Wolfgang drobnik - Academia.edu (original) (raw)

Uploads

Papers by Wolfgang drobnik

Research paper thumbnail of Soluble thrombomodulin and endothelial dysfunction in early atherosclerosis

Lancet, 1999

... Communities (ARIC) Study: a case-control study. Lancet 1999; 353: 1729-1734. Summary | Full T... more ... Communities (ARIC) Study: a case-control study. Lancet 1999; 353: 1729-1734. Summary | Full Text | PDF(86KB) | CrossRef | PubMed. 2 John S, Schlaich M, Langenfeld M, et al. Increased bioavailability of nitric oxide after lipid ...

Research paper thumbnail of Pharmacogenomics and Pharmacogenetics of Cholesterol-Lowering Therapy

Clinical Chemistry and Laboratory Medicine, 2003

Cholesterol-lowering therapy is the central approach in the primary and secondary prevention of c... more Cholesterol-lowering therapy is the central approach in the primary and secondary prevention of cardiovascular disease, the leading cause of death in industrialized countries. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are currently the most potent and widely used cholesterol-lowering drugs. Large-scale clinical trials unequivocally demonstrated the efficacy of statin treatment in reducing the risk of cardiovascular events. In general, HMG-CoA reductase inhibitors are well tolerated, although in a minority of patients severe adverse effects like myopathy or rhabdomyolysis may develop. The incidence of this potentially life-threatening side effects increases with co-adminstration of drugs that are metabolized via the same pharmacokinetic pathways or at high-dose statin therapy. The recent focus on the pleiotropic effects of statins that are more frequently observed at higher doses and the conclusion drawn from the large statin trials that low-density lipoprotein (LDL)-cholesterol is "the lower the better", may need careful consideration in individuals at risk of adverse drug reactions. On the other hand, not all patients respond to statin therapy with a reduction in coronary heart disease (CHD) risk. It is therefore of interest to develop diagnostic test systems, which would allow to identify patients at increased risk of adverse drug reactions or patients with a lack of therapeutic effect. Beside exogenous factors, genetic variability determines the response of an individual to drug therapy and the analysis of genetic variants affecting pharmacokinetic or pharmacodynamic aspects of drug therapy is the subject of pharmacogenomics. This review summarizes current knowledge of the pharmacology and the pharmacogenomics of statin therapy.

Research paper thumbnail of Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients

Journal of Lipid Research, 2003

Research paper thumbnail of ATP-Binding Cassette Transporter A1 (ABCA1) in Macrophages: A Dual Function in Inflammation and Lipid Metabolism

Pathobiology, 1999

Activated lipid-laden macrophages in the vascular wall are key modulators of the inflammatory pro... more Activated lipid-laden macrophages in the vascular wall are key modulators of the inflammatory processes underlying atherosclerosis. We demonstrate here that the ATP-binding cassette (ABC) transporter ABCA1 is induced during differentiation of human monocytes into macrophages. ABCA1 has been implicated in macrophage interleukin-1beta secretion and apoptosis. Moreover, ABCA1 mRNA and protein levels are strongly upregulated by uptake of modified LDL and downregulated by HDL(3)-mediated lipid efflux in macrophages. Mutation analysis in patients with the classical Tangier disease (TD), a monogenetic disorder characterized by hypersplenism, macrophage accumulation and deposition of cholesteryl esters in the reticuloendothelial system, low plasma HDL and premature atherosclerosis, revealed deleterious mutations in their ABCA1 gene. The localization pattern of the mutations within the ABCA1 protein appears to determine the tropism for either the reticuloendothelial system, as seen in the classical TD phenotype, or the artery wall, as in the case of HDL deficiency in the absence of splenomegaly. In a comprehensive analysis of the expression and regulation of all currently known human ABC transporters, we identified additional cholesterol-responsive genes that are induced during monocyte differentiation into macrophages. Our results indicate a dual regulatory function for ABCA1 in macrophage lipid metabolism and inflammation.

