Showing papers in "Annual Review of Pharmacology and Toxicology in 1996"

Oxidative Stress in Neurodegenerative Diseases

Abstract: Oxidative stress refers to the cytopathologic consequences of a mismatch between the production of free radicals and the ability of the cell to defend against them. Growing data from experimental models and human brain studies suggest oxidative stress may play an important role in neuronal degeneration in diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Mitochondrial oxidative metabolism, nitric oxide, phospholipid metabolism, and proteolytic pathways are potential sources of intracellular free radicals. Alterations in free radical defense systems may also contribute to oxidative stress. A net increase in reactive oxygen species can produce damage to lipids, proteins, and DNA and induce necrosis or apoptosis. Elucidating the pathways important in the production of and defense from free radicals may be important in devising new pharmacologic strategies to slow or halt neuronal degeneration.

Complexity and Diversity of Mammalian Adenylyl Cyclases

Abstract: Molecular cloning has permitted identification of several novel isoforms of mammalian adenylyl cyclase; these proteins now comprise a family of at least 10. All of the membrane-bound enzymes are activated by the alpha subunit of G alpha, a receptor-regulated, heterotrimeric guanine nucleotide-binding protein, and by the diterpene forskolin. Certain cyclases are also activated by Ca(2+)-calmodulin, while some are inhibited by the alpha subunits of the three Gi proteins. The discovery of new isoforms has also revealed unanticipated mechanisms of regulation, including activation or inhibition by the G-protein beta gamma subunit complex, inhibition by G(o) alpha, inhibition by Ca2+, and phosphorylation by protein kinases C and A. The effects of activators are often highly synergistic or conditional, suggesting function of these enyzmes as coincidence detectors. The plethora of receptors, G proteins, and adenylyl cyclases permits assembly of very complex signaling systems with a wide variety of integrative characteristics.

Pathophysiological Basis of Vulnerability to Drug Abuse: Role of an Interaction Between Stress, Glucocorticoids, and Dopaminergic Neurons

Abstract: Research on drug abuse has recently focused on understanding the vulnerability to develop addiction that is present in certain individuals. These investigations suggest that addiction results from an interaction between drugs and specific individual substrates. Differences in the propensity to develop drug intake can be demonstrated in animals with equal access to drugs under stable laboratory conditions and can be predicted by drug-independent behaviors. Stress, corticosterone, and mesencephalic dopaminergic neurons seem to be organized in a pathophysiological chain determining such a vulnerability. An increased corticosterone secretion, or a higher sensitivity to the effects of this hormone, either naturally present in certain individuals or induced by stress in others, increases the vulnerability to develop drug intake, via an enhancement of the activity of mesencephalic dopaminergic neurons. These findings suggest that addiction therapies should counteract the biological peculiarity that leads some in...

Molecular Mechanisms of Estrogen Carcinogenesis

Abstract: In western society, the causes of several cancers--including breast, endometrium, ovary, liver, and prostate--have been linked to inappropriate and/or prolonged exposure to synthetic or endogenous steroidal hormones. In this review, we discuss the mechanisms of estrogen carcinogenesis with a focus on estrogen metabolism to 16 alpha-hydroxy estrone and 2- and 4-hydroxy catechol estrogens and the potential effects of these metabolites in vitro and in vivo on hamster liver and kidney and rat liver carcinogenesis models. The examples demonstrate that the parent compounds and their metabolites cause both nongenotoxic cell proliferative effects as well as direct and indirect genotoxic effects, which illustrates the complex nature of estrogen carcinogenesis. These effects, in combination with the metabolic state of the tissue and the timing of its exposure, may determine the cell type (organ) of tumor development and the severity of disease.

