Showing papers in "Pharmacological Reviews in 2004"

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Abstract: The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

Vascular Endothelial Growth Factor and Angiogenesis

Abstract: Angiogenesis is a hallmark of wound healing, the menstrual cycle, cancer, and various ischemic and inflammatory diseases. A rich variety of pro- and antiangiogenic molecules have already been discovered. Vascular endothelial growth factor (VEGF) is an interesting inducer of angiogenesis and lymphangiogenesis, because it is a highly specific mitogen for endothelial cells. Signal transduction involves binding to tyrosine kinase receptors and results in endothelial cell proliferation, migration, and new vessel formation. In this article, the role of VEGF in physiological and pathological processes is reviewed. We also discuss how modulation of VEGF expression creates new therapeutic possibilities and describe recent developments in this field.

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most highly utilized classes of pharmaceutical agents in medicine. All NSAIDs act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective drugs. These pharmaceutical agents have quickly become established as important therapeutic medications with potentially fewer side effects than traditional NSAIDs. Additionally, characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever. Of particular importance has been the investigation of COX-1 and -2 isozymic functions in cancer, dysregulation of inflammation, and Alzheimer's disease. More recently, additional heterogeneity in COX-related proteins has been described, with the finding of variants of COX-1 and COX-2 enzymes. These variants may function in tissue-specific physiological and pathophysiological processes and may represent important new targets for drug therapy.

Catecholamine Metabolism: A Contemporary View with Implications for Physiology and Medicine

Abstract: This article provides an update about catecholamine metabolism, with emphasis on correcting common misconceptions relevant to catecholamine systems in health and disease. Importantly, most metabolism of catecholamines takes place within the same cells where the amines are synthesized. This mainly occurs secondary to leakage of catecholamines from vesicular stores into the cytoplasm. These stores exist in a highly dynamic equilibrium, with passive outward leakage counterbalanced by inward active transport controlled by vesicular monoamine transporters. In catecholaminergic neurons, the presence of monoamine oxidase leads to formation of reactive catecholaldehydes. Production of these toxic aldehydes depends on the dynamics of vesicular-axoplasmic monoamine exchange and enzyme-catalyzed conversion to nontoxic acids or alcohols. In sympathetic nerves, the aldehyde produced from norepinephrine is converted to 3,4-dihydroxyphenylglycol, not 3,4-dihydroxymandelic acid. Subsequent extraneuronal O-methylation consequently leads to production of 3-methoxy-4-hydroxyphenylglycol, not vanillylmandelic acid. Vanillylmandelic acid is instead formed in the liver by oxidation of 3-methoxy-4-hydroxyphenylglycol catalyzed by alcohol and aldehyde dehydrogenases. Compared to intraneuronal deamination, extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines represent minor pathways of metabolism. The single largest source of metanephrines is the adrenal medulla. Similarly, pheochromocytoma tumor cells produce large amounts of metanephrines from catecholamines leaking from stores. Thus, these metabolites are particularly useful for detecting pheochromocytomas. The large contribution of intraneuronal deamination to catecholamine turnover, and dependence of this on the vesicular-axoplasmic monoamine exchange process, helps explain how synthesis, release, metabolism, turnover, and stores of catecholamines are regulated in a coordinated fashion during stress and in disease states.

Mediators of Chronic Obstructive Pulmonary Disease

Abstract: Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem that is now a leading cause of death. COPD is associated with a chronic inflammatory response, predominantly in small airways and lung parenchyma, which is characterized by increased numbers of macrophages, neutrophils, and T lymphocytes. The inflammatory mediators involved in COPD have not been clearly defined, in contrast to asthma, but it is now apparent that many lipid mediators, inflammatory peptides, reactive oxygen and nitrogen species, chemokines, cytokines, and growth factors are involved in orchestrating the complex inflammatory process that results in small airway fibrosis and alveolar destruction. Many proteases are also involved in the inflammatory process and are responsible for the destruction of elastin fibers in the lung parenchyma, which is the hallmark of emphysema. The identification of inflammatory mediators and understanding their interactions is important for the development of anti-inflammatory treatments for this important disease.

