Showing papers in "Annual Review of Pharmacology and Toxicology in 1998"

Cyclooxygenases 1 and 2

Abstract: Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer’s disease.

The role of receptor kinases and arrestins in g protein–coupled receptor regulation

Abstract: G protein-coupled receptors (GPRs) play a key role in controlling hormonal regulation of numerous second-messenger pathways. However, following agonist activation, most GPRs rapidly lose their ability to respond to hormone. For many GPRs, this process, commonly referred to as desensitization, appears to be primarily mediated by two protein families: G protein-coupled receptor kinases (GRKs) and arrestins. GRKs specifically bind to the agonist-occupied receptor, thereby promoting receptor phosphorylation, which in turn leads to arrestin binding. Arrestin binding precludes receptor/G protein interaction leading to functional desensitization. Many GPRs are then removed from the plasma membrane via clathrin-mediated endocytosis. Recent studies have implicated endocytosis in the resensitization of GPRs and have linked both GRKs and arrestins to this process. In this review, we discuss the role of GRKs and arrestins in regulating agonist-specific signaling and trafficking of GPRs.

In vitro and in vivo drug interactions involving human cyp3a

Abstract: Cytochrome P4503A (CYP3A) is importantly involved in the metabolism of many chemically diverse drugs administered to humans. Moreover, its localization in high amounts both in the small intestinal epithelium and liver makes it a major contributor to presystemic elimination following oral drug administration. Drug interactions involving enzyme inhibition or induction are common following the coadministration of two or more CYP3A substrates. Studies using in vitro preparations are useful in identifying such potential interactions and possibly permitting extrapolation of in vitro findings to the likely in vivo situation. Even if accurate quantitative predictions cannot be made, several classes of drugs can be expected to result in a drug interaction based on clinical experience. In many instances, the extent of such drug interactions is sufficiently pronounced to contraindicate the therapeutic use of the involved drugs.

THE MAMMALIAN CARBOXYLESTERASES: From Molecules to Functions

Abstract: Multiple carboxylesterases (EC 3.1.1.1) play an important role in the hydrolytic biotransformation of a vast number of structurally diverse drugs. These enzymes are major determinants of the pharmacokinetic behavior of most therapeutic agents containing ester or amide bonds. Carboxylesterase activity can be influenced by interactions of a variety of compounds either directly or at the level of enzyme regulation. Since a significant number of drugs are metabolized by carboxylesterase, altering the activity of this enzyme class has important clinical implications. Drug elimination decreases and the incidence of drug-drug interactions increases when two or more drugs compete for hydrolysis by the same carboxylesterase isozyme. Exposure to environmental pollutants or to lipophilic drugs can result in induction of carboxylesterase activity. Therefore, the use of drugs known to increase the microsomal expression of a particular carboxylesterase, and thus to increase associated drug hydrolysis capacity in humans, requires caution. Mammalian carboxylesterases represent a multigene family, the products of which are localized in the endoplasmic reticulum of many tissues. A comparison of the nucleotide and amino acid sequence of the mammalian carboxylesterases shows that all forms expressed in the rat can be assigned to one of three gene subfamilies with structural identities of more than 70% within each subfamily. Considerable confusion exists in the scientific community in regards to a systematic nomenclature and classification of mammalian carboxylesterase. Until recently, adequate sequence information has not been available such that valid links among the mammalian carboxylesterase gene family or evolutionary relationships could be established. However, sufficient basic data are now available to support such a novel classification system.

Cannabinoid receptors and their endogenous agonists.

