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- ArticleIngelman-Sundberg M.Pharmacogenomics J. 2005;5(1):6-13.CYP2D6 is of great importance for the metabolism of clinically used drugs and about 20-25% of those are metabolised by this enzyme. In addition, the enzyme utilises hydroxytryptamines as endogenous substrates. The polymorphism of the enzyme results in poor, intermediate, efficient or ultrarapid metabolisers (UMs) of CYP2D6 drugs. It is plausible that the UM genotype, where more than one active gene on one allele occurs, is the outcome of selective dietary selection in certain populations in North East Africa. The UM phenotype affects 5.5% of the population in Western Europe. A hypothesis for the evolutionary basis behind selection for CYP2D6 gene duplications is presented in relation to selection for Cyp6 variants in insecticide resistant Drosophila strains. The polymorphism of CYP2D6 significantly affects the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. The consequences of the polymorphism at ordinary drug doses can be either adverse drug reactions or no drug response. Examples are presented where CYP2D6 polymorphism affects the efficacy and costs of drug treatment. Predictive CYP2D6 genotyping is estimated by the author to be beneficial for treatment of about 30-40% of CYP2D6 drug substrates, that is, for about 7-10% of all drugs clinically used, although prospective clinical studies are necessary to evaluate the exact benefit of drug selection and dosage based on the CYP2D6 genotype.
- ArticleFoster MW, Sharp RR.Pharmacogenomics J. 2005;5(2):75-80.
- ArticlePickard BS, Millar JK, Porteous DJ, Muir WJ, Blackwood DH.Pharmacogenomics J. 2005;5(2):81-8.The disruption of genes by balanced translocations and other rare germline chromosomal abnormalities has played an important part in the discovery of many common Mendelian disorder genes, somatic oncogenes and tumour supressors. A search of published literature has identified 15 genes whose genomic sequences are directly disrupted by translocation breakpoints in individuals with neuropsychiatric illness. In these cases, it is reasonable to hypothesise that haploinsufficiency is a major factor contributing to illness. These findings suggest that the predicted polygenic nature of psychiatric illness may not represent the complete picture; genes of large individual effect appear to exist. Cytogenetic events may provide important insights into neurochemical pathways and cellular processes critical for the development of complex psychiatric phenotypes in the population at large.
- ArticleMaring JG, Groen HJ, Wachters FM, Uges DR, de Vries EG.Pharmacogenomics J. 2005;5(4):226-43.Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumour-specific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5'-nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.
- ArticleJones WK, Brown M, Wilhide M, He S, Ren X.Cardiovasc Toxicol. 2005;5(2):183-202.The transcription factor NF-kappaB regulates a wide variety of biological effects in diverse cell types and organs, particularly stress and adaptive responses. Recently, it has become recognized that NF-kappaB and its upstream regulator tumor necrosis factor (TNF)-alpha regulate specific antithetical effects. For instance, in the heart, NF-kappaB has been found to be required for development of late preconditioning against myocardial infarction and yet is critically involved in mediating cell death after ischemia/reperfusion injury. There remains a bias that NF-kappaB is a "general" transcription factor that is activated by a plethora of stimuli, including neurohormonal, pathophysiological, and stress stimuli, and affects regulation of numerous downstream genes. The question has become, how can such a "general" transcription factor be critically involved in mediating specific effects? An emerging hypothesis is that NF-kappaB is part of a complicated signaling network or web, and that different combinatorial interactions between various activated signaling pathway components produce specific outcomes. This idea is supported by the large number of interactions discovered in the past 14 years between NF-kappaB and other signaling pathways at multiple levels. Notwithstanding the complexities of signal-induced activation of NF-kappaB, since it is a transcription factor, specific effects of NF-kappaB activation must be underlain by the activation and/or suppression of distinct subsets of NF-kappaB-dependent genes. At this level, selectivity is conferred by the expression of specific NF-kappaB subunits, their post translational modifications, and by combinatorial interactions between NF-kappaB and other transcription factors and coactivators that form specific enhanceosome complexes in association with particular promoters. These enhanceosome complexes represent another level of signaling integration whereby the activities of multiple upstream pathways converge to impress a distinct pattern of gene expression upon the NF-kappaB-dependent transcriptional network. Understanding how the overall cellular signaling network translates NF-kappaB activation into the regulation of specific subsets of NF-kappaB-dependent genes will lead to a mechanistic understanding of how NF-kappaB mediates diverse and paradoxical biological effects.