Aging Biology and Geriatric Clinical Pharmacology

Abstract: Population aging evokes doomsday economic and sociological prognostication, despite a minority of older people suffering significant dependency and the potential for advances in therapeutics of age-related disease and primary aging. Biological aging processes are linked mechanistically to altered drug handling, altered physiological reserve, and pharmacodynamic responses. Parenteral loading doses need only be adjusted for body weight as volumes of distribution are little changed, whereas oral loading doses in some cases may require reduction to account for age-related increases in bioavailability. Age-related reduction of hepatic blood flow and hepatocyte mass and primary aging changes in hepatic sinusoidal endothelium with effects on drug transfer and oxygen delivery reduce hepatic drug clearance. Primary renal aging is evident, although renal clearance reduction in older people is predominantly disease-related and is poorly estimated by standard methods. The geriatric dosing axiom, "start low and go slow" is based on pharmacokinetic considerations and concern for adverse drug reactions, not from clinical trial data. In the absence of generalizable dosage guidelines, individualization via effect titration is required. Altered pharmacodynamics are well documented in the cardiovascular system, with changes in the autonomic system, autacoid receptors, drug receptors, and endothelial function to modify baseline cardiovascular tone and responses to stimuli such as postural change and feeding. Adverse drug reactions and polypharmacy represent major linkages to avoidable morbidity and mortality. This, combined with a deficient therapeutic evidence base, suggests that extrapolation of risk-benefit ratios from younger adults to geriatric populations is not necessarily valid. Even so, therapeutic advances generally may convert healthy longevity from an asset of fortunate individuals into a general social benefit.

Enzyme-Catalyzed Activation of Anticancer Prodrugs

Abstract: The rationale fo the development of prodrugs relies upon delivery of higher concentrations of a drug to target cells compared to administration of the drug itself. In the last decades, numerous prodrugs that are enzymatically activated into anti-cancer agents have been developed. This review describes the most important enzymes involved in prodrug activation notably with respect to tissue distribution, up-regulation in tumor cells and turnover rates. The following endogenous enzymes are discussed: aldehyde oxidase, amino acid oxidase, cytochrome P450 reductase, DT-diaphorase, cytochrome P450, tyrosinase, thymidylate synthase, thymidine phosphorylase, glutathione S-transferase, deoxycytidine kinase, carboxylesterase, alkaline phosphatase, beta-glucuronidase and cysteine conjugate beta-lyase. In relation to each of these enzymes, several prodrugs are discussed regarding organ- or tumor-selective activation of clinically relevant prodrugs of 5-fluorouracil, axazaphosphorines (cyclophosphamide, ifosfamide, and trofosfamide), paclitaxel, etoposide, anthracyclines (doxorubicin, daunorubicin, epirubicin), mercaptopurine, thioguanine, cisplatin, melphalan, and other important prodrugs such as menadione, mitomycin C, tirapazamine, 5-(aziridin-1-yl)-2,4-dinitrobenzamide, ganciclovir, irinotecan, dacarbazine, and amifostine. In addition to endogenous enzymes, a number of nonendogenous enzymes, used in antibody-, gene-, and virus-directed enzyme prodrug therapies, are described. It is concluded that the development of prodrugs has been relatively successful; however, all prodrugs lack a complete selectivity. Therefore, more work is needed to explore the differences between tumor and nontumor cells and to develop optimal substrates in terms of substrate affinity and enzyme turnover rates fo prodrug-activating enzymes resulting in more rapid and selective cleavage of the prodrug inside the tumor cells.