Pharmacology of nicotine: addiction and therapeutics

Abstract: Nicotine maintains tobacco addiction and has therapeutic utility to aid smoking cessation and possibly to treat other medical diseases. Nicotine acts on nicotinic cholinergic receptors, which demonstrate diversity in subunit structure, function, and distribution within the nervous system, presumably mediating the complex actions of nicotine described in tobacco users. The effects of nicotine in people are influenced by the rate and route of dosing and by the development of tolerance. The metabolism of nicotine is now well characterized in humans. A few individuals with deficient C-oxidation of nicotine, unusually slow metabolism of nicotine, and little generation of cotinine have been described. Nicotine affects most organ systems in the body, although its contribution to smoking-related disease is still unclear. Nicotine as a medication is currently available as a gum, a transdermal delivery device, and a nasal spray, all of which are used for smoking cessation. Nicotine is also being investigated for therapy of ulcerative colitis, Alzheimer's disease, Parkinson's disease, Tourette's syndrome, sleep apnea, and attention deficit disorder.

Diversity and Selectivity of Receptor-G Protein Interaction

Abstract: Cells in a living organism communicate with each other through extracellular molecules such as hormones, neurotransmitters, and growth factors. The majority of these molecules transmit their signal by interacting with a three-protein transmembrane signal transduction system whose single components interact sequentially and reversibly. Agonist binding to a heptahelical receptor results in activation of heterotrimeric guanine nucleotide-binding proteins (G proteins) that modulate the activity of one or more effector systems. Considering that hundreds of G protein-coupled receptors transduce signals by interacting with a limited repertoire of G proteins, the question of specificity governing the coupling of receptors to G proteins arises. The conceptualization of signal transduction pathways in a linear fashion (one receptor coupling to one G protein that activates one effector) is inadequate to explain experimental results. In the present review, G protein-mediated signal transduction is depicted as a complex signaling network with divergent and convergent pathways at each transduction level, i.e. receptor, G protein, and effector. The recent realization that "classical" signaling pathways appear to be activated in parallel with signaling cascades primarily described for growth factors and cytokines adds an additional level of intriguing complexity.

Regulation of Phosphoinositide Phospholipases by Hormones, Neurotransmitters, and Other Agonists Linked to G Proteins

Abstract: The actions of many hormones, neurotransmitters, and growth factors are mediated by the hydrolysis of phosphatidylinositol 4,5-bisphosphate catalyzed by specific isozymes of phospholipase C. This hydrolysis releases inositol 1,4,5-trisphosphate, which mobilizes Ca2+ ions from components of the endoplasmic reticulum, and 1,2-diacylglycerol, which activates isozymes of protein kinase C. The hormones and neurotransmitters activate beta-isozymes of phospholipase C through receptors that have seven transmembrane segments and couple to G proteins of the Gq and Gi/o families. Activation of phospholipase C by the Gq family involves their alpha-subunits, whereas activation by the Gi/o family involves their beta gamma-subunits. The growth factors activate gamma-isozymes of phospholipase C through receptors that become autophosphorylated due to their stimulated tyrosine kinase activity and provide binding sites for the Src homology domains of the isozymes. The molecular mechanisms by which agonists activate phopholipase isozymes are described in detail.

Progress in antisense oligonucleotide therapeutics.

Abstract: The past several years have seen substantial progress in the development of antisense oligonucleotides as pharmacological tools and as therapeutic agents. With properly designed and executed experiments, it has been possible to demonstrate selective inhibition of gene expression, owing to an antisense mechanisms of action both in cell culture-based experiments and in vivo. As the field has matured, it has also realized that oligonucleotides can produce a variety of effects in cell culture and in vivo that cannot be ascribed to an antisense mechanism of action. Nevertheless, with proper controls it has been possible to demonstrate that the pharmacological activity of an oligonucleotide is consistent with an antisense mechanism of action. The pharmacokinetic properties of first-generation phosphorothioate oligodeoxynucleotides and their toxicological limitations have been characterized in rodents, primates, and humans. Finally, it has been demonstrated that medicinal chemistry can improve the properties of oligonucleotides, as several modifications have been identified that have increased potency, altered pharmacokinetic properties and potentially decreased toxicological liabilities.

Insulin signal transduction and the IRS proteins.