Research paper thumbnail of High-throughput quantification of phosphatidylcholine and sphingomyelin by electrospray ionization tandem mass spectrometry coupled with isotope correction algorithm

Biochimica Et Biophysica Acta-molecular and Cell Biology of Lipids, 2004

Research paper thumbnail of Mutation analysis of the human adipocyte-specific apM1 gene

European Journal of Clinical Investigation, 2000

The aim of this study was to analyse the human adipocyte-specific apM-1 gene for sequence variati... more The aim of this study was to analyse the human adipocyte-specific apM-1 gene for sequence variations. Sequence analysis was performed in 344 randomly chosen blood samples using a capillary sequencer. Whereas no mutations were detected in intronic regions and in 2.7 kb of the promoter, two sequence variations were found within the coding sequence of apM-1. For both mutations, a polymerase chain reaction-(PCR) based restriction fragment length polymorphism (RFLP) analysis was developed, which provided a rapid screening method. A conservative T --> G transition at nucleotide + 45 within exon-2 [Gly15Gly] was detected with an allelic frequency of 0.9 for the wild-type allele and 0.1 for the mutated allele. In addition, a missense point mutation at nucleotide + 331 within exon-3 [Tyr111His] was detected with an allelic frequency of 0.97 for the wild-type allele and 0.03 for the mutated allele. This mutation replaces a tyrosine by an histidine within the carboxyterminal globular domain of apM-1. Concerning the Gly15Gly polymorphism, the TT genotype was found in 275 subjects (79.9%), the TG genotype in 67 subjects (19.5%) and the GG genotype in 2 subjects (0.6%): one with maturity onset diabetes of young age (MODY-diabetes) and one with Lipoatrophic Diabetes Syndrome (LPDS). Concerning the Tyr111His polymorphism, the TT genotype was found in 328 subjects (95.4%), the TC genotype in 15 subjects (4.3%) and the CC genotype in 1 subject (0.3%). The existence of two yet unknown mutations within the apM-1 gene was demonstrated and RFLP analysis was established for rapid screening. Well defined cohorts of patients are necessary to determine the putative role of apM-1 gene mutations in the pathogenesis of metabolic disorders.

Research paper thumbnail of High-Throughput Quantification of Lysophosphatidylcholine by Electrospray Ionization Tandem Mass Spectrometry

Research paper thumbnail of Apolipoprotein AI and HDL 3 inhibit spreading of primary human monocytes through a mechanism that involves cholesterol depletion and regulation of CDC42

Research paper thumbnail of A New Endotoxin Adsorber: First Clinical Application

Therapeutic Apheresis and Dialysis, 2001

Research paper thumbnail of ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport

Proceedings of The National Academy of Sciences, 2000

Research paper thumbnail of The VP1 Unique Region of Parvovirus B19 and Its Constituent Phospholipase A2Like Activity

Journal of Virology, 2002

Research paper thumbnail of High-density lipoprotein and low-density lipoprotein-mediated signal transduction in cultured human skin fibroblasts

Cellular Signalling, 1995

... Christoph Möllers a , Corresponding Author Contact Information , Wolfgang Drobnik a ,Thérèse ... more ... Christoph Möllers a , Corresponding Author Contact Information , Wolfgang Drobnik a ,Thérèse Resink b and Gerd Schmitz a. ... Chem. 266, 1033710343. 47. Mendez AJ, Oram JF and Bierman EL (1991) J. Biol. Chem. 266, 1010410111. 48. ...