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

Abstract: The lower urinary tract constitutes a functional unit controlled by a complex interplay between the central and peripheral nervous systems and local regulatory factors. In the adult, micturition is controlled by a spinobulbospinal reflex, which is under suprapontine control. Several central nervous system transmitters can modulate voiding, as well as, potentially, drugs affecting voiding; for example, noradrenaline, GABA, or dopamine receptors and mechanisms may be therapeutically useful. Peripherally, lower urinary tract function is dependent on the concerted action of the smooth and striated muscles of the urinary bladder, urethra, and periurethral region. Various neurotransmitters, including acetylcholine, noradrenaline, adenosine triphosphate, nitric oxide, and neuropeptides, have been implicated in this neural regulation. Muscarinic receptors mediate normal bladder contraction as well as at least the main part of contraction in the overactive bladder. Disorders of micturition can roughly be classified as disturbances of storage or disturbances of emptying. Failure to store urine may lead to various forms of incontinence, the main forms of which are urge and stress incontinence. The etiology and pathophysiology of these disorders remain incompletely known, which is reflected in the fact that current drug treatment includes a relatively small number of more or less well-documented alternatives. Antimuscarinics are the main-stay of pharmacological treatment of the overactive bladder syndrome, which is characterized by urgency, frequency, and urge incontinence. Accepted drug treatments of stress incontinence are currently scarce, but new alternatives are emerging. New targets for control of micturition are being defined, but further research is needed to advance the pharmacological treatment of micturition disorders.

Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation

Abstract: Adrenocorticotropic hormone and alpha-, beta-, and gamma-melanocyte-stimulating hormones, collectively called melanocortin peptides, exert multiple effects upon the host. These effects range from modulation of fever and inflammation to control of food intake, autonomic functions, and exocrine secretions. Recognition and cloning of five melanocortin receptors (MCRs) has greatly improved understanding of peptide-target cell interactions. Preclinical investigations indicate that activation of certain MCR subtypes, primarily MC1R and MC3R, could be a novel strategy to control inflammatory disorders. As a consequence of reduced translocation of the nuclear factor kappaB to the nucleus, MCR activation causes a collective reduction of the major molecules involved in the inflammatory process. Therefore, anti-inflammatory influences are broad and are not restricted to a specific mediator. Short half-life and lack of selectivity could be an obstacle to the use of the natural melanocortins. However, design and synthesis of new MCR ligands with selective chemical properties are already in progress. This review examines how marshaling MCR could control inflammation.

The Significance of Vasoactive Intestinal Peptide in Immunomodulation

Abstract: First identified by Said and Mutt some 30 years ago, the vasoactive intestinal peptide (VIP) was originally isolated as a vasodilator peptide. Subsequently, its biochemistry was elucidated, and within the 1st decade, their signature features as a neuropeptide became consolidated. It did not take long for these insights to permeate the field of immunology, out of which surprising new attributes for VIP were found in the last years. VIP is rapidly transforming into something more than a mere hormone. In evolving scientifically from a hormone to a novel agent for modifying immune function and possibly a cytokine-like molecule, VIP research has engaged many physiologists, molecular biologists, biochemists, endocrinologists, and pharmacologists and it is a paradigm to explore mutual interactions between neural and neuroendocrine links in health and disease. The aim of this review is firstly to update our knowledge of the cellular and molecular events relevant to VIP function on the immune system and secondly to gather together recent data that support its role as a type 2 cytokine. Recognition of the central functions VIP plays in cellular processes is focusing our attention on this "very important peptide" as exciting new candidates for therapeutic intervention and drug development.

Pharmacology of Brain Na+/Ca2+ Exchanger: From Molecular Biology to Therapeutic Perspectives