Abstract: ▪ Abstract Marijuana has been in use for over 4000 years as a therapeutic and as a recreational drug. Within the past decade, two cannabinoid receptor types have been identified, their signal transduction characterized, and an endogenous lipid agonist isolated from mammalian tissues. The CB1 cannabinoid receptor is widely distributed in mammalian tissues, with the highest concentrations found in brain neurons. CB1 receptors are coupled to modulation of adenylate cyclase and ion channels. The CB2 receptor is found in cells of the immune system and is coupled to inhibition of adenylate cyclase. Both receptor types selectively bind Δ9-THC, the active principle in marijuana, and anandamide (arachidonylethanolamide), an endogenous cannabimimetic eicosanoid. Progress is being made in the development of novel agonists and antagonists with receptor subtype selectivity, mice with genetic deletion of the cannabinoid receptors, and receptor-specific antibodies, which should help in providing a better understanding o...

Quantitative prediction of in vivo drug clearance and drug interactions from in vitro data on metabolism, together with binding and transport

Abstract: It is of great importance to predict in vivo pharmacokinetics in humans based on in vitro data. We summarize recent findings of the quantitative prediction of the hepatic metabolic clearance from in vitro studies using human liver microsomes, hepatocytes, or P450 isozyme recombinant systems. Furthermore, we propose a method to predict pharmacokinetic alterations caused by drug-drug interactions that is based on in vitro metabolic inhibition studies using human liver microsomes or human enzyme expression systems. Although we attempt to avoid the false negative prediction, the inhibitory effect was underestimated in some cases, indicating the possible contribution of the active transport into hepatocytes and/or interactions at the processes other than the hepatic metabolism, such as the metabolism and transport processes during gastrointestinal absorption.

Mechanisms of action of bisphosphonates.

Abstract: Bisphosphonates (BPs) are pyrophosphate analogs in which the oxygen bridge has been replaced by carbon and diverse carbon side chains have generated a large family of compounds. Several are potent inhibitors of bone destruction (resorption) and are in clinical use for the treatment and prevention of osteoporosis, Paget's disease, hypercalcemia caused by malignancy, tumor metastases in bone, and other bone ailments. Selective action on bone is based on the binding of the BP moiety to the bone mineral. The molecular mode of action of BPs, which may differ from compound to compound, is unknown. However, at the tissue level, all BPs inhibit bone destruction and lead to an increase in bone mineral density by decreasing bone resorption and bone turnover. At the cellular level, the ultimate target of BP action is the osteoclast, the bone resorbing cell. In vitro evidence shows BP inhibition of osteoclast formation, via action on osteoblasts, and there is in vitro and in vivo evidence for BP inhibition of osteoclast activity. There is in vivo and in vitro evidence for increased apoptosis. The relative contribution of these various effects on the therapeutic action of BPs remains to be established. At the molecular level, it is not known if BPs act on a single or multiple targets. Enzymes in the cholesterol biosynthesis pathway and protein tyrosine phosphatases were shown to be inhibited by BPs.

Ethnopharmacology of mexican asteraceae (compositae)

Abstract: ▪ Abstract Traditional herbal remedies have increased in popularity in Europe and the United States in recent years but have always been important to people living in rural Mexico and to their Mexican American/Chicano descendants in the United States. Mexican American patients will often be ingesting herbal teas at the same time that they are being treated for their ailments with antibiotics or antiinflammatory agents. The plant family Asteraceae (Compositae) has contributed the largest number of plants to this pharmacopoeia; the reasons for the importance of this family include its large number of species in Mexico and its wide array of natural products that are useful in the treatment of the maladies that have afflicted the inhabitants of rural Mexico. These natural products include sesquiterpene lactones, polyacetylenes, alkaloids, monoterpenes, and various phenolics such as flavonoids. In this review, we emphasize the sesquiterpene lactones, a large group of compounds with antiinflammatory properties ...

Role of organic cation transporters in drug absorption and elimination

Abstract: Organic cation transporters are critical in drug absorption, targeting, and disposition. It has become increasingly clear that multiple mechanisms are involved in organic cation transport in the key tissues responsible for drug absorption and disposition: the kidney, liver, and intestine. In this review, we discuss current models of transepithelial flux of organic cations in these three tissues. Particular emphasis is placed on the more recent molecular studies that have paved the way for a more complete understanding of the physiological and pharmacological roles of the organic cation transporters. Such information is essential in predicting pharmacokinetics and pharmacodynamics and in the design and development of cationic drugs.

