Annual Review of Pharmacology and Toxicology - Volume 37, 1997
Volume 37, 1997
- Review Articles
-
-
-
THE TOXICOLOGY OF ENVIRONMENTAL TOBACCO SMOKE
Vol. 37 (1997), pp. 29–52More Less▪ AbstractIt has by now become obvious that environmental tobacco smoke (ETS) may pose a health risk to nonsmokers. Epidemiological data suggest that exposure to ETS may increase the risk of developing lung cancer, cardiovascular disease, intrauterine growth retardation, predisposition to chronic lung disease, and sudden infant death syndrome. The human populations most at risk from ETS exposure appear to be neonates, young children, and possibly the fetus while in utero. Experimental studies with cigarette sidestream smoke (SS) have successfully duplicated several of these disease conditions in laboratory animals, particularly the effects of SS on fetal growth, lung maturation, and altered airway reactivity. The availability of animal models may open the way to fruitful experimental studies on mechanisms that help us to better understand disease.
-
-
-
TISSUE RENIN-ANGIOTENSIN SYSTEM:A Site of Drug Action?
Vol. 37 (1997), pp. 53–69More Less▪ AbstractIn this review, we present background material that provides partial support for a tissue renin-angiotensin system (RAS). Evidence for the existence of this system relied in part the use of drugs, which has entailed using low doses or concentrations of angiotensin-converting enzyme inhibitors, renin inhibitors, and angiotensin antagonists to block the RAS in vascular beds and in isolated arteries or organs.
Other evidence for a tissue RAS has depended upon measurements of the components of the system, i.e. enzymes, substrates, and mRNAs for these proteins. All of these components were first believed to be present in the heart and blood vessels; however, it is now known that renin in the circulating blood derived from the kidney is used for the local synthesis of angiotensins.
The main emphasis of the review is on the renal RAS because it is believed that the local RAS is most prominent in this organ. The renal RAS is probably involved in the long- rather than short-term regulation of renal vascular resistance and maintenance of normal blood pressure through the regulation of sodium reabsorption.
-
-
-
STRUCTURE-BASED DRUG DESIGN:Computational Advances
Vol. 37 (1997), pp. 71–90More Less▪ AbstractStructure-based computational methods continue to enhance progress in the discovery and refinement of therapeutic agents. Several such methods and their applications are described. These include molecular visualization and molecular modeling, docking, fragment methods, 3-D database techniques, and free-energy perturbation. Related issues that are discussed include the use of simplified potential energy functions and the determination of the positions of tightly bound waters. Strengths and weaknesses of the various methods are described.
-
-
-
PROTEIN TARGETS OF XENOBIOTIC REACTIVE INTERMEDIATES
Vol. 37 (1997), pp. 91–117More Less▪ AbstractMany xenobiotics are metabolically activated to electrophilic intermediates that form covalent adducts with proteins; the mechanism of toxicity is either intrinsic or idiosyncratic in nature. Many intrinsic toxins covalently modify cellular proteins and somehow initiate a sequence of events that leads to toxicity. Major protein adducts of several intrinsic toxins have been identified and demonstrate significant decreases in enzymatic activity. The reactivity of intermediates and subcellular localization of major targets may be important in the toxicity. Idiosyncratic toxicities are mediated through either a metabolic or immune-mediated mechanism. Xenobiotics that cause hypersensitivity/autoimmunity appear to have a limited number of protein targets, which are localized within the subcellular fraction where the electrophile is produced, are highly substituted, and are accessible to the immune system. Metabolic idiosyncratic toxins appear to have limited targets and are localized within a specific subcellular fraction. Identification of protein targets has given us insights into mechanisms of xenobiotic toxicity.
