Annual Review of Pharmacology and Toxicology - Volume 48, 2008
Volume 48, 2008
-
-
The Tangle of Nuclear Receptors that Controls Xenobiotic Metabolism and Transport: Crosstalk and Consequences
Vol. 48 (2008), pp. 1–32More LessThe expression of many genes involved in xenobiotic/drug metabolism and transport is regulated by at least three nuclear receptors or xenosensors: aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR). These receptors establish crosstalk with other nuclear receptors or transcription factors controlling signaling pathways that regulate the homeostasis of bile acids, lipids, glucose, inflammation, vitamins, hormones, and others. These crosstalks are expected to modify profoundly our vision of xenobiotic/drug disposition and toxicity. They provide molecular mechanisms to explain how physiopathological stimuli affect xenobiotic/drug disposition, and how xenobiotics/drugs may affect physiological functions and generate toxic responses. In addition, the possibility that xenosensors may control other signaling pathways opens the way to new pharmacological opportunities.
-
-
-
Mechanisms of Placebo and Placebo-Related Effects Across Diseases and Treatments
Vol. 48 (2008), pp. 33–60More LessThe placebo effect has evolved from being thought of as a nuisance in clinical and pharmacological research to a biological phenomenon worthy of scientific investigation in its own right. It is now clear that the term placebo effect is too restrictive and, in fact, many placebo-related effects have recently been investigated. A placebo effect differs from a placebo-like effect in that the former follows the administration of a placebo, whereas in the latter no placebo is administered. However, in both cases, the psychosocial context around the treatment plays a key role. In recent years, placebo and placebo-related effects have been analyzed with sophisticated biological tools that have uncovered specific mechanisms at both the biochemical and cellular level. This recent research has revealed that these psychosocial-induced biochemical changes in a patient's brain and body in turn may affect the course of a disease and the response to a therapy.
-
-
-
Pharmacotherapy for the Treatment of Choroidal Neovascularization Due to Age-Related Macular Degeneration
Vol. 48 (2008), pp. 61–78More LessAge-related macular degeneration (AMD) is a progressive, degenerative disease of the macula that threatens central vision. It initially occurs in a “dry” form, and can progress to choroidal neovascularization (CNV) or geographic atrophy. It is the leading cause of blindness among European-descended people older than 65 years, with a prevalence of 1.5%. The treatment of CNV in developed nations in 2007 is substantially different than it was in 1997. Focal, photocoagulating, laser therapy was replaced by intravenous verteporfin and then by intravitreal pegaptanib, which is now being replaced by intravitreal ranibizumab and off-label use of bevacizumab. Other than a ranibizumab versus verteporfin trial, there are no published comparative studies of the three approved pharmacological treatments for CNV. Although frequent intravitreal injections are accepted as a current standard of care, their use is still far from ideal. Thus, there is an opportunity for improving therapy of CNV with respect to mechanism-targeted treatments, efficacy, and route of administration.
-
-
-
Nicotinic Acid: Pharmacological Effects and Mechanisms of Action
Vol. 48 (2008), pp. 79–106More LessPharmacological doses of nicotinic acid induce a profound change in the plasma levels of various lipids and lipoproteins. The ability of nicotinic acid to strongly increase the plasma concentration of high-density lipoprotein (HDL) cholesterol has in recent years led to an increased interest in the pharmacological potential of nicotinic acid. There is increasing evidence that nicotinic acid alone or in addition to LDL cholesterol–lowering drugs can reduce the progression of atherosclerosis and reduce the risk of cardiovascular events. The clinical use of nicotinic acid is, however, hindered by harmless but unpleasant side effects, especially by a strong cutaneous vasodilation called flushing. The recent discovery of the G protein–coupled receptor GPR109A (HM74A or PUMA-G) as a receptor for nicotinic acid has allowed for better understanding of the mechanisms underlying the metabolic and vascular effects of nicotinic acid. On the basis of recent progress in understanding the pharmacological effects of nicotinic acid, new strategies are in development to better exploit the pharmacological potential of nicotinic acid. New drugs acting via the nicotinic acid receptor or related receptors, as well as new co-medications that suppress unwanted effects of nicotinic acid, will most likely be introduced as new therapeutic options in the treatment of dyslipidemia and the prevention of cardiovascular diseases.