- ArticleDoris PA, Fornage M.Cardiovasc Toxicol. 2005;5(2):95-108.Gene expression can be now assessed quantitatively and comprehensively. In addition to reflecting the specialized differentiation of the cell or tissue type from which gene expression is sampled, it also manifests patterns determined by inheritance. Thus gene expression is a phenotypic trait, at least when assessed comprehensively. This trait shows familial aggregation and segregation patterns indicative of an inherited contribution. The molecular evolution of genes includes mutations affecting regulatory sequences in the genome that influence gene expression in cis and in trans. Such mutations may increase in frequency in a population either by genetic drift or by selection. Traits of gene expression, acting alone or in concert with other gene expression traits, may generate phenotypes that extend beyond transcript abundance. Indeed, the divergence of species and the traits that distinguish related species appear to rely importantly on inherited divergence in the control of gene expression. Variation in gene expression may contribute to the pathogenesis of a prevalent human disease trait that shows heritability--essential hypertension. Along with other common heritable diseases, hypertension susceptibility arises from the actions of multiple genome sequence variations. The identity of such variation has proven elusive when sought by methods that have been successfully applied to Mendelian diseases. This review explores the potential to uncover hypertension genes by exploiting quantitative variation in the heritable control of gene expression.
- ArticleSeamon MJ, Clauson KA.J Herb Pharmacother. 2005;5(3):67-86.The Dietary Supplement Heath and Education Act of 1994 (DSHEA) established the regulatory framework for dietary supplements in the United States, triggering the growth of a multi-billion dollar industry. Ephedra is a dietary supplement used for weight loss. However, due to its sympathomimetic activity, it has caused stroke, cardiac arrhythmia, and death. Accordingly, the Food and Drug Administration (FDA) has prohibited its sale in the United States since April 12, 2004. Consequently, numerous other dietary supplements are attempting to fill the marketing void. An evaluation of these products demonstrates a general lack of efficacy and safety data. Thus, in the ten years since the passage of DSHEA, the dietary supplement industry remains controversial and a concern for consumer safety.
- ArticleSweeney B, Vora M, Ulbricht C, Basch E.J Herb Pharmacother. 2005;5(1):79-93.
- ArticleBasch E, Ulbricht C, Basch S, Dalton S, Ernst E, Foppa I, Szapary P, Tiffany N, Orlando CW, Vora M.J Herb Pharmacother. 2005;5(2):57-88.
- ArticleUlbricht C, Brendler T, Gruenwald J, Kligler B, Keifer D, Abrams TR, Woods J, Boon H, Kirkwood CD, Hackman DA, Basch E, Lafferty HJ, Natural Standard Research Collaboration.J Herb Pharmacother. 2005;5(4):71-114.An evidence-based systematic review including written and statistical analysis of scientific analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetic/dynamics, interactions, adverse effect, toxicology, and dosing.
- ArticleSpelman K.J Herb Pharmacother. 2005;5(2):31-47.Philosophy profoundly influences the sciences. In research models Ockham's Razor is often utilized as an operational principle in understanding the outcomes of modeling. However this principle of parsimony may delay the progress of understanding phytochemical matrices and the emergence of synergy that can arise from their interaction with human biology. Presented is a philosophical argument for synergy and medicinal plants as well as multiple examples of synergic systems occurring in the literature.
- ArticleBasch EM, Servoss JC, Tedrow UB.J Herb Pharmacother. 2005;5(1):3-15.Herbal therapies are used by more than 12% of the U.S. population each year, resulting in annual out-of-pocket expenses above $5 billion. Utilization rates are particularly high among patients with chronic diseases, and in patients frequently seen in clinic by physicians and nurse practitioners. Most physicians do not receive formal education regarding the safety of these therapies, and there is growing concern in the medical community about the potential risks to patients and the paucity of reliable information. Numerous adverse effects and interactions have been attributed to dietary supplements, based on variable levels of evidence ranging from historical use or anecdotes to pre-clinical research or high-quality clinical trials. Significant potential morbidity and costs have been indirectly associated with herb/supplement-drug interactions, including increased emergency room visits, outpatient clinic visits, and perioperative complications. However, most research has focused on efficacy rather than safety. Post-market surveillance is complicated by the uneven standardization of products between manufacturers, and in some cases between batches produced by the same manufacturer. To assure public safety around the use of dietary supplements within the framework of existing legislation and market realities, schema must evolve to more systematically monitor the safety of agents in the post-market environment; identify potentially dangerous supplements (and/or constituents); study the mechanism and potential hazards of these identified products; and clarify the process by which products may be considered for removal from the market. We discuss research and educational paradigms within this context which make use of existing surveillance mechanisms to more efficiently identify agents of particular concern. Specific examples are given.