-
-
-
TRANSGENIC ANIMALS AS NEW APPROACHES IN PHARMACOLOGICAL STUDIES
Vol. 37 (1997), pp. 119–141More Less▪ AbstractTransgenic animals are becoming useful tools for pharmacological studies. The use of transgenic technology raises two types of questions, “How are transgenic animals made?” and “What types of pharmacological questions can be answered using transgenic technologies?” Answers to these questions are discussed in this review. The production of animals with specific genetic alteration can be achieved by two strategies. The first involves the simple addition of DNA sequences to the chromosomes. The second strategy is to select particular genetic loci for site-specific changes. There are two well-established procedures for simple introduction of DNA into an animal genome, pronuclear DNA injection and transduction using a retrovirus. In contrast, methods for targeting specific DNA sequences to definite sites in the chromosomes are evolving rapidly. Some of these procedures can be used in combination to make a different variety of gene alterations in animals. Pharmacological studies where transgenic technology has been extensively used are discussed, including studies in the cardiovascular system, the nervous system, the endocrine system, cancer, and toxicology.
-
-
-
THE POTENTIAL OF FARNESYLTRANSFERASE INHIBITORS AS CANCER CHEMOTHERAPEUTICS1
Vol. 37 (1997), pp. 143–166More LessMutant ras oncogenes and alterations in the mitogenic signaling pathways that they regulate are associated with a wide variety of solid tumors and leukemias for which existing chemotherapeutics have limited utility. Of the possible approaches to inhibit Ras function, much attention has focused on a posttranslational modification, farnesylation, which is required for the subcellular localization of Ras to the plasma membrane and is critical to Ras cell-transforming activity. Inhibitors of the enzyme that catalyzes Ras farnesylation, farnesyl-protein transferase (FPTase), have been developed. These compounds inhibit the tumorigenic phenotypes of ras-transformed cells and human tumor cells in cell culture and in animal models. Moreover, FPTase inhibitors have not demonstrated toxicity to normal cells in culture or to normal tissues in mice. FPTase inhibitors are among the first small molecule compounds designed from studies of oncogenes that might serve as novel cancer chemotherapeutics.
-
-
-
G PROTEIN βγ SUBUNITS
Vol. 37 (1997), pp. 167–203More Less▪ AbstractGuanine nucleotide binding (G) proteins relay extracellular signals encoded in light, small molecules, peptides, and proteins to activate or inhibit intracellular enzymes and ion channels. The larger G proteins, made up of Gαβγ heterotrimers, dissociate into Gα and Gβγ subunits that separately activate intracellular effector molecules. Only recently has the Gβγ subunit been recognized as a signal transduction molecule in its own right; Gβγ is now known to directly regulate as many different protein targets as the Gα subunit. Recent X-ray crystallography of Gα, Gβγ, and Gαβγ subunits will guide the investigation of structure-function relationships.
-
-
-
PHARMACOLOGY AND FUNCTIONS OF METABOTROPIC GLUTAMATE RECEPTORS
Vol. 37 (1997), pp. 205–237More Less▪ AbstractIn the mid to late 1980s, studies were published that provided the first evidence for the existence of glutamate receptors that are not ligand-gated cation channels but are coupled to effector systems through GTP-binding proteins. Since those initial reports, tremendous progress has been made in characterizing these metabotropic glutamate receptors (mGluRs), including cloning and characterization of cDNA that encodes a family of eight mGluR subtypes, several of which have multiple splice variants. Also, tremendous progress has been made in developing new highly selective mGluR agonists and antagonists and toward determining the physiologic roles of the mGluRs in mammalian brain. These findings have exciting implications for drug development and suggest that the mGluRs provide a novel target for development of therepeutic agents that could have a significant impact on neuropharmacology.
-
-
-
PHARMACOLOGY OF NEUROTROPHIC FACTORS
Vol. 37 (1997), pp. 239–267More Less▪ AbstractThe field of neurotrophic factor pharmacology emerged during the past decade with the discovery that these proteins can counteract neuronal atrophy and death in the adult nervous system. These concepts are being tested in clinical trials. Therapeutic use of neurotrophic proteins seems practical for diseases of the peripheral nervous system (PNS), where they can be given by systemic administration. For diseases of the CNS, special administration strategies will have to be developed to deliver the neurotrophic factors into the brain. The development of small molecule mimetics represents an alternative approach that is actively pursued to provide brain-penetrant neurotrophics.
