

NK cells and cancer immunosurveillance.

Abstract: Natural killer (NK) cells are lymphocytes of the innate immune system that monitor cell surfaces of autologous cells for an aberrant expression of MHC class I molecules and cell stress markers. Since their first description more than 30 years ago, NK cells have been implicated in the immune defence against tumours. Here, we review the broadly accumulating evidence for a crucial contribution of NK cells to the immunosurveillance of tumours and the molecular mechanisms that allow NK cells to distinguish malignant from healthy cells. Particular emphasis is placed on the activating NK receptor NKG2D, which recognizes a variety of MHC class I-related molecules believed to act as 'immuno-alerters' on malignant cells, and on tumour-mediated counterstrategies promoting escape from NKG2D-mediated recognition.

Think to Move: a Neuromagnetic Brain-Computer Interface (BCI) System for Chronic Stroke

Abstract: Background and Purpose— Stroke is a leading cause of long-term motor disability among adults. Present rehabilitative interventions are largely unsuccessful in improving the most severe cases of motor impairment, particularly in relation to hand function. Here we tested the hypothesis that patients experiencing hand plegia as a result of a single, unilateral subcortical, cortical or mixed stroke occurring at least 1 year previously, could be trained to operate a mechanical hand orthosis through a brain-computer interface (BCI). Methods— Eight patients with chronic hand plegia resulting from stroke (residual finger extension function rated on the Medical Research Council scale=0/5) were recruited from the Stroke Neurorehabilitation Clinic, Human Cortical Physiology Section of the National Institute for Neurological Disorders and Stroke (NINDS) (n=5) and the Clinic of Neurology of the University of Tubingen (n=3). Diagnostic MRIs revealed single, unilateral subcortical, cortical or mixed lesions in all pati...

Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation

Abstract: We investigated the elimination routes for the 200 drugs that are sold most often by prescription count in the United States. The majority (78%) of the hepatically cleared drugs were found to be subject to oxidative metabolism via cytochromes P450 of the families 1, 2 and 3, with major contributions from CYP3A4/5 (37% of drugs) followed by CYP2C9 (17%), CYP2D6 (15%), CYP2C19 (10%), CYP1A2 (9%), CYP2C8 (6%), and CYP2B6 (4%). Clinically well-established polymorphic CYPs (i.e., CYP2C9, CYP2C19, and CYP2D6) were involved in the metabolism of approximately half of those drugs, including (in particular) NSAIDs metabolized mainly by CYP2C9, proton-pump inhibitors metabolized by CYP2C19, and beta blockers and several antipsychotics and antidepressants metabolized by CYP2D6. In this review, we provide an up-to-date summary of the functional polymorphisms and aspects of the functional genomics of the major human drug-metabolizing cytochrome P450s, as well as their clinical significance.