Neuronal injury associated with HIV-1: approaches to treatment.

Abstract: Mounting evidence suggests that cognitive dysfunction developing as a result of HIV-1 infection is mediated at least in part by generation of excitotoxins and free radicals in the brain. This syndrome is currently designated HIV-1-associated cognitive/motor complex, was originally termed the AIDS Dementia Complex, and for simplicity, is called AIDS dementia in this review. Recently, brains of patients with AIDS have been shown to manifest neuronal injury and apoptotic-like cell death. How can HIV-1 result in neuronal damage if neurons themselves are only rarely, if ever, infected by the virus? Experiments from several different laboratories have lent support to the existence of HIV- and immune-related toxins in a variety of in vitro and in vivo paradigms. In one recently defined pathway to neuronal injury, HIV-infected macrophages and microglia, or immune-activated macrophages and astrocytes (activated by the shed HIV-1 envelope protein, gp120, or other viral proteins and cytokines), appear to secrete excitants and neurotoxins. These substances may include arachidonic acid, platelet-activating factor, free radicals (NO. and O2.-), glutamate, quinolinate, cysteine, amines, and as yet unidentified factors emanating from stimulated macrophages and reactive astrocytes. A final common pathway for neuronal susceptibility is operative, similar to that observed in stroke and several neurodegenerative diseases. This mechanism involves excessive activation of N-methyl-D-aspartate (NMDA) receptor-operated channels, with resultant excessive influx of Ca2+ and the generation of free radicals, leading to neuronal damage. With the very recent development of clinically tolerated NMDA antagonists, there is hope for future pharmacological intervention.

FROM GABAA RECEPTOR DIVERSITY EMERGES A UNIFIED VISION OF GABAergic INHIBITION

Abstract: Transmitter receptor diversity often indicates differences in transmitter receptor transduction mechanisms. This is not the case for gamma-aminobutyric acid subtype A (GABAA) receptor subtypes despite the presence of 16 genes to encode the 5 families of native GABAA receptor subtypes. Similar considerations apply to GABAC receptors and GABAB receptors. Both GABAA and GABAB receptors cause hyperpolarization of neuronal membranes and inhibition of neuronal excitability, but their mechanisms differ. GABAB receptors involve an efflux of K+ rather than an influx of Cl-, as in the case of GABAA and GABAC receptors. The stimulation of GABAA receptors can sometimes cause depolarization by Cl- efflux; this efflux is not the result of a transduction mechanism modification, but of Cl(-)-concentration gradient modification. Presumably, GABAA receptor diversity is directly linked to the inhibitory activity of basket cells and other interneuron axons, each innervating several postsynaptic neurons (cortical and hippocampal pyramidal cells for instance). Since the role of this inhibition is to entrain hippocampal and cortical pyramidal neurons into columnary activity, the GABAA receptor diversification may be a mechanism expressed by these postsynaptic neuron populations that uses different GABA potencies to synchronize pyramidal neurons into columnary activity. Thus, GABA potency variability, which emerges from GABAA receptor diversity, plays a unifying role in the intrinsic functional mechanism of laminated structures. GABAA receptor structural differences also play a role in diazepam tolerance, which is a mechanism operative in neuronal circuit adaptation to the extreme amplification of GABA-gated Cl- current intensities. Partial agonists (such as imidazenil), which modestly amplify GABA action at many GABAA receptor subtypes, fail to cause tolerance, dependence, ataxia, or ethanol and barbiturate potentiation. Partial agonists might become a new class of anxiolytic and anticonvulsant drugs that are virtually devoid of the side effects that cause serious concerns in the clinical use of full allosteric positive modulators of GABA action, such as diazepam, alprazolam, triazolam, and others. None of the above can be used as anticonvulsants because of an extremely high tolerance liability. When there is tolerance to diazepam, signs of sensitization to proconvulsive action are exhibited simultaneously. After tolerance, associated changes in GABAA recepter subtype expression are virtually reversed in 72 h. Also, 96 h after termination of long-term diazepam treatment, rats exhibit anxiety and are more sensitive to kainic acid-elicited convulsions. At the same time, these rats have an increase in brain expression of GLuR1, R2, and R3. It is believed that the supersensitivity to kainic acid, convulsions and anxiety, and the increased expression of GLuR1, R2, and R3 may be parts of the mechanism of diazepam dependence.