Abstract: Insulin controls organismal and cellular physiology by initiating numerous intracellular signals. Insulin first binds the extracellular domain of the insulin receptor, which activates the receptor's intracellular tyrosine kinase. Receptor-mediated phosphorylation of the IRS proteins is required for the propagation of signals for mitogenesis, glucose transport, and numerous other biological and biochemical events during insulin signaling. IRS proteins also mediate signaling by a subset of other growth factor and cytokine receptors; recognition and phosphorylation by specific receptors appears to be mediated by the PH and PTB domains of the IRS proteins. The best understood mechanism of IRS-protein-mediated signaling is the binding of SH2 domain-containing signaling molecules (such as PI 3'-kinase) by tyrosine phosphorylation sites on IRS proteins. Other paradigms of IRS-protein signaling are beginning to emerge, however, and these exciting molecules promise to teach us much in the next few years.

P-Glycoproteins and Multidrug Resistance

Abstract: Multidrug resistance represents a major obstacle in the successful therapy of neoplastic diseases. Studies have demonstrated that this form of drug resistance occurs both in cultured tumor cell lines as well as in human cancers. P-glycoprotein appears to play an important role in such cells by acting as an energy-dependent efflux pump to remove various natural product drugs from the cell before they have a chance to exert their cytotoxic effects. Expression of the MDR1 gene product has been associated with a poor prognosis in clinical studies. It has been demonstrated in the laboratory that resistance mediated by the P-glycoprotein may be modulated by a wide variety of compounds. These compounds, which include verapamil and cyclosporin, generally have little or no effect by themselves on the tumor cells, but when used in conjunction with antineoplastic agents, they decrease, and in some instances eliminate, drug resistance. Clinical trials to modulate P-glycoprotein activity are underway at the present time to determine if such strategies will be feasible. Although the P-glycoprotein is expressed in many cell lines and occurs in patient tumors, its expression is not a universal feature of multidrug resistance, suggesting that other mechanisms are operating.

Cardiac Actions of Antihistamines

Abstract: Two of the nonsedating antihistaminic drugs, terfenadine and astemizole, have recently been recognized in rare cases to induce the syndrome of torsades de pointes, i.e. QT interval prolongation and life-threatening ventricular tachycardia. Each was found to prolong cardiac repolarization when its metabolic elimination was impaired, such as by liver disease or drugs that inhibit the 3A family of cytochrome P450. In vitro studies indicate that this action is due to blockade of one or more of the cardiac potassium channels that determine the duration of the action potential. Prescription guidelines are now available to reduce the risk of developing arrhythmias with these two drugs. Two agents recently marketed in the United States, Ioratidine and cetirizine, appear to lack the ability to prolong repolarization and induce torsades de pointes. Evaluation of the potential cardiac actions of investigational antihistamines is essential and may be of value for some of the older conventional agents.

Angiotensin Receptors and Their Therapeutic Implications

Abstract: Angiotensin II is a multifunctional hormone that exerts its effects by interacting will cell surface receptors. Two major subtypes of receptors (AT1 and AT2) have been distinguished by pharmacological and molecular biological techniques. AT1 receptors have been further subdivided into AT1A and AT1B receptors. Several other isoforms have been found, notably in nonmammalian systems, but further information is necessary before definitive classification can be made. AT1 receptors mediate most known functions of angiotensin II, while AT2 receptors may be important developmentally. The molecular, structural, and biochemical characteristics of these receptors have been described, as well as the factors that regulate their expression. This receptor system has been implicated in several cardiovascular diseases, including hypertension, restenosis after angioplasty, cardiac hypertrophy, heart failure, myocardial infarction, and ventricular remodeling. Structural analysis of AT receptors may provide the basis for the development of new therapeutic agents with enhanced specificity for the treatment of these diseases.