Research paper thumbnail of Quantitative measurement of different ceramide species from crude cellular extracts by electrospray ionization tandem mass spectrometry (ESI-MS/MS

Research paper thumbnail of Growth and Cell Cycle Abnormalities of Fibroblasts From Tangier Disease Patients

Research paper thumbnail of HDL-mediated efflux of newly synthesized cholesterol is impaired in Tangier fibroblasts due to defective lipoprotein-induced activation of protein kinase C

Research paper thumbnail of Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child???Pugh classification in male patients with alcoholic and virus-related cirrhosis

European Journal of Gastroenterology & Hepatology, 2003

To investigate anterior pituitary function (adrenal, somatotropic, thyroid and gonadal axes, and ... more To investigate anterior pituitary function (adrenal, somatotropic, thyroid and gonadal axes, and prolactin) in relation to the Child-Pugh score in male patients with alcoholic and virus-related liver cirrhosis. Anterior pituitary function was evaluated in 52 male cirrhotics (26 Child-Pugh class A (CPA), 16 Child-Pugh class B (CPB) and 10 Child-Pugh class C (CPC)) by a combined pituitary stimulation test, and was compared with 50 age-matched controls. A normal cortisol response to corticotropin-releasing hormone (CRH) stimulation was demonstrated in 57.6% of CPA patients, 31.1% of CPB patients and 20% of CPC patients, while basal levels of adrenocorticotropic hormone (ACTH) and cortisol in cirrhotics were comparable to those in controls. Levels of basal growth hormone (P < 0.001) and stimulated growth hormone (P < 0.01) were significantly higher in cirrhotics compared with controls, while levels of insulin-like growth factor 1 (IGF-1) were significantly lower (P < 0.001). Basal prolactin levels were elevated significantly in CPC patients (P < 0.01), while stimulated prolactin as well as basal and stimulated thyroid-stimulating hormone (TSH) levels were comparable. Basal luteinizing hormone levels were significantly higher in CPA (P < 0.001) and CPB (P < 0.001) patients, and stimulated luteinizing hormone levels were significantly lower in CPC patients than in controls (P < 0.005). Basal and stimulated follicle-stimulating hormone (FSH) levels were comparable in all groups. Child-Pugh score was correlated positively to prolactin and was correlated negatively to IGF-1, stimulated luteinizing hormone and free testosterone. In cirrhotics, the hypothalamic-pituitary-adrenal and -gonadal axes and prolactin secretion are impaired. Growth hormone response to growth hormone-releasing hormone (GHRH) is accelerated in cirrhotics. Thus, elevated basal and stimulated levels of growth hormone probably reflect compensation for low levels of IGF-1, which are associated with deteriorating liver function. The aetiology of cirrhosis was found to have no influence on the degree of alteration of the hypothalamic-pituitary-glandular axes.

Research paper thumbnail of Definition and characterization of relative hypo- and hyperleptinemia in a large Caucasian population

Journal of Endocrinology, 2002

Research paper thumbnail of Apo AI/ABCA1Dependent and HDL3-Mediated Lipid Efflux from Compositionally Distinct Cholesterol-Based Microdomains

Research paper thumbnail of The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease

Nature Genetics, 1999

Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism. It is characterized ... more Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism. It is characterized by absence of plasma high-density lipoprotein (HDL) and deposition of cholesteryl esters in the reticulo-endothelial system with splenomegaly and enlargement of tonsils and lymph nodes. Although low HDL cholesterol is associated with an increased risk for coronary artery disease, this condition is not consistently found in TD pedigrees. Metabolic studies in TD patients have revealed a rapid catabolism of HDL and its precursors. In contrast to normal mononuclear phagocytes (MNP), MNP from TD individuals degrade internalized HDL in unusual lysosomes, indicating a defect in cellular lipid metabolism. HDL-mediated cholesterol efflux and intracellular lipid trafficking and turnover are abnormal in TD fibroblasts, which have a reduced in vitro growth rate. The TD locus has been mapped to chromosome 9q31. Here we present evidence that TD is caused by mutations in ABC1, encoding a member of the ATP-binding cassette (ABC) transporter family, located on chromosome 9q22-31. We have analysed five kindreds with TD and identified seven different mutations, including three that are expected to impair the function of the gene product. The identification of ABC1 as the TD locus has implications for the understanding of cellular HDL metabolism and reverse cholesterol transport, and its association with premature cardiovascular disease.