Predictive value of in vitro model systems in toxicology

Abstract: The application of in vitro model systems to evaluate the toxicity of xenobiotics has significantly enhanced our understanding of drug- and chemical-induced target toxicity. From a scientific perspective, there are several reasons for the popularity of in vitro model systems. From the public perspective, in vitro model systems enjoy increasing popularity because their application may allow a reduction in the number of live animals employed in toxicity testing. In this review, we present an overview of the use of in vitro model systems to investigate target organ toxicity of drugs and chemicals, and provide selective examples of these model systems to better understand cutaneous and ocular toxicity and the role of drug metabolism in the hepatotoxicity of selected agents. We conclude by examining the value and use of in vitro model systems in industrial development of new pharmaceutical agents.

Glutathione-dependent bioactivation of haloalkenes

Abstract: ▪ Abstract Several halogenated alkenes are nephrotoxic in rodents A mechanism for the organ-specific toxicity of these compounds to the kidney has been elucidated The mechanism involves hepatic glutathione conjugation to dihaloalkenyl or 1,1-difluoroalkyl glutathione S-conjugates, which are cleaved by γ-glutamyltransferase and dipeptidases to cysteine S-conjugates Haloalkene-derived cysteine S-conjugates may have four fates in the organism: (a) They may be substrates for renal cysteine conjugate β-lyases, which cleave them to form reactive intermediates identified as thioketenes (chloroalkene-derived S-conjugates), thionoacyl halides (fluoroalkene-derived S-conjugates not containing bromide), thiiranes, and thiolactones (fluoroalkene-derived S-conjugates containing bromine); (b) cysteine S-conjugates may be N-acetylated to excretable mercapturic acids; (c) they may undergo transamination or oxidation to the corresponding 3-mercaptopyruvic acid S-conjugate; (d) finally, oxidation of the sulfur atom in h

The pharmacology and toxicology of polyphenolic-glutathione conjugates

Abstract: Polyphenolic-glutathione (GSH) conjugates and their metabolites retain the electrophilic and redox properties of the parent polyphenol. Indeed, the reactivity of the thioether metabolites frequently exceeds that of the parent polyphenol. Although the active transport of polyphenolic-GSH conjugates out of the cell in which they are formed will limit their potential toxicity to those cells, once within the circulation they can be transported to tissues that are capable of accumulating these metabolites. There are interesting physiological similarities between the organs that are known to be susceptible to polyphenolic-GSH conjugate-mediated toxicity. In addition, the frequent localization of gamma-glutamyl transpeptidase to cells separating the circulation from a second fluid-filled compartment coincides with tissues that are susceptible either to polyphenolic-GSH conjugate-induced toxicity or to quinone and reactive oxygen species-induced toxicity. Polyphenolic-GSH conjugates therefore contribute to the nephrotoxicity, nephrocarcinogenicity, and neurotoxicity of a variety of polyphenols.

Insights from in vivo modification of adrenergic receptor gene expression

Abstract: ▪ Abstract Adrenergic receptors are key targets within the autonomic nervous system, regulating a wide variety of physiological processes. The ability to modify adrenergic receptor expression patterns in vivo has added a powerful new tool to the functional analysis of these receptors. Modification of adrenergic receptor gene expression by overexpression, genetic ablation, or site-specific mutation has added new insight to models of receptor coupling behavior, pharmacology, and subtype-specific physiological function. This review highlights some of the recent advances resulting from such genetic approaches to the study of adrenergic receptors.