-
-
-
Activation of G Protein–Coupled Receptors: Beyond Two-State Models and Tertiary Conformational Changes
Vol. 48 (2008), pp. 107–141More LessTransformation of G protein–coupled receptors (GPCRs) from a quiescent to an active state initiates signal transduction. All GPCRs share a common architecture comprising seven transmembrane-spanning α-helices, which accommodates signal propagation from a diverse repertoire of external stimuli across biological membranes to a heterotrimeric G protein. Signal propagation through the transmembrane helices likely involves mechanistic features common to all GPCRs. The structure of the light receptor rhodopsin may serve as a prototype for the transmembrane architecture of GPCRs. Early biochemical, biophysical, and pharmacological studies led to the conceptualization of receptor activation based on the context of two-state equilibrium models and conformational changes in protein structure. More recent studies indicate a need to move beyond these classical paradigms and to consider additional aspects of the molecular character of GPCRs, such as the oligomerization and dynamics of the receptor.
-
-
-
Apoptin: Therapeutic Potential of an Early Sensor of Carcinogenic Transformation
Vol. 48 (2008), pp. 143–169More LessThe avian virus-derived protein apoptin induces p53-independent apoptosis in a tumor-specific way. Apoptin acts as a multimeric complex and forms superstructures upon binding to DNA. In tumor cells, apoptin is phosphorylated and mainly nuclear, whereas in normal cells it is unphosphorylated, cytoplasmic, and becomes readily neutralized. Interestingly, apoptin phosphorylation, nuclear translocation, and apoptosis can transiently be induced in normal cells by cotransfecting SV40 large T oncogene, indicating that apoptin recognizes early stages of oncogenic transformation. In cancer cells, apoptin appears to recognize survival signals, which it is able to redirect into cell death impulses. Apoptin targets include DEDAF, Nur77, Nmi, Hippi, and the potential drug target APC1. Apoptin-transgenic mice and animal tumor models have revealed apoptin as a safe and efficient antitumor agent, resulting in significant tumor regression. Future antitumor therapies could use apoptin either as a therapeutic bullet or as an early sensor of druggable tumor-specific processes.
-
-
-
Chemokines and Their Receptors: Drug Targets in Immunity and Inflammation
Vol. 48 (2008), pp. 171–197More LessThe chemokine system coordinates leukocyte migration in immunity and inflammation and is implicated in the pathogenesis of many human diseases. Although several successful strategies have been identified to develop drugs targeting chemokines and their receptors, this has not yet resulted in many new therapeutics. This is likely due to a complexity of the chemokine system, which was not initially appreciated, that is characterized by redundancy, pleiotropy, and differences among species. Nevertheless, our understanding of chemokine biology is continuing to grow and several promising drugs are currently being tested in late-stage clinical trials. In this review, we examine the role of chemokines in health and diseases and discuss strategies to target the chemokine system.
-
-
-
Apoptosis Signal-Regulating Kinase 1 in Stress and Immune Response
Vol. 48 (2008), pp. 199–225More LessApoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK) kinase kinase of the c-Jun N-terminal kinase (JNK) and p38 MAPK pathways. ASK1 is preferentially activated by various cytotoxic stressors and plays pivotal roles in a wide variety of cellular response to them. Recent analyses of ASK1 orthologs in Caenorhabditis elegans and Drosophila melanogaster have revealed that ASK1 is an evolutionarily conserved signaling intermediate in stress responses and appears to constitute a primitive but efficient defense system against stimuli harmful to organisms. Consistent with this notion, ASK1 has been shown to be required for the innate immune response, which is essential for host defense against a wide range of pathogens. In this review, we focus on the molecular mechanisms by which ASK1 functions in stress and immune responses and discuss the possible involvement of ASK1 in human diseases.
-
-
-
Pharmacogenetics of Anti-HIV Drugs
A. Telenti, and U. M. ZangerVol. 48 (2008), pp. 227–256More LessPharmacogenetics holds promise in HIV treatment because of the complexity and potential toxicity of multidrug therapies that are prescribed for long periods. Thus far, few candidate genes have been examined for a limited number of allelic variants, but a number of confirmed associations have already emerged. A change in paradigm emerges from the availability of the HapMap, the wealth of data on less-common genetic polymorphisms, and new genotyping technology. This review presents a comprehensive analysis of the existing literature on pharmacogenetic determinants of antiretroviral drug exposure, drug toxicity, as well as genetic markers associated with the rate of disease progression. It is expected that larger-scale comprehensive genome approaches will profoundly change the landscape of knowledge in the future.