Research paper thumbnail of Quantification of sphingosine and sphinganine from crude lipid extracts by HPLC electrospray ionization tandem mass spectrometry

Journal of Lipid Research, 2003

Research paper thumbnail of Soluble thrombomodulin and endothelial dysfunction in early atherosclerosis

Lancet, 1999

... Communities (ARIC) Study: a case-control study. Lancet 1999; 353: 1729-1734. Summary | Full T... more ... Communities (ARIC) Study: a case-control study. Lancet 1999; 353: 1729-1734. Summary | Full Text | PDF(86KB) | CrossRef | PubMed. 2 John S, Schlaich M, Langenfeld M, et al. Increased bioavailability of nitric oxide after lipid ...

Research paper thumbnail of Pharmacogenomics and Pharmacogenetics of Cholesterol-Lowering Therapy

Clinical Chemistry and Laboratory Medicine, 2003

Cholesterol-lowering therapy is the central approach in the primary and secondary prevention of c... more Cholesterol-lowering therapy is the central approach in the primary and secondary prevention of cardiovascular disease, the leading cause of death in industrialized countries. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are currently the most potent and widely used cholesterol-lowering drugs. Large-scale clinical trials unequivocally demonstrated the efficacy of statin treatment in reducing the risk of cardiovascular events. In general, HMG-CoA reductase inhibitors are well tolerated, although in a minority of patients severe adverse effects like myopathy or rhabdomyolysis may develop. The incidence of this potentially life-threatening side effects increases with co-adminstration of drugs that are metabolized via the same pharmacokinetic pathways or at high-dose statin therapy. The recent focus on the pleiotropic effects of statins that are more frequently observed at higher doses and the conclusion drawn from the large statin trials that low-density lipoprotein (LDL)-cholesterol is "the lower the better", may need careful consideration in individuals at risk of adverse drug reactions. On the other hand, not all patients respond to statin therapy with a reduction in coronary heart disease (CHD) risk. It is therefore of interest to develop diagnostic test systems, which would allow to identify patients at increased risk of adverse drug reactions or patients with a lack of therapeutic effect. Beside exogenous factors, genetic variability determines the response of an individual to drug therapy and the analysis of genetic variants affecting pharmacokinetic or pharmacodynamic aspects of drug therapy is the subject of pharmacogenomics. This review summarizes current knowledge of the pharmacology and the pharmacogenomics of statin therapy.

Research paper thumbnail of Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients

Journal of Lipid Research, 2003

Research paper thumbnail of ATP-Binding Cassette Transporter A1 (ABCA1) in Macrophages: A Dual Function in Inflammation and Lipid Metabolism

Pathobiology, 1999

Activated lipid-laden macrophages in the vascular wall are key modulators of the inflammatory pro... more Activated lipid-laden macrophages in the vascular wall are key modulators of the inflammatory processes underlying atherosclerosis. We demonstrate here that the ATP-binding cassette (ABC) transporter ABCA1 is induced during differentiation of human monocytes into macrophages. ABCA1 has been implicated in macrophage interleukin-1beta secretion and apoptosis. Moreover, ABCA1 mRNA and protein levels are strongly upregulated by uptake of modified LDL and downregulated by HDL(3)-mediated lipid efflux in macrophages. Mutation analysis in patients with the classical Tangier disease (TD), a monogenetic disorder characterized by hypersplenism, macrophage accumulation and deposition of cholesteryl esters in the reticuloendothelial system, low plasma HDL and premature atherosclerosis, revealed deleterious mutations in their ABCA1 gene. The localization pattern of the mutations within the ABCA1 protein appears to determine the tropism for either the reticuloendothelial system, as seen in the classical TD phenotype, or the artery wall, as in the case of HDL deficiency in the absence of splenomegaly. In a comprehensive analysis of the expression and regulation of all currently known human ABC transporters, we identified additional cholesterol-responsive genes that are induced during monocyte differentiation into macrophages. Our results indicate a dual regulatory function for ABCA1 in macrophage lipid metabolism and inflammation.

