Pharmacogenetics of the arylamine N-acetyltransferases: a symposium in honor of Wendell W. Weber. (9/1551)

This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics presented at the joint meeting of the American Society for Biochemistry and Molecular Biology and the American Society for Pharmacology and Experimental Therapeutics, June 4-8, Boston, Massachusetts. The presentations focused on the pharmacogenetics of the NAT1 and NAT2 arylamine N-acetyltransferases, including developmental regulation, structure-function relationships, and their possible role in susceptibility to breast, colon, and pancreatic cancers. The symposium honored Wendell W. Weber for over 35 years of leadership and scientific advancement in pharmacogenetics and was highlighted by his overview of the historical development of the field.  (+info)

Enabling large-scale pharmacogenetic studies by high-throughput mutation detection and genotyping technologies. (10/1551)

BACKGROUND: Pharmacogenetics is a scientific discipline that examines the genetic basis for individual variations in response to therapeutics. Pharmacogenetics promises to develop individualized medicines tailored to patients' genotypes. However, identifying and genotyping a vast number of genetic polymorphisms in large populations also pose a great challenge. APPROACH: This article reviews the recent technology development in mutation detection and genotyping with a focus on genotyping of single nucleotide polymorphisms (SNPs). CONTENT: Novel mutations/polymorphisms are commonly identified by conformation-based mutation screening and direct high-throughput heterozygote sequencing. With a large amount of public sequence information available, in silico SNP mapping has also emerged as a cost-efficient way for new polymorphism identification. Gel electrophoresis-based genotyping methods for known polymorphisms include PCR coupled with restriction fragment length polymorphism analysis, multiplex PCR, oligonucleotide ligation assay, and minisequencing. Fluorescent dye-based genotyping technologies are emerging as high-throughput genotyping platforms, including oligonucleotide ligation assay, pyrosequencing, single-base extension with fluorescence detection, homogeneous solution hybridization such as TaqMan, and molecular beacon genotyping. Rolling circle amplification and Invader assays are able to genotype directly from genomic DNA without PCR amplification. DNA chip-based microarray and mass spectrometry genotyping technologies are the latest development in the genotyping arena. SUMMARY: Large-scale genotyping is crucial to the identification of the genetic make-ups that underlie the onset of diseases and individual variations in drug responses. Enabling technologies to identify genetic polymorphisms rapidly, accurately, and cost effectively will dramatically impact future drug and development processes.  (+info)

Challenges and limitations of gene expression profiling in mechanistic and predictive toxicology. (11/1551)

RNA and protein expression profiling technologies have revolutionized how toxicologists can study the molecular basis of adverse effects of chemicals and drugs. It is expected that these new technologies will afford efficient and high-throughput means to delineate mechanisms of action and predict toxicity of unknown agents. To reach these goals, a more thorough understanding of the constraints of the methodology is needed to design genome-scale studies and to interpret the vast amount of data collected. This paper addresses some of the limitations and uncertainties of gene expression profiling in mechanistic and predictive toxicology with respect to the expectations of toxicogenomics. The challenges associated with interpreting information from large-scale gene expression experiments in vivo is also discussed.  (+info)

Genomics and large scale phenotypic databases. (12/1551)

Progress in the development of molecular genetic tools and in sequencing the human genome will accelerate the understanding of complex genetic diseases. However, phenotypic clinical data needs to be obtained and recorded to a similar degree of precision in order to match the wealth of molecular genetic data. To achieve this goal, large scale phenotypic databases of complex genetic diseases are under construction. LURIC (the LUwigshafen Risk and Cardiovascular Health Study) is such a project, aiming to identify new genetic and environmental risk factors or markers for cardiovascular disease in order to better understand the pathophysiology of complex genetic disease. It should also allow the determination of the prognostic role of new markers by studying functional genomics, (the association between a gene variant and phenotype), and pharmacogenomics (the influence of genetic variation on the response to therapeutic agents).  (+info)

Preparing for the revolution--pharmacogenomics and the clinical lab. (13/1551)