- ArticleCambien F, Tiret L.Cardiovasc Toxicol. 2005;5(2):143-52.It is generally considered that the genetics of atherosclerosis and its complications involves a large number of genes with common alleles having weak effects on disease risk but possibly interacting with each other and with non-genetic factors. In such a complex system, absence of marginal effects (effects of polymorphisms considered one at a time) is insufficient to exclude the implication of a polymorphism on disease risk. Investigating polymorphisms and even genes one by one is no longer appropriate. It is necessary to focus on biological systems and integrate the contribution of genetic as well as non-genetic factors and their interactions. Hopefully, system genetics will ultimately improve our understanding of the genetic architecture of complex traits.
- ArticleRamos KS, Partridge CR.Cardiovasc Toxicol. 2005;5(3):245-55.Scientific and medical evidence over the past 30 years has established striking parallels between atherosclerosis and cancer--pathogenetic relationships that cross the boundaries of fiction into the realm of reason. Both diseases in humans are characterized by uncontrolled regulation of cellular growth and differentiation and share many common genomic targets during the course of growth dysregulation. Such parallels can be reconciled if atherosclerotic plaques are viewed as neoplasms of smooth muscle origin.
- ArticleMastin JP.Cardiovasc Toxicol. 2005;5(2):91-4.The last decade has seen a remarkable growth in the evidence establishing exposure to environmental agents as a risk factor for cardiovascular disease (CVD). Most of this has come from research linking exposure to ambient particulate matter with CVD, although more recent evidence suggests that the ozone might also be contributing factor. Research on the cardiovascular toxicity of other pollutants, notably arsenic, has also grown during this period. In addition to their effects in adults, environmental agents, such as dioxin, have also been shown to adversely affect development of the heart in laboratory animals. Taken together, these results suggest that environmental exposure must be considered as an important risk factor for CVD and that further research to determine mechanisms of action and susceptible populations is needed. This research will require interdisciplinary approaches, and should yield data not only on the toxic effects of pollutants on the cardiovascular system, but on the basic pathophysiology of cardiovascular diseases as well.
- ArticleImumorin IG, Dong Y, Zhu H, Poole JC, Harshfield GA, Treiber FA, Snieder H.Cardiovasc Toxicol. 2005;5(2):109-32.The case for a gene-environment interaction model of stress-induced hypertension is detailed in this paper. We hypothesize that repeated exposure to stress in combination with an environmentally and/or genetically mediated susceptibility may lead to the development of essential hypertension. Previously, we reviewed the evidence for a genetic influence on the two major intermediate phenotypes of our model: cardiovascular reactivity to psychological stress and stress-induced sodium retention, representing the cardiovascular and renal stress response, respectively. Here we first describe how genes underlying the physiological systems mediating the stress response of heart, vasculature, and kidney (i.e., the sympathetic nervous system, renin-angiotensin- aldosterone system and sodium reabsorption, and the endothelial system) may increase vulnerability to stress and confer susceptibility to development of essential hypertension. Next, we extend our model and review genes underlying three additional systems that may mediate the influence of stress on the development of essential hypertension: the parasympathetic nervous system, the serotonergic system, and the hypothamamus-pituitary-adrenal axis. The elucidation of our gene-environment interaction model of stress-induced essential hypertension will improve the understanding of the contribution of stress to the development of essential hypertension. This knowledge may lead to more effective primary and secondary prevention programs involving lifestyle interventions in which the role of stress, both acute and chronic, will be taken into account, particularly for individuals at increased genetic risk of essential hypertension.
- ArticleKurland L, Liljedahl U, Lind L.Cardiovasc Toxicol. 2005;5(2):133-42.Hypertension is prevalent, affecting approx 20--25% of the adult population in the Western world. Primary hypertension is a multifactorial, complex disorder where many genes and genetic variants are assumed to interact with environmental factors in order to produce the specific blood pressure level for a given individual. Family and twin studies show that between 30 and 60% of blood pressure variation is determined by genetic factors. Monogenic disorders of hypertension are rare and do not explain blood pressure variability in the population at large. Obvious candidate genes for the study of hypertension are those that encode components of a blood pressure regulating system targeted by an antihypertensive drug, or those that are involved in counter-regulatory systems. In this review, we give a brief pathophysiological background to hypertension and the rational behind utilizing SNP genotyping in the study of hypertension and the antihypertensive response to treatment. We also discuss some of the novel results of pharmacodynamic studies in antihypertensive treatment, an area in its infancy.