Research paper thumbnail of High-throughput quantification of phosphatidylcholine and sphingomyelin by electrospray ionization tandem mass spectrometry coupled with isotope correction algorithm

Biochimica Et Biophysica Acta-molecular and Cell Biology of Lipids, 2004

Research paper thumbnail of Mutation analysis of the human adipocyte-specific apM1 gene

European Journal of Clinical Investigation, 2000

The aim of this study was to analyse the human adipocyte-specific apM-1 gene for sequence variati... more The aim of this study was to analyse the human adipocyte-specific apM-1 gene for sequence variations. Sequence analysis was performed in 344 randomly chosen blood samples using a capillary sequencer. Whereas no mutations were detected in intronic regions and in 2.7 kb of the promoter, two sequence variations were found within the coding sequence of apM-1. For both mutations, a polymerase chain reaction-(PCR) based restriction fragment length polymorphism (RFLP) analysis was developed, which provided a rapid screening method. A conservative T --> G transition at nucleotide + 45 within exon-2 [Gly15Gly] was detected with an allelic frequency of 0.9 for the wild-type allele and 0.1 for the mutated allele. In addition, a missense point mutation at nucleotide + 331 within exon-3 [Tyr111His] was detected with an allelic frequency of 0.97 for the wild-type allele and 0.03 for the mutated allele. This mutation replaces a tyrosine by an histidine within the carboxyterminal globular domain of apM-1. Concerning the Gly15Gly polymorphism, the TT genotype was found in 275 subjects (79.9%), the TG genotype in 67 subjects (19.5%) and the GG genotype in 2 subjects (0.6%): one with maturity onset diabetes of young age (MODY-diabetes) and one with Lipoatrophic Diabetes Syndrome (LPDS). Concerning the Tyr111His polymorphism, the TT genotype was found in 328 subjects (95.4%), the TC genotype in 15 subjects (4.3%) and the CC genotype in 1 subject (0.3%). The existence of two yet unknown mutations within the apM-1 gene was demonstrated and RFLP analysis was established for rapid screening. Well defined cohorts of patients are necessary to determine the putative role of apM-1 gene mutations in the pathogenesis of metabolic disorders.

Research paper thumbnail of High-Throughput Quantification of Lysophosphatidylcholine by Electrospray Ionization Tandem Mass Spectrometry

Research paper thumbnail of Apolipoprotein AI and HDL 3 inhibit spreading of primary human monocytes through a mechanism that involves cholesterol depletion and regulation of CDC42

Research paper thumbnail of A New Endotoxin Adsorber: First Clinical Application

Therapeutic Apheresis and Dialysis, 2001

Research paper thumbnail of ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport

Proceedings of The National Academy of Sciences, 2000

Research paper thumbnail of The VP1 Unique Region of Parvovirus B19 and Its Constituent Phospholipase A2Like Activity

Journal of Virology, 2002

Research paper thumbnail of High-density lipoprotein and low-density lipoprotein-mediated signal transduction in cultured human skin fibroblasts

Cellular Signalling, 1995

... Christoph Möllers a , Corresponding Author Contact Information , Wolfgang Drobnik a ,Thérèse ... more ... Christoph Möllers a , Corresponding Author Contact Information , Wolfgang Drobnik a ,Thérèse Resink b and Gerd Schmitz a. ... Chem. 266, 1033710343. 47. Mendez AJ, Oram JF and Bierman EL (1991) J. Biol. Chem. 266, 1010410111. 48. ...

Research paper thumbnail of Quantitative measurement of different ceramide species from crude cellular extracts by electrospray ionization tandem mass spectrometry (ESI-MS/MS

Research paper thumbnail of Growth and Cell Cycle Abnormalities of Fibroblasts From Tangier Disease Patients

Research paper thumbnail of HDL-mediated efflux of newly synthesized cholesterol is impaired in Tangier fibroblasts due to defective lipoprotein-induced activation of protein kinase C

Research paper thumbnail of Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child???Pugh classification in male patients with alcoholic and virus-related cirrhosis