Abstract: In the last two decades, there has been a growing interest in unraveling the role that the Na+/Ca2+ exchanger (NCX) plays in the function and regulation of several cellular activities. Molecular biology, electrophysiology, genetically modified mice, and molecular pharmacology have helped to delve deeper and more successfully into the physiological and pathophysiological role of this exchanger. In fact, this nine-transmembrane protein, widely distributed in the brain and in the heart, works in a bidirectional way. Specifically, when it operates in the forward mode of operation, it couples the extrusion of one Ca2+ ion with the influx of three Na+ ions. In contrast, when it operates in the reverse mode of operation, while three Na+ ions are extruded, one Ca2+ enters into the cells. Different isoforms of NCX, named NCX1, NCX2, and NCX3, have been described in the brain, whereas only one, NCX1, has been found in the heart. The hypothesis that NCX can play a relevant role in several pathophysiological conditions, including hypoxia-anoxia, white matter degeneration after spinal cord injury, brain trauma and optical nerve injury, neuronal apoptosis, brain aging, and Alzheimer's disease, stems from the observation that NCX, in parallel with selective ion channels and ATP-dependent pumps, is efficient at maintaining intracellular Ca2+ and Na+ homeostasis. In conclusion, although studies concerning the involvement of NCX in the pathological mechanisms underlying brain injury during neurodegenerative diseases started later than those related to heart disease, the availability of pharmacological agents able to selectively modulate each NCX subtype activity and antiporter mode of operation will provide a better understanding of its pathophysiological role and, consequently, more promising approaches to treat these neurological disorders.

Neuromedin U and Its Receptors: Structure, Function, and Physiological Roles

Abstract: Neuromedin U (NmU) is a structurally highly conserved neuropeptide. It is ubiquitously distributed, with highest levels found in the gastrointestinal tract and pituitary. Originally isolated from porcine spinal cord, it has since been isolated and sequenced from several species. Amino acid alignment of NmU from different species reveals a high level of conservation, and particular features within its structure are important for bioactivity. Specifically, the C terminus, including a terminal asparagine-linked amidation, is essential for activity. The conservation of NmU across a wide range of species indicates a strong evolutionary pressure to conserve this peptide and points to its physiological significance. Despite this, the precise physiological and indeed pathophysiological roles of NmU have remained elusive. NmU was first isolated based on its ability to contract rat uterine smooth-muscle (hence the suffix “U”) and has since been implicated inthe regulation of smooth-muscle contraction, blood pressure and local blood flow, ion transport in the gut, stress responses, cancer, gastric acid secretion, pronociception, and feeding behavior. Two G-protein-coupled receptors for NmU have recently been cloned. These receptors are widespread throughout the body but have differential distributions suggesting diverse but specific roles for the receptor subtypes. Here we detail the isolation and characterization of NmU, describe the discovery, cloning, distribution, and structure of its two receptors, and outline its possible roles in both physiology and pathophysiology. Ultimately the development of receptor-specific ligands and the generation of animals in which the receptors have been selectively knocked out will hopefully reveal the true extent of the biological roles of NmU and suggest novel therapeutic indications for selective activation or blockade of either of its receptors.

Liver-Enriched Transcription Factors in Liver Function and Development. Part II: the C/EBPs and D Site-Binding Protein in Cell Cycle Control, Carcinogenesis, Circadian Gene Regulation, Liver Regeneration, Apoptosis, and Liver-Specific Gene Regulation

Abstract: In the first part of our review (see Pharmacol Rev 2002;54:129-158), we discussed the basic principles of gene transcription and the complex interactions within the network of hepatocyte nuclear factors, coactivators, ligands, and corepressors in targeted liver-specific gene expression. Now we summarize the role of basic region/leucine zipper protein family members and particularly the albumin D site-binding protein (DBP) and the CAAT/enhancer-binding proteins (C/EBPs) for their importance in liver-specific gene expression and their role in liver function and development. Specifically, regulatory networks and molecular interactions were examined in detail, and the experimental findings summarized in this review point to pivotal roles of DBP and C/EBPs in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation. These regulatory proteins are therefore of great importance in liver physiology, liver disease, and liver development. Furthermore, interpretation of the vast data generated by novel genomic platform technologies requires a thorough understanding of regulatory networks and particularly the hierarchies that govern transcription and translation of proteins as well as intracellular protein modifications. Thus, this review aims to stimulate discussions on directions of future research and particularly the identification of molecular targets for pharmacological intervention of liver disease.