-
-
-
Epigenetics and Complex Disease: From Etiology to New Therapeutics
Vol. 48 (2008), pp. 257–276More LessEpigenetics is a new development in complex non-Mendelian disease, which may not only uncover etiologic and pathogenic mechanisms but may also provide the basis for the development of medications that would target the primary epigenetic causes of such diseases. Such epigenetic drugs would be novel, potentially possessing substantially higher therapeutic potential and a much lower rate of adverse effects in comparison to current symptomatic treatments. A collection of epigenetic drugs already exist at various stages of development and, although their effectiveness has yet to be maximized, they show great promise in the treatment of cancer, psychiatric disorders, and other complex diseases. Here we present a review of the epigenetic theory of complex disease and an evaluation of current epigenetic therapies, as well as predictions of the future directions in this expanding field.
-
-
-
Vesicular Neurotransmitter Transporters as Targets for Endogenous and Exogenous Toxic Substances
Vol. 48 (2008), pp. 277–301More LessExocytotic release of neurotransmitters requires their accumulation inside preformed secretory vesicles. Distinct vesicular transport activities translocate classical transmitters into synaptic vesicles energized by a H+ electrochemical gradient (ΔμH+), with subtle but important differences in dependence on the electrical and chemical components. The vesicular transporters also interact with toxic compounds and drugs. They mediate neuroprotection by sequestering toxic compounds as well as neurotransmitters into vesicles, reducing their concentration in the cytosol where they may have detrimental effects. Both therapeutic agents and psychostimulants interfering with vesicular transport have yielded insight into the pathogenesis of psychiatric as well as neurodegenerative diseases. Thus, specific inhibitors have helped to characterize both the physiological role and mechanism of vesicular neurotransmitter transport.
-
-
-
Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics
Vol. 48 (2008), pp. 303–332More LessGrowth and development can be investigated using readily observable demographic factors such as weight and age. Size is the primary covariate and can be referenced to a 70-kg person with allometry using a coefficient of 0.75 for clearance and 1 for volume. The use of these coefficients is supported by fractal geometric concepts and observations from diverse areas in biology. Fat free mass (FFM) might be expected to do better than total body weight when there are wide variations in fat affecting body composition. Clearance pathways develop in the fetus before birth. The use of postnatal age as a descriptor of maturation is unsatisfactory because birth may occur prematurely; therefore postmenstrual age is a superior predictor of elimination function. A sigmoid Emax model (Hill equation) describes gradual maturation of clearance in early life leading to a mature adult clearance achieved at a later age.
-
-
-
Role of CYP1B1 in Glaucoma*
Vol. 48 (2008), pp. 333–358More LessGlaucoma is a leading cause of blindness, estimated to affect 60 million people by 2010, and represents a heterogeneous group of neurodegenerative disease. The two major types of glaucoma include primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG). A genetically heterogeneous group of developmental disorders known as anterior segment dysgenesis (ASD) have been reported to be associated with increased intraocular pressure (IOP) and glaucoma. These include Peters’ anomaly, Rieger's anomaly, aniridia, iris hypoplasia, and iridogoniodysgenesis. Genetic linkage analysis and mutation studies have identified CYP1B1 as a causative gene in PCG, as a modifier gene in POAG, and, on rare occasions, as causative gene in POAG as well as in several ASD disorders. CYP1B1-deficient mice exhibit abnormalities in their ocular drainage structure and trabecular meshwork that are similar to those reported in human PCG patients. Accordingly, it is speculated that diminished or absent metabolism of key endogenous CYP1B1 substrates adversely affects the development of the trabecular meshwork. CYP1B1 protein is involved in the metabolism of steroids, retinol and retinal, arachidonate, and melatonin. The conserved expression of CYP1B1 in both murine and human eyes, its higher expression in fetal than adult eyes, and its biochemical properties are consistent with this hypothesis. The exact role of CYP1B1 in the pathogenesis of glaucoma and other ASD disorders remains to be elucidated.