European Journal of Gastroenterology & Hepatology, 2003

To investigate anterior pituitary function (adrenal, somatotropic, thyroid and gonadal axes, and ... more To investigate anterior pituitary function (adrenal, somatotropic, thyroid and gonadal axes, and prolactin) in relation to the Child-Pugh score in male patients with alcoholic and virus-related liver cirrhosis. Anterior pituitary function was evaluated in 52 male cirrhotics (26 Child-Pugh class A (CPA), 16 Child-Pugh class B (CPB) and 10 Child-Pugh class C (CPC)) by a combined pituitary stimulation test, and was compared with 50 age-matched controls. A normal cortisol response to corticotropin-releasing hormone (CRH) stimulation was demonstrated in 57.6% of CPA patients, 31.1% of CPB patients and 20% of CPC patients, while basal levels of adrenocorticotropic hormone (ACTH) and cortisol in cirrhotics were comparable to those in controls. Levels of basal growth hormone (P < 0.001) and stimulated growth hormone (P < 0.01) were significantly higher in cirrhotics compared with controls, while levels of insulin-like growth factor 1 (IGF-1) were significantly lower (P < 0.001). Basal prolactin levels were elevated significantly in CPC patients (P < 0.01), while stimulated prolactin as well as basal and stimulated thyroid-stimulating hormone (TSH) levels were comparable. Basal luteinizing hormone levels were significantly higher in CPA (P < 0.001) and CPB (P < 0.001) patients, and stimulated luteinizing hormone levels were significantly lower in CPC patients than in controls (P < 0.005). Basal and stimulated follicle-stimulating hormone (FSH) levels were comparable in all groups. Child-Pugh score was correlated positively to prolactin and was correlated negatively to IGF-1, stimulated luteinizing hormone and free testosterone. In cirrhotics, the hypothalamic-pituitary-adrenal and -gonadal axes and prolactin secretion are impaired. Growth hormone response to growth hormone-releasing hormone (GHRH) is accelerated in cirrhotics. Thus, elevated basal and stimulated levels of growth hormone probably reflect compensation for low levels of IGF-1, which are associated with deteriorating liver function. The aetiology of cirrhosis was found to have no influence on the degree of alteration of the hypothalamic-pituitary-glandular axes.

Research paper thumbnail of Definition and characterization of relative hypo- and hyperleptinemia in a large Caucasian population

Journal of Endocrinology, 2002

Research paper thumbnail of Apo AI/ABCA1Dependent and HDL3-Mediated Lipid Efflux from Compositionally Distinct Cholesterol-Based Microdomains

Research paper thumbnail of The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease

Nature Genetics, 1999

Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism. It is characterized ... more Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism. It is characterized by absence of plasma high-density lipoprotein (HDL) and deposition of cholesteryl esters in the reticulo-endothelial system with splenomegaly and enlargement of tonsils and lymph nodes. Although low HDL cholesterol is associated with an increased risk for coronary artery disease, this condition is not consistently found in TD pedigrees. Metabolic studies in TD patients have revealed a rapid catabolism of HDL and its precursors. In contrast to normal mononuclear phagocytes (MNP), MNP from TD individuals degrade internalized HDL in unusual lysosomes, indicating a defect in cellular lipid metabolism. HDL-mediated cholesterol efflux and intracellular lipid trafficking and turnover are abnormal in TD fibroblasts, which have a reduced in vitro growth rate. The TD locus has been mapped to chromosome 9q31. Here we present evidence that TD is caused by mutations in ABC1, encoding a member of the ATP-binding cassette (ABC) transporter family, located on chromosome 9q22-31. We have analysed five kindreds with TD and identified seven different mutations, including three that are expected to impair the function of the gene product. The identification of ABC1 as the TD locus has implications for the understanding of cellular HDL metabolism and reverse cholesterol transport, and its association with premature cardiovascular disease.

Research paper thumbnail of Quantification of sphingosine and sphinganine from crude lipid extracts by HPLC electrospray ionization tandem mass spectrometry

Journal of Lipid Research, 2003