Opioids As Modulators of Cell Death and Survival—Unraveling Mechanisms and Revealing New Indications

Abstract: Opioids are powerful analgesics but also drugs of abuse. Because opioid addicts are susceptible to certain infections, opioids have been suspected to suppress the immune response. This was supported by the finding that various immune-competent cells express opioid receptors and undergo apoptosis when treated with opioid alkaloids. Recent evidence suggests that opioids may also effect neuronal survival and proliferation or migrating properties of tumor cells. A multitude of signaling pathways has been suggested to be involved in these extra-analgesic effects of opioids. Growth-promoting effects were found to be mediated through Akt and Erk signaling cascades. Death-promoting effects have been ascribed to inhibition of nuclear factor-kappaB, increase of Fas expression, p53 stabilization, cytokine and chemokine release, and activation of nitric oxide synthase, p38, and c-Jun-N-terminal kinase. Some of the observed effects were inhibited with opioid receptor antagonists or pertussis toxin; others were unaffected. It is still unclear whether these properties are mediated through typical opioid receptor activation and inhibitory G-protein-signaling. The present review tries to unravel controversial findings and provides a hypothesis that may help to integrate diverse results.

Autonomic Nervous System Pharmacogenomics: A Progress Report

Abstract: Pharmacogenetics, the inherited basis for interindividual differences in drug response, has rapidly expanded with the advent of new molecular tools and the sequencing of the human genome, yielding pharmacogenomics. We review here recent ideas and findings regarding pharmacogenomics of components of the autonomic nervous system, in particular, neuronal nicotinic acetylcholine receptors, postsynaptic receptors with which the parasympathetic and sympathetic neurotransmitters, acetylcholine (ACh) and norepinephrine, respectively, interact. The receptor subtypes that mediate these responses, M(1-3) muscarinic cholinergic receptors (mAChRs), and alpha(1A,B,D)-, alpha(2A,B,C)-, and beta(1,2,3)-adrenergic receptors (AR), show highly variable expression of genetic variants; variants of mAChRs and alpha(1)-ARs are relatively rare, whereas alpha(2)-AR and beta-AR subtype variants are quite common. The largest amount of data is available regarding variants of the latter ARs and represents efforts to associate certain receptor genotypes, most commonly, single nucleotide polymorphisms, with particular phenotypes (e.g., cardiovascular and metabolic responses). In vitro and in vivo studies have yielded inconsistent results; definitive conclusions are limited. We identify several conceptual and methodological problems with available data: sample size, ethnicity, tissue differences, coding versus noncoding variants, limited studies of haplotypes, and interaction among variants. Thus, although progress has been made in identifying genetic variation that influences drug response fo autonomic nervous system components, we are still at the early stages of defining the most critical genetic determinants and their role in human physiology and pharmacology.

Pharmacological Modulation of Sarcoplasmic Reticulum Function in Smooth Muscle

Abstract: The sarco/endoplasmic reticulum (SR/ER) is the primary storage and release site of intracellular calcium (Ca2+) in many excitable cells. The SR is a tubular network, which in smooth muscle (SM) cells distributes close to cellular periphery (superficial SR) and in deeper aspects of the cell (deep SR). Recent attention has focused on the regulation of cell function by the superficial SR, which can act as a buffer and also as a regulator of membrane channels and transporters. Ca2+ is released from the SR via two types of ionic channels [ryanodine- and inositol 1,4,5-trisphosphate-gated], whereas accumulation from thecytoplasm occurs exclusively by an energy-dependent sarco-endoplasmic reticulum Ca2+-ATPase pump (SERCA). Within the SR, Ca2+ is bound to various storage proteins. Emerging evidence also suggests that the perinuclear portion of the SR may play an important role in nuclear transcription. In this review, we detail the pharmacology of agents that alter the functions of Ca2+ release channels and of SERCA. We describe their use and selectivity and indicate the concentrations used in investigating various SM preparations. Important aspects of cell regulation and excitation-contractile activity coupling in SM have been uncovered through the use of such activators and inhibitors of processes that determine SR function. Likewise, they were instrumental in the recent finding of an interaction of the SR with other cellular organelles such as mitochondria. Thus, an appreciation of the pharmacology and selectivity of agents that interfere with SR function in SM has greatly assisted in unveiling the multifaceted nature of the SR.