Imidazoline receptors and their endogenous ligands

Abstract: Imidazoline (I) receptors constitute a family of nonadrenergic high-affinity binding sites for clonidine, idazoxan, and allied drugs. One major subclass, the I1 receptors, whose subcellular distribution and signal transduction mechanisms are uncertain, partly mediates the central hypotensive actions of clonidine-like drugs. The I2 receptors, another subclass, are mitochondrial, not G protein coupled, and have diversified functions. Several endogenous ligands for I receptors, collectively termed clonidine-displacing substances (CDSs), have been detected in tissues and serum, but the structure of only one, agmatine (decarboxylated arginine), is known. Agmatine, widely distributed and bioactive, binds, like clonidine, to alpha 2-adrenergic and I receptors of all subclasses. The presence of agmatine and its biosynthetic enzyme in synaptosomes and specific neuronal pathways as well as serum suggests that it may be a novel neurotransmitter/hormone. Another CDS that binds to I receptors and to antibodies to imidazoline drugs has been detected, but its structure is unknown.

Cyclic Nucleotide Phosphodiesterases and Vascular Smooth Muscle

Abstract: At least 30 different phosphodiesterase (PDE) enzymes have now been identified in mammalian tissues and cells, many of which are products of separate genes. These different isoenzyme forms can be subdivided into seven families based on their genetic and functional characteristics. Relatively specific inhibitors are available for at least five of these PDE families. A functional classification based on substrate specificity, regulatory properties, and sensitivity to inhibition by isozyme- and tissue-selective inhibitors can be used in describing the PDEs of vascular smooth muscle. Inhibition of these PDEs, especially with inhibitors of the PDE3 isoform, promotes vascular relaxation, particularly if the preparation of smooth muscle has been preconracted. For the most part, the drugs appear to act directly on smooth muscle; their effects are usually observed in endothelium-denuded preparations. In addition to their cardiotonic properties, many PDE3 inhibitors possess antiplatelet and thrombolytic activities, thereby suggesting the potential benefit of these drugs in treating diseases of the cardiovascular system. Isozyme- and cell-specific drugs have been shown to alter the synthetic state (i.e. proliferative phenotype) of smooth muscle cultures toward the appearance of the contractile phenotype. This suggests the possible use of selective PDE inhibitors to minimize the problem of restenosis seen after angioplasty. The development of novel methods to deliver more potent and selective PDE inhibitors to individual cell types and subcellular locales will lead to new therapeutic uses for this class of drugs in diseases of the cardiovascular system.

Lipid vs protein theories of alcohol action in the nervous system.

Abstract: There has been a long-standing debate concerning whether alcohols produce their effects in the central nervous system (CNS) by acting on lipids or proteins. Lipid theories postulate that alcohols act via some perturbation of the membrane lipids of CNS neurons, whereas protein theories propose that alcohols act by interacting with a neuronal protein site. Although the primary site of action differs in the two theories, both theories postulate that the CNS effects of alcohols ultimately result from alterations in protein function. This review discusses lipid and protein theories of alcohol action and the evidence supporting these theories. In addition, the effects of alcohols on the function of neurotransmitter-gated ion channels are discussed, as several types of these receptor-ion channels have been found to be sensitive to the actions of alcohols, and recent studies on those actions have yielded new insights into the question of whether the primary action of alcohols involves lipids or proteins.

Structural Mechanisms of HIV Drug Resistance

Abstract: Antiviral therapy for AIDS has focused on the discovery and design of inhibitors for two main enzyme targets of the human immunodeficiency virus type 1 (HIV)--reverse transcriptase (RT) and protease (PR). Despite several classes of promising new anti-HIV agents, the clinical emergence of drug-resistant variants of HIV has severely limited the long-term effectiveness of these drugs. Genetic analysis of resistant virus has identified a number of critical mutations in the RT and PR genes. Structural analysis of inhibitor-enzyme complexes and mutational modeling studies are leading to a better understanding of how these drug-resistance mutations exert their effects at a structural level. These insights have implications of the design of new drugs and therapeutic strategies to combat drug resistance to AIDS.