- ArticleIvnitski-Steele I, Walker MK.Cardiovasc Toxicol. 2005;5(2):215-26.The formation of new blood vessels, neovascularization, occurs by two unique processes: vasculogenesis, the de novo assembly of blood vessels from angioblast precursors, and angiogenesis, the formation of new capillary sprouts from preexisting vessels. There are many potential targets by which environmental pollutants may inhibit neovascularization and thus there are many possible phenotypic outcomes. Two examples of environmental pollutants that have been demonstrated to inhibit neovascularization include 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a prototypical halogenated aromatic hydrocarbon, and constituents found in environmental tobacco smoke. Studies have shown that TCDD disrupts neoangiogenesis by inhibiting the expression of angiogenic stimuli as well as by reducing the responsiveness of endothelial cells to those stimuli. Additionally, studies have shown that constituents of environmental tobacco smoke, including pyradine and pyrazine derivatives, can potently inhibit the angiogenic process of branching as well as the vasculogenic process involved in capillary plexus formation. Further, the inhibition of neovascularization by either TCDD or environmental tobacco smoke constituents is associated with reduced endothelial cell proliferation and altered expression of extracellular matrix proteins. Future research that identifies the specific angiogenic signaling pathways that are disrupted by these pollutants will improve our ability to assess their risk to human health. Finally, it is likely that many other environmental pollutants impact neovascularization; however, very few have been studied in sufficient detail. Thus, additional research also is needed to identify those environmental agents that mediate their toxicity by disrupting neovascularization.
- ArticleHennig B, Reiterer G, Majkova Z, Oesterling E, Meerarani P, Toborek M.Cardiovasc Toxicol. 2005;5(2):153-60.We hypothesize that nutrition can modulate the toxicity of environmental pollutants and thus modulate health and disease outcome associated with chemical insult. There is now increasing evidence that exposure to persistent organic pollutants, such as PCBs, can contribute to the development of inflammatory diseases such as atherosclerosis. Activation, chronic inflammation, and dysfunction of the vascular endothelium are critical events in the initiation and acceleration of atherosclerotic lesion formation. Our studies indicate that an increase in cellular oxidative stress and an imbalance in antioxidant status are critical events in PCB-mediated induction of inflammatory genes and endothelial cell dysfunction. Furthermore, we have found that specific dietary fats can further compromise endothelial dysfunction induced by selected PCBs and that antioxidant nutrients (such as vitamin E and dietary flavonoids) can protect against endothelial cell damage mediated by these persistent organic pollutants. Our recent data suggest that membrane lipid rafts such as caveolae may play a major role in the regulation of PCB-induced inflammatory signaling in endothelial cells. In addition, PCB- and lipid-induced inflammation can be down-regulated by ligands of anti-atherogenic peroxisome proliferator-activated receptors (PPARs). We hypothesize that PCBs contribute to an endothelial inflammatory response in part by down-regulating PPAR signaling. Our data so far support our hypothesis that antioxidant nutrients and related bioactive compounds common in fruits and vegetables protect against environmental toxic insult to the vascular endothelium by down-regulation of signaling pathways involved in inflammatory responses and atherosclerosis. Even though the concept that nutrition may modify or ameliorate the toxicity of environmental chemicals is provocative and warrants further study, the implications for human health could be significant. More research is needed to understand observed interactions of PCB toxicity with nutritional interventions.
- ArticleGhesquiere SA, Hofker MH, de Winther MP.Cardiovasc Toxicol. 2005;5(2):161-82.Phospholipases have received wide attention as it has become clear that several isoforms of the phospholipase family play a role in onset and progression of atherosclerosis. The release of free fatty acids (FFA) and lysophospholipids (lysoPL) provide metabolites for various inflammatory pathways, and this has been considered the main mechanism of phospholipase-driven inflammation. However, generation of FFA and lysoPL are only part of the story. The induction of low-density phospholipoprotein (LDL) aggregation and accumulation, receptor binding, co-regulation with cyclooxygenase (COX) and lip-oxygenase (LO) pathways, internalization through heparan sulfate proteoglycan (HSPG) shuttling, and crosstalk between phospholipases all play a role in atherosclerosis.Group IIA phospholipase has long been considered a key enzyme in the initiation of various inflammatory diseases, but new data also indicate a role in the subsequent resolution of inflammatory processes. Recently, secreted group V and group X phospholipase and platelet activating factor acetylhydrolase (PAF-AH) are also recognized as important enzymes in atherosclerosis, modifying LDL and leading to lipid accumulation. The phospholipases and their function in atherosclerosis are not fully under-stood. Future investigations can deliver better insight in the complex role of these enzymes. The present review summarizes the current state of phospholipase research related to atherosclerosis.