-
-
-
Caveolae as Organizers of Pharmacologically Relevant Signal Transduction Molecules
Vol. 48 (2008), pp. 359–391More LessCaveolae, a subset of membrane (lipid) rafts, are flask-like invaginations of the plasma membrane that contain caveolin proteins, which serve as organizing centers for cellular signal transduction. Caveolins (-1, -2, and -3) have cytoplasmic N and C termini, palmitolylation sites, and a scaffolding domain that facilitates interaction and organization of signaling molecules so as to help provide coordinated and efficient signal transduction. Such signaling components include upstream entities (e.g., G protein–coupled receptors (GPCRs), receptor tyrosine kinases, and steroid hormone receptors) and downstream components (e.g., heterotrimeric and low-molecular-weight G proteins, effector enzymes, and ion channels). Diseases associated with aberrant signaling may result in altered localization or expression of signaling proteins in caveolae. Caveolin-knockout mice have numerous abnormalities, some of which may reflect the impact of total body knockout throughout the life span. This review provides a general overview of caveolins and caveolae, signaling molecules that localize to caveolae, the role of caveolae/caveolin in cardiac and pulmonary pathophysiology, pharmacologic implications of caveolar localization of signaling molecules, and the possibility that caveolae might serve as a therapeutic target.
-
-
-
Proteases for Processing Proneuropeptides into Peptide Neurotransmitters and Hormones
Vol. 48 (2008), pp. 393–423More LessPeptide neurotransmitters and peptide hormones, collectively known as neuropeptides, are required for cell-cell communication in neurotransmission and for regulation of endocrine functions. Neuropeptides are synthesized from protein precursors (termed proneuropeptides or prohormones) that require proteolytic processing primarily within secretory vesicles that store and secrete the mature neuropeptides to control target cellular and organ systems. This review describes interdisciplinary strategies that have elucidated two primary protease pathways for prohormone processing consisting of the cysteine protease pathway mediated by secretory vesicle cathepsin L and the well-known subtilisin-like proprotein convertase pathway that together support neuropeptide biosynthesis. Importantly, this review discusses important areas of current and future biomedical neuropeptide research with respect to biological regulation, inhibitors, structural features of proneuropeptide and protease interactions, and peptidomics combined with proteomics for systems biological approaches. Future studies that gain in-depth understanding of protease mechanisms for generating active neuropeptides will be instrumental for translational research to develop pharmacological strategies for regulation of neuropeptide functions. Pharmacological applications for neuropeptide research may provide valuable therapeutics in health and disease.
-
-
-
Targeting Chemokine Receptors in HIV: A Status Report
Vol. 48 (2008), pp. 425–461More LessSince the identification of CCR5 and CXCR4 as HIV coreceptors a little over a decade ago, there has been hope that coreceptor inhibitors will be able to make an impact on the HIV epidemic, both as novel therapeutic drugs and as agents used in prevention. Significant progress has been made in the understanding of how coreceptor choice might impact HIV pathology and how coreceptor blockade may affect health. In this review, we focus on some of the key issues that are emerging now that CCR5 has been validated as a promising target for HIV prevention strategies and at a time when a CCR5 inhibitor has been approved in the United States as the first in a new class of anti-HIV therapeutic drugs.
-
-
-
Biomarkers of Acute Kidney Injury
Vol. 48 (2008), pp. 463–493More LessAcute kidney injury (AKI) is a common condition with a high risk of death. The standard metrics used to define and monitor the progression of AKI, such as serum creatinine and blood urea nitrogen levels, are insensitive, nonspecific, and change significantly only after significant kidney injury and then with a substantial time delay. This delay in diagnosis not only prevents timely patient management decisions, including administration of putative therapeutic agents, but also significantly affects the preclinical evaluation of toxicity thereby allowing potentially nephrotoxic drug candidates to pass the preclinical safety criteria only to be found to be clinically nephrotoxic with great human costs. Studies to establish effective therapies for AKI will be greatly facilitated by two factors: (a) development of sensitive, specific, and reliable biomarkers for early diagnosis/prognosis of AKI in preclinical and clinical studies, and (b) development and validation of high-throughput innovative technologies that allow rapid multiplexed detection of multiple markers at the bedside.
-
-
-
The Role of Cellular Accumulation in Determining Sensitivity to Platinum-Based Chemotherapy*
Vol. 48 (2008), pp. 495–535More LessThe platinum (Pt) drugs cisplatin and carboplatin are heavily employed in chemotherapy regimens; however, similar to other classes of drugs, a number of intrinsic and acquired resistance mechanisms hamper their effectiveness. The method by which Pt drugs enter cells has traditionally been attributed to simple passive diffusion. However, recent evidence suggests a number of active uptake and efflux mechanisms are at play, and altered regulation of these transporters is responsible for the reduced accumulation of drug in resistant cells. This review suggests a model that helps reconcile the disparate literature by describing multiple pathways for Pt-containing drugs into and out of the cell.