Opioid Receptor Types and Subtypes: The delta Receptor as a Model

Abstract: Since the discovery of opioid receptors over two decades ago, an increasing body of work has emerged supporting the concept of multiple opioid receptors. Molecular cloning has identified three opioid receptor types--mu, delta, and kappa--confirming pharmacological studies that previously postulated the existence of these three receptors. The cloned opioid receptors are highly homologous and belong to the family of seven-transmembrane, G protein-coupled receptors. With the development of novel opioid ligands, subtypes of the mu, delta, and kappa receptors have been proposed, although the molecular basis of these subtypes has not been elucidated. In this review, we present the pharmacological data supporting the concept of multiple delta opioid receptor subtypes and offer hypothetical mechanisms which might generate these "subtypes."

Assessment of follicle destruction in chemical-induced ovarian toxicity

Abstract: The ovary plays a pivotal role in the regulation of reproductive function in females. Development, maturation, and ovulation of oocytes occur within ovarian follicles. Females are born with a finite number of undeveloped, primordial follicles. Chemicals that destroy oocytes contained in these follicles can produce premature ovarian failure (menopause) because once a primordial follicle is destroyed, it cannot be replaced. This article focuses on chemicals that have been shown to destroy these small follicles in laboratory animals. An ovotoxic compound of particular interest is 4-vinylcyclohexene (VCH) and its epoxide metabolites. The specific information discussed here relates to various aspects of VCH-inuced ovarian toxicity. This includes species specificity, disposition and metabolism, direct follicular effects, bioactivity of metabolites, and long-term responses to exposure. Using these studies as a model approach, a method for evaluation of the ovotoxic potential of other chemicals can be designed.

Breast Cancer and Environmental Risk Factors: Epidemiological and Experimental Findings

Abstract: Breast cancer has long been associated with reproductive hormone exposures. Recently, greater attention has been focused on environmental exposures that may be responsible for some proportion of breast cancer incidence. Several etiologic aspects are discussed. A number of chemicals induce breast cancer in rodents--including solvents, pesticides, and polycyclic aromatic hydrocarbons--and these might serve as leads for studies in humans. In women, strong links have been established between breast cancer risk and ionizing radiation. Evidence for nonionizing radiation (electromagnetic field) exposures and breast cancer is suggestive, albeit limited. Occupational exposures have not been identified as breast cancer risks, but several associations need further study, including solvents and pesticides. Time of life when exposures take place is important, and this claim is strongly supported by data on cigarette smoking and radiation. Also, basic research has demonstrated that mammary tissue is more susceptible to carcinogenesis at certain periods of breast development. Likewise, prenatal, neonatal, and adolescent exposures deserve continuing attention. Research on etiology of breast cancer should measure environmental exposures and take into account the time of life at which these occur. Complex interactions between exogenous and endogenous carcinogenic agents need further focus, as modulated by varying genetically determined individual susceptibilities.

Exocytosis: proteins and perturbations.

Abstract: Exocytosis is the primary means of cellular secretion. Because exocytosis involves fusion between the plasma membrane and the membrane of secretory vesicles, it is likely that proteins on these two membranes, as well as additional proteins in cellular cytoplasm, mediate exocytosis. Although we know much about the proteins of secretory cells, we still have much to learn about how these proteins participate in exocytosis; in no case has an unambiguous exocytotic function been assigned to any of these proteins. To identify the roles of proteins in exocytosis it is necessary to perturb protein function in living secretory cells. We review a number of perturbation strategies and summarize what this approach has taught us about the functional roles of proteins in exocytosis, concluding with a molecular model of protein dynamics during exocytosis.