-
-
-
MOLECULAR MECHANISMS OF GENETIC POLYMORPHISMS OF DRUG METABOLISM
Vol. 37 (1997), pp. 269–296More Less▪ AbstractOne of the major causes of interindividual variation of drug effects is genetic variation of drug metabolism. Genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups in the population that differ in their ability to perform certain drug biotransformation reactions. Polymorphisms are generated by mutations in the genes for these enzymes, which cause decreased, increased, or absent enzyme expression or activity by multiple molecular mechanisms. Moreover, the variant alleles exist in the population at relatively high frequency. Genetic polymorphisms have been described for most drug metabolizing enzymes. The molecular mechanisms of three polymorphisms are reviewed here.
The acetylation polymorphism concerns the metabolism of a variety of arylamine and hydrazine drugs, as well as carcinogens by the cytosolic N-acetyltransferase NAT2. Seven mutations of the NAT2 gene that occur singly or in combination define numerous alleles associated with decreased function.
The debrisoquine-sparteine polymorphism of drug oxidation affects the metabolism of more than 40 drugs. The poor metabolizer phenotype is caused by several “loss of function” alleles of the cytochrome P450 CYP2D6 gene. On the other hand, “ultrarapid” metabolizers are caused by duplication or amplification of an active CYP2D6 gene. Intermediate metabolizers are often heterozygotes or carry alleles with mutations that decrease enzyme activity only moderately.
The mephenytoin polymorphism affects the metabolism of mephenytoin and several other drugs. Two mutant alleles of CYP2C19 have so far been identified to cause this polymorphism.
These polymorphisms show recessive transmission of the poor or slow metabolizer phenotype, i.e. two mutant alleles define the genotype in these individuals. Simple DNA tests based on the primary mutations have been developed to predict the phenotype. Analysis of allele frequencies in different populations revealed major differences, thereby tracing the molecular history and evolution of these polymorphisms.
-
-
-
THE ROLE OF THEhsp90-BASED CHAPERONE SYSTEM IN SIGNAL TRANSDUCTION BY NUCLEAR RECEPTORS AND RECEPTORS SIGNALING VIA MAP KINASE
Vol. 37 (1997), pp. 297–326More Less▪ AbstractThe multicomponent heat-shock protein (hsp) 90–based chaperone system is an ubiquitous protein-folding system in the cytoplasm of eukaryotes. Several signal transduction systems utilize an interaction with hsp90 as an essential component of the signaling pathway. The steroid and dioxin receptors are bound to hsp90 through their hormone-binding domains, and several of them must be bound to hsp90 in order to have a ligand-binding site. The binding of ligands to these receptors promotes their dissociation from hsp90, an event that is the first step in their signaling pathways. Several protein kinases, including the Src and Raf components of the MAP kinase system, are also bound to hsp90. Genetic studies in yeast have demonstrated that hsp90 is required for normal signaling via steroid and dioxin receptors and for the activity of Src in vivo. The hsp90-based chaperone system has been reconstituted from purified components, permitting detailed analysis of the molecular basis of the chaperone's role in signal transduction.
-
-
-
REPERFUSION INJURY AFTER LIVER PRESERVATION FOR TRANSPLANTATION
Vol. 37 (1997), pp. 327–338More Less▪ AbstractPreservation injury remains an obstacle to greater utilization of liver transplantation therapy. Livers can be preserved a maximum of 24 h in University of Wisconsin solution. After longer times, reperfusion precipitates endothelial cell killing and activation of Kupffer cells (liver macrophages). Together, Kupffer cell activation and endothelial cell killing cause microcirculatory disturbances, leukocyte and platelet adhesion, and a systemic inflammatory response after graft implantation. Down-regulation of Kupffer cells with calcium blockers or pentoxifylline improves graft survival, whereas priming with lipopolysaccharide or alcohol worsens survival. Flushing grafts after storage with Carolina rinse solution containing antioxidants, adenosine, calcium blocker, energy substrates, and glycine at pH 6.5 decreases endothelial cell killing, reduces Kupffer cell activation, and improves graft survival. Understanding of the roles of different cells in storage/reperfusion injury forms the basis for strategies to prolong organ storage, improve graft function, and reduce failure of fatty grafts from alcoholic donors.