-
-
-
Regulation of GPCRs by Endocytic Membrane Trafficking and Its Potential Implications
Vol. 48 (2008), pp. 537–568More LessThe endocytic pathway tightly controls the activity of G protein–coupled receptors (GPCRs). Ligand-induced endocytosis can drive receptors into divergent lysosomal and recycling pathways, producing essentially opposite effects on the strength and duration of cellular signaling via heterotrimeric G proteins, and may also promote distinct signaling events from intracellular membranes. This chapter reviews recent developments toward understanding the molecular machinery and functional implications of GPCR sorting in the endocytic pathway, focusing on mammalian GPCRs whose ligand-induced endocytosis is mediated primarily by clathrin-coated pits. Lysosomal sorting of a number of GPCRs occurs via a highly conserved mechanism requiring covalent tagging of receptors with ubiquitin. There is increasing evidence that additional, noncovalent mechanisms control the sorting of endocytosed GPCRs to lysosomes in mammalian cells. Recycling of several GPCRs to the plasma membrane is also specifically sorted, via a mechanism requiring both receptor-specific and shared sorting proteins. The current data reveal an unprecedented degree of specificity and plasticity in the cellular regulation of mammalian GPCRs by endocytic membrane trafficking. These developments have fundamental implications for GPCR pharmacology, and suggest new mechanisms that could be exploited in GPCR-directed pharmacotherapy.
-
-
-
PKC Isozymes in Chronic Cardiac Disease: Possible Therapeutic Targets?
Vol. 48 (2008), pp. 569–599More LessCardiovascular disease is the leading cause of death in the United States. Therefore, identifying therapeutic targets is a major focus of current research. Protein kinase C (PKC), a family of serine/threonine kinases, has been identified as playing a role in many of the pathologies of heart disease. However, the lack of specific PKC regulators and the ubiquitous expression and normal physiological functions of the 11 PKC isozymes has made drug development a challenge. Here we discuss the validity of therapeutically targeting PKC, an intracellular signaling enzyme. We describe PKC structure, function, and distribution in the healthy and diseased heart, as well as the development of rationally designed isozyme-selective regulators of PKC functions. The review focuses on the roles of specific PKC isozymes in atherosclerosis, fibrosis, and cardiac hypertrophy, and examines principles of pharmacology as they pertain to regulators of signaling cascades associated with these diseases.
-
Previous Volumes
-
Volume 65 (2025)
-
Volume 64 (2024)
-
Volume 63 (2023)
-
Volume 62 (2022)
-
Volume 61 (2021)
-
Volume 60 (2020)
-
Volume 59 (2019)
-
Volume 58 (2018)
-
Volume 57 (2017)
-
Volume 56 (2016)
-
Volume 55 (2015)
-
Volume 54 (2014)
-
Volume 53 (2013)
-
Volume 52 (2012)
-
Volume 51 (2011)
-
Volume 50 (2010)
-
Volume 49 (2009)
-
Volume 48 (2008)
-
Volume 47 (2007)
-
Volume 46 (2006)
-
Volume 45 (2005)
-
Volume 44 (2004)
-
Volume 43 (2003)
-
Volume 42 (2002)
-
Volume 41 (2001)
-
Volume 40 (2000)
-
Volume 39 (1999)
-
Volume 38 (1998)
-
Volume 37 (1997)
-
Volume 36 (1996)
-
Volume 35 (1995)
-
Volume 34 (1994)
-
Volume 33 (1993)
-
Volume 32 (1992)
-
Volume 31 (1991)
-
Volume 30 (1990)
-
Volume 29 (1989)
-
Volume 28 (1988)
-
Volume 27 (1987)
-
Volume 26 (1986)
-
Volume 25 (1985)
-
Volume 24 (1984)
-
Volume 23 (1983)
-
Volume 22 (1982)
-
Volume 21 (1981)
-
Volume 20 (1980)
-
Volume 19 (1979)
-
Volume 18 (1978)
-
Volume 17 (1977)
-
Volume 16 (1976)
-
Volume 15 (1975)
-
Volume 14 (1974)
-
Volume 13 (1973)
-
Volume 12 (1972)
-
Volume 11 (1971)
-
Volume 10 (1970)
-
Volume 9 (1969)
-
Volume 8 (1968)
-
Volume 7 (1967)
-
Volume 6 (1966)
-
Volume 5 (1965)
-
Volume 4 (1964)
-
Volume 3 (1963)
-
Volume 2 (1962)
-
Volume 1 (1961)
-
Volume 0 (1932)