Single Transmembrane Spanning Heterotrimeric G Protein-Coupled Receptors and Their Signaling Cascades

Abstract: Heptahelical of serpentine receptors such as the adrenergic receptors are well known to mediate their actions via heterotrimeric GTP-binding proteins. Likewise, receptors that traverse the cell membrane once have been shown to mediate their biological actions by activating several different mechanisms including stimulation of their intrinsic tyrosine kinase activities or the kinase activities of other proteins. Some of these single transmembrane receptors have an intrinsic guanylyl cyclase activity and can stimulate the cyclic GMP second messenger system; however, over the last few years, several studies have shown the involvement of heterotrimeric GTP-binding proteins in mediating signals that eventually culminate in the biological actions of single transmembrane spanning receptors and proteins. These receptors include the receptor tyrosine kinases that mediate the actions of growth factors such as epidermal growth factor, insulin, insulin-like growth factor as well as receptors for atrial natiuretic hormone or the zona pellucida protein (ZP3) and integrins. In this review, the significance of the coupling of the single transmembrane spanning receptors to G proteins has been highlighted by providing several examples of the concept that signaling via these receptors may involve the activation of multiple signaling cascades.

Structural Effects and Neurofunctional Sequelae of Developmental Exposure to Psychotherapeutic Drugs: Experimental and Clinical Aspects

Abstract: The advent of psychotherapeutic drugs has enabled management of mental illness and other neurological problems such as epilepsy in the general population, without requiring hospitalization. The success of these drugs in controlling symptoms has led to their widespread use in the vulnerable population of pregnant women as well, where the potential embryotoxicity of the drugs has to be weighed against the potential problems of the maternal neurological state. This review focuses on the developmental toxicity and neurotoxicity of five broad categories of widely available psychotherapeutic drugs: the neuroleptics, the antiepileptics, the antidepressants, the anxiolytics and mood stabilizers, and a newly emerging class of nonprescription drugs, the herbal remedies. A brief review of nervous system development during gestation and following parturition in mammals is provided, with a description of the development of neurochemical pathways that may be involved in the action of the psychotherapeutic agents. A thorough discussion of animal research and human clinical studies is used to determine the risk associated with the use of each drug category. The potential risks to the fetus, as demonstrated in well described neurotoxicity studies in animals, are contrasted with the often negative findings in the still limited human studies. The potential risk for the human fetus in the continued use of these chemicals without more adequate research is also addressed. The direction of future research using psychotherapeutic drugs should more closely parallel the methodology developed in the animal laboratories, especially since these models have already been used extremely successfully in specific instances in the investigation of neurotoxic agents.

International Union of Pharmacology XLIV. Nomenclature for the Oxoeicosanoid Receptor

Abstract: Oxoeicosanoids are a family of biologically active arachidonic acid derivatives that have been intimately linked with cellular migration. These metabolites are not only potent chemotaxins but also elicit oxygen radical production as well as induce secretory events in different cells. The most potent native ligand reported is 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and the cell membrane receptor activated has now been cloned. This receptor is distinct from those receptors activated by either the prostaglandins or the leukotrienes. The purpose of this review is to briefly summarize the molecular evidence and highlight the significance of this receptor. In addition, an official nomenclature for this oxoeicosanoid receptor is proposed.

PharmGKB Update: II. CYP3A5, Cytochrome P450, Family 3, Subfamily A, Polypeptide 5

Abstract: Category: Genotype PharmGKB Submission Numbers: PS113737, PS115406, PS114503, PS200420, PS201057, PS115245 Date of Submission: May 19, 2003 Project: Pharmacogenetics of Anticancer Agents, St. Jude Children's Research Hospital HGNC Symbol

PharmGKB Update: III. Genetic Variants of SLC22A1, Solute Carrier Family 22 (Organic Cation Transporter), Member 1

Abstract: Category: Genotype PharmGKB Submission Number: PS203001 Date of Submission: June 16, 2003 Project: Pharmacogenetics of Membrane Transporters HGNC Symbol: SLC22A1 HGNC Name: solute carrier family 22 (organic cation transporter), member 1