New Pharmacological Strategies for Pain Relief

Abstract: The recent advances made in elucidating the processes of nociception have altered the way that chronic pain therapy and analgesic drug development are approached. Recent studies have highlighted new targets for drug discovery, including inhibition of inflammatory mediators (kinins, growth factors), newly expressed proteins (B1 receptors, COX-2), and blockers of afferent fiber activity (capsaicin analogues, ion channel blockers). In the CNS, a further multiplicity of strategies can be pursued, including the development of antagonists of specific neuropeptide and glutamate receptors or agonists for purine and amine receptors. Such drugs will inevitably supplement or replace conventional NSAID and opioid analgesics. Further characterization of gene regulation will allow the development of drugs that genetically modify cellular activity altered by chronic pain conditions.

Antiprogestins: Mechanism of action and contraceptive potential

Abstract: Antiprogestins are characterized by substitutions at the 11 beta and 17 alpha positions of the steroid ring system and bind strongly to both progesterone and glucocorticoid receptors. Although they function predominantly as antiprogestins and antiglucocorticoids, on occasion they display progestin agonistic and even antiestrogenic properties. The most common clinical use of the antiprogestin mifepristone is to induce a medical abortion in the early stages of pregnancy. Progesterone maintains the endometrium, transforming it from a proliferative to a secretory state. It also facilitates the luteinizing hormone surge, which initiates ovulation. As a consequence, antiprogestins may also have contraceptive potential. Although antiprogestins do delay ovulation, this effect is inconsistent unless high doses are given, and under these circumstances, the antiprogestin effect is associated with unopposed estrogen action on the endometrium. Very low doses of antiprogestins do not affect hormonal secretion or ovulation or alter bleeding patterns, but they do have contraceptive potential by inducing profound alterations in endometrial morphology. Mifepristone is also a very effective and safe postcoital agent. This new class of pharmacological agents has numerous other gynecological and obstetrical indications, such as endometriosis, uterine myoma, and expulsion of the fetus in the case of fetal death in utero. Antiprogestins may also be used in the treatment of steroid-dependent tumors. There are also therapeutic implications consequent to their antiglucocorticoid properties.

CNS Effects and Abuse Liability of Anabolic-Androgenic Steroids

Abstract: Anabolic-androgenic steroids (AAS) have become more widely used and abused not only by elite athletes, but by nonathletes as well. It appears that these drugs are being used for cosmetic purposes as well as for promoting aggressive behavior. However, AASs may also be used in combination with other drugs such as ethyl alcohol and cocaine--a practice that may contribute to the observed increase in aggressive behavior. As there are no reliable animal models of AAS self-administration, it has been difficult to characterize the abuse liability and physical dependence potential of this class of drugs. A better understanding of neuroactive steroids, improved methods for assessing AAS abuse, and a revised interpretation of drug-seeking behavior is needed to develop improved treatment strategies for this emerging health-related problem.

Molecular Mechanisms of Toxicant-Induced Immunosuppression: Role of Second Messengers

Abstract: Changes in immunocompetence following chemical exposure have been established for a wide variety of unrelated agents. For the vast majority of immunotoxic compounds thus far identified, disruption of normal immune function is clearly mediated through direct interactions between the agent, or its metabolite, and immunocompetent cells. Regardless of whether this interaction occurs at the level of the cell membrane or at intracellular sites, basic regulatory processes mediated by second messengers are often altered. These alterations can ultimately result in immunologic dysfunction, which is most often manifested as immunosuppression. The specific disruptions in intracellular signaling produced by a number of immunotoxic compounds have now been identified, leading to a basic understanding of their molecular mechanism of action. Equally important, through the application of these agents as biological probes, new insights have been gained pertaining to which intracellular processes control which cellular functions within various populations of immunocompetent cells.

A Personal View of Pharmacology

Abstract: This essay is an account of the author's experience in trying to interpret the action of drugs as seen in in vitro bioassays. The central theme is how the development of simple mathematical models has assisted in the interpretation of drug actions. Starting from encounters with partial agonists, the essay describes the development of an operational model of agonist activity, the significance of receptor distribution, the analysis of indirect competitive antagonism and various two-receptor systems, followed by examples of pharmacological resultant activity. Analyses of tissue and species variations are described. The essay ends with an assessment of the future of bioassay in pharmacology.