-
-
-
STRUCTURE-FUNCTION ASPECTS IN THE NITRIC OXIDE SYNTHASES
Vol. 37 (1997), pp. 339–359More Less▪ AbstractResearch on the biological roles of nitric oxide has revealed that it functions as an important signal and effector molecule in a variety of physiologic and pathologic settings. In animals, nitric oxide is synthesized enzymatically from l-arginine through the actions of the nitric oxide synthases (NOSs). The three known NOS isoforms are all dimeric, bi-domain enzymes that contain iron protoporphyrin IX, flavin adenine dinucleotide, flavin mononucleotide, and tetrahydrobiopterin as bound prosthetic groups. This chapter summarizes information regarding the structure-function aspects of the NOSs, which includes composition of the domains, the protein residues and regions involved in prosthetic group binding, catalytic properties of the domains, the relationship between dimeric structure and prosthetic group binding and function, and factors that control assembly of NOS in cells. A general model for NOS structure and assembly is presented.
-
-
-
MOLECULAR DETERMINANTS OF DRUG BINDING AND ACTION ON L-TYPE CALCIUM CHANNELS
Vol. 37 (1997), pp. 361–396More Less▪ AbstractThe crucial role of L-type Ca2+ channels in the initiation of cardiac and smooth muscle contraction has made them major therapeutic targets for the treatment of cardiovascular disease. L-type channels share a common pharmacological profile, including high-affinity voltage- and frequency-dependent block by the phenylalkylamines, the benz(othi)azepines, and the dihydropyridines. These drugs are thought to bind to three separate receptor sites on L-type Ca2+ channels that are allosterically linked. Results from different experimental approaches implicate the IIIS5, IIIS6, and IVS6 transmembrane segments of the α1 subunits of L-type Ca2+ channels in binding of all three classes of drugs. Site-directed mutagenesis has identified single amino acid residues within the IIIS5, IIIS6, and IVS6 transmembrane segments that are required for high-affinity binding of phenylalkylamines and/or dihydropyridines, providing further support for identification of these transmembrane segments as critical elements of the receptor sites for these two classes of drugs. The close proximity of the receptor sites for phenylalkylamines, benz(othi)azepines, and dihydropyridines raises the possibility that individual amino acid residues may be required for high-affinity binding of more than one of these ligands. Therefore, we suggest that phenylalkylamines and dihydropyridines bind to different faces of the IIIS6 and IVS6 transmembrane segments and, in some cases, bind to opposite sides of the side chains of the same amino acid residues. The results support the domain interface model for binding and channel modulation by these three classes of drugs.
-
-
-
ENZYMATIC METHYLATION OF ARSENIC SPECIES AND OTHER NEW APPROACHES TO ARSENIC TOXICITY
Vol. 37 (1997), pp. 397–419More Less▪ AbstractArsenic metabolism has typically been studied by administering arsenate or arsenite into animals and humans and then studying the metabolites excreted in the urine. Although such studies have yielded information about the beginning and the end of the metabolic pathways for the metabolism of inorganic arsenic compounds, any statements as to the molecular mechnisms of these reactions have had to be highly speculative. Now that the rabbit and the rhesus monkey liver enzymes that transfer methyl groups from S-adenosylmethionine to arsenite and monomethlyarsonic acid have been purified and the reactions characterized, meaningful investigations of species diversity and polymorphism of these enzymes have become possible. New World animals studied thus far appear to be deficient in or totally lacking these enzymes. Old World animals, with the exception of the chimpanzee, have ample amounts of arsenite and monomethylarsonic acid methyltransferases. A hypothesis that the lack of arsenite methlytransferases may have had an evolutionary advantage for certain species is proposed.