Pharmacogenomics seeks to apply the field of genomics to improve the efficacy and safety of therapeutics. Sinmply put, pharmacogenomics is genetic-based testing to determine patient therapy. Interestingly, the clinical lab has rarely been discussed within the context of pharmacogenomics. Since clinical labs fill a key role in drug development it is important that they are included in pharmacogenomic discussions. Currently, clinical labs assist pharmaceutical sponsors in preclinical pharmacogenetic testing. In the future, clinical labs will be looked to for genetic test development and validation, and high-throughput genotyping of patients in clinical trials and routine testing. Clinical labs are an essential link in the chain of pharmacogenomic drug development, a fact which must be recognised by both the labs themselves and the industry as a whole.  (+info)

Pharmacogenetics of alcohol response and alcoholism: the interplay of genes and environmental factors in thresholds for alcoholism. (14/1551)

Recent advances in neuroscience and genetics have enabled a better understanding of genetically influenced differences in ethanol ("alcohol")-related responses and differential vulnerability to alcohol dependence at the cellular and molecular levels. Heritability studies reveal that the role of genetic factors in alcoholism is largely substance-specific, with the exception of nicotine. One focus of genetic research in alcoholism is the study of functional polymorphisms influencing alcohol metabolism, such as the aldehyde dehydrogenase type 2 Glu487Lys and alcohol dehydrogenase type 2 His47Arg polymorphisms, which affect vulnerability to alcoholism via pharmacokinetic mechanisms, and cross-population studies have begun to reveal important gene-environment interactions. The other focus is on functional genetic variants of proteins involved in the neuronal response to alcohol, including alcohol sensitivity, reward, tolerance, and withdrawal. Studies on the roles of GABA(A) alpha6-amino acid substitutions in rodents in alcohol and benzodiazepine sensitivity, and potential roles in human alcohol and benzodiazepine sensitivity are reviewed. These studies, together with recently developed knowledge on a GABA(A) receptor gene cluster at a quantitative trait loci for alcohol withdrawal on mouse chromosome 11, indicate that research investigation of variation at GABA(A) neurotransmission is a promising area in the pharmacodynamics of alcohol and in differential susceptibility to alcoholism. Genes for proteins involved in alcohol-mediated reward include genes for transporters and receptors for dopamine, serotonin, opioids, and GABA. These genes and their functional variants also represent important targets for understanding alcohol's effects in humans. Identification of genes for alcoholism vulnerability is important in the near future, not only for prevention, but also for development and targeting treatments.  (+info)

Pharmacogenetics of the vitamin D receptor and osteoporosis. (15/1551)

Osteoporosis is a major health care problem internationally with important implications for health care costs, morbidity, and mortality. Bone density, an important predictor of osteoporotic fracture risk, is affected by hormonal and environmental factors. However, in twin and family studies most of its age-specific variance is genetically determined. Common allelic variations in the vitamin D receptor (VDR) gene were the first to be linked to bone density. Recently, other candidate genes, notably oestrogen receptor, collagen 1alphaI, and PTH receptor genes and a chromosome 11 locus, have been associated with bone density and fracture. Polymorphisms in adjacent regulatory regions may be important mechanisms since functional coding region mutations have not been defined. For example, the polymorphic region in the collagen 1alphaI gene alters a SpI binding site and may alter collagen gene expression. At the pharmacogenetic level, VDR alleles predict differences in gut calcium absorption and long-term bone density response to calcium intake and active vitamin D analog treatment. Understanding the mechanisms underlying these allelic differences in relation to diet and lifestyle factors as well as response to therapy could aid selection of optimal therapy for osteoporosis prevention and treatment.  (+info)

Pharmacogenetic application in drug development and clinical trials. (16/1551)

Pharmacogenetics examines the genetic characteristics of individuals to understand variations in response to therapeutics. This approach has the potential to significantly affect the development of new medicines. The application of pharmacogenetic principles could yield significant time and resource savings within the drug development process. In preclinical drug development, pharmacogenetics could be applied to compound screening and identifying potential side effects before entering full clinical testing. Subpopulations of patients with different drug responses and underlying genetic markers could be stratified in clinical trials by analyzing their genotype. These data can improve clinical trial design and offer the possibility of optimized drug prescription based on patient genotype. Pharmacogenetics can guide the development of therapeutic interventions by identifying nonresponder patient groups. Advances in high-throughput genotyping technologies have added potential by facilitating the technical hurdles and improving drug development strategies, clinical trial design, and postmarket pharmaco-vigilance. Pharmacogenetics, thus, impacts all phases of drug development and will fundamentally change the practice of medicine in the near future.  (+info)