Signal transduction in environmental neurotoxicity

Abstract: Signal transduction is the process by which specific information is transferred from the cell surface to the cytosol and ultimately to the nucleus, leading to changes in gene expression. Since these chains of biochemical and molecular steps control the normal function of each cell, disruption of these processes would have a significant impact on cell physiology. Some of the major signal transduction pathways are briefly reviewed. The interactions of four chemicals (lead, ethanol, polychlorinated biphenyls, and trimethyltin) with different cell signaling systems, particularly the phospholipid hydrolysis/protein kinase C pathway, are discussed. The possible causal relationship of such cellular and molecular interactions with known signs and symptoms of neurotoxicity are highlighted.

Interactions between hormones and chemicals in breast cancer

Abstract: ▪ Abstract Development of breast cancer in women is dependent on diverse factors, including genetic predisposition, exposure to both exogenous and endogenous chemicals, which can modulate initiation, promotion and progression of this disease, and the timing of exposure to these agents Several compounds—including 16α-hydroxyestrone (16α-OHE1), catecholestrogens, and aromatic amines—have been proposed as initiators of mammary carcinogenesis in humans; however, their role as genotoxins is unconfirmed Lifetime exposure to estrogens has been established as an important risk factor for breast cancer, and it has been suggested that xenoestrogens may directly add to the hormonal risk or indirectly increase risk by decreasing 2-hydroxyestrone (2-OHE1)/16α-OHE1 metabolite ratios Results of recent studies suggest that chemical-induced modulation of 2-OHE1/16α-OHE1 metabolite ratios is not predictive of xenoestrogens or mammary carcinogens Moreover, based on current known dietary intakes of natural and xenoestrog

A quest for erythropoietin over nine decades

Abstract: The major research accomplishments of the author are described from the time of his PhD thesis work on the mechanism of cobalt polycythemia to the present day. His early work on the quest for the cell that produces erythropoietin (Epo) to his current work on oxygen sensing and signal transduction pathways involved in erythropoietin gene expression are reported. He describes his main research interest in the mechanism of cobalt polycythemia between 1954 and 1962 and his research on how hormones such as the glucocorticoids function in the regulation of erythropoiesis (1956-1962). His major findings during this period were the discovery that hydrocortisone and corticosterone stimulated erythropoiesis (1958) and that cobalt increased erythropoietin production in the isolated perfused dog kidney (1961). He describes how he was led astray in some of his early studies on the cells in the kidney that produce erythropoietin, because of the less-developed technology available to him at that time; and how in situ hybridization and other molecular biology techniques enabled him to confirm some of the earlier work in mice by other investigators that interstitial cells in the kidney were the site of production of erythropoietin in the primate. His work in the controversial area of the mechanism of the anemia of end-stage renal disease is described in detail, as it pertains to Epo deficiency and suppressed erythroid progenitor cell response to Epo. He also discusses his recent work on signal transduction pathways (hypoxia, nitric oxide, adenosine, and C kinase) in oxygen sensing and Epo gene expression.

Growth hormone as therapy for older men and women

Abstract: ▪ Abstract Progressive deficits in the growth hormone (GH)/insulin-like growth factor I axis may contribute to the acquired biochemical, body composition, and functional changes of normal human aging, but they do not offer a sole, or even a major explanation for these changes. The concept that GH “replacement” would materially benefit the daily function of older men and women finds little support in the results of the controlled clinical trials that have been reported. GH, either as monotherapy or in combination with antiresorptive medication, does not offer a clinically useful improvement in bone mass, and it is difficult to find a rationale for its use in the treatment of osteoporosis. GH may yet prove to be a useful agent for older men and women in the management of other clinical syndromes, such as visceral obesity, but conclusions in this area await compelling evidence. For the time being, potential benefits of GH in older men and women must be viewed with skepticism, and use of this agent outside th...