-
-
-
STRUCTURE AND FUNCTION OF THE β3-ADRENERGIC RECEPTOR
Vol. 37 (1997), pp. 421–450More Less▪ AbstractThe β3 subtype of adrenaline and noradrenaline receptors has now been extensively characterized at the structural and functional levels. Ligand binding and adenylyl cyclase activation studies helped define a β-adrenergic profile that is quite distinct from that of the β1-and β2-adrenergic receptors, but strongly reminiscent of most of the “atypical” responses reported in earlier pharmacologic studies.
Human, other large mammal, and rodent receptors share most of the characteristic β3 properties, although obvious species-specific differences have been identified. Recently, the incidence of a naturally occurring variant of the human β3-adrenergic receptor was shown to be correlated with hereditary obesity in Pima Indians and in Japanese individuals, and in Western obese patients with increased dynamic capacity to add on weight and develop non–insulin-dependent diabetes mellitus (NIDDM). A mild weight increase was also shown to develop in female, but not male, mice in which the β3 receptor gene was disrupted.
Taken together, these results now provide a consistent picture of an important role of the β3-adrenoceptor in the regulation of lipid metabolism and as an obvious target for drugs to treat some forms of obesity.
-
-
-
MEDICATION COMPLIANCE AS A FEATURE IN DRUG DEVELOPMENT
Vol. 37 (1997), pp. 451–475More Less▪ AbstractWell-designed clinical trials maximize the information that can be obtained regarding the clinical pharmacology of a drug and, in turn, can streamline and enhance the drug development process. Until recently, little emphasis has been placed on integrating the role of variability in individual patterns of drug-taking into the drug development process.
With the use of electronic monitoring, the temporal relationship between an individual's pattern of dosing and the prescribed regimen may be examined, and individual drug exposure may be estimated based on the actual history of dosing. As a result, accurate estimation of exposure-response relationships (or surrogate markers of response) can be obtained. Considerations in the design of clinical trials must therefore be expanded to include appropriate methods to measure compliance, sufficient frequency of monitoring to allow the time course of response to be mapped, and the use of statistically valid methods of data analysis.
-
-
-
ESTROGENS AND ATHEROSCLEROSIS
Vol. 37 (1997), pp. 477–515More Less▪ AbstractEstrogens prevent heart disease in women and have also been shown to retard atherogenesis in animal models. Estrogens may act at several steps in the atherogenic process to prevent cardiovascular disease. Some of the benefits of estrogens can be ascribed to their ability to favorably alter the lipoprotein profile, i.e. increase high-density lipoprotein and decrease low-density lipoprotein, and also to their ability to prevent oxidative modification of low-density lipoprotein. Other beneficial effects of estrogens include direct actions on the vascular endothelium and vascular smooth muscle, leading to a decrease in the expression of adhesion molecules involved in monocyte adhesion to endothelial cells, and to a decrease in certain chemokines involved in monocyte migration into the subendothelial space. Estrogens may also affect the later stages of atherogenesis. Finally, estrogens may modify the behavior of atherosclerotic vessels by altering their reactivity and thereby promoting vasodilation, and this may also partly account for their ability to prevent clinical events due to cardiovascular disease.
-
-
-
THE HEME OXYGENASE SYSTEM:A Regulator of Second Messenger Gases
Vol. 37 (1997), pp. 517–554More Less▪ AbstractThe heme oxygenase (HO) system consists of two forms identified to date: the oxidative stress–inducible protein HO-1 (HSP32) and the constitutive isozyme HO-2. These proteins, which are different gene products, have little in common in primary structure, regulation, or tissue distribution. Both, however, catalyze oxidation of heme to biologically active molecules: iron, a gene regulator; biliverdin, an antioxidant; and carbon monoxide, a heme ligand. Finding the impressive heme-degrading activity of brain led to the suggestion that “HO in brain has functions aside from heme degradation” and to subsequent exploration of carbon monoxide as a promising and potentially significant messenger molecule. There is much parallelism between the biological actions and functions of the CO- and NO-generating systems; and their regulation is intimately linked. This review highlights the current information on molecular and biochemical properties of HO-1 and HO-2 and addresses the possible mechanisms for mutual regulatory interactions between the CO- and NO-generating systems.
-
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)