Showing papers in "Annual Review of Pharmacology and Toxicology in 1983"

Superoxide Radical: An Endogenous Toxicant

Abstract: The Two Faces of Oxygen Molecular oxygen is both benign and malign On the one hand it provides enormous advantages and on the other it imposes a universal toxicity This toxicity is largely due to the intermediates of oxygen reduction, ie 0;, H202, and OH·, and any organism that avails itself of the benefits of oxygen does so at the cost of maintaining an elaborate system of defenses against these intermediates We will here concern ourselves with the superoxide dismutases which, by catalytically scavenging 0;, provide a defense against it and against any reactive radical species which can be derived from it

Cardiovascular Effects of Endogenous Opiate Systems

Abstract: Opiates are among the oldest pharmacological substances known to man; their analgesic, euphoric, and addictive effects have been traditional focal points for opiate research. Without doubt, the cardiovascular effects of opiates have also been apparent to the user or abuser of opiate substances for several centuries. Persons seeking analgesic, euphoric, or antidiarrheal actions from opiate alkaloids have probably noted dizziness upon sudden st,anding due to the orthostatic hypotension these substances produce. His­ torically, however, scientific study on the cardiovascular responses to ad­ ministered opiates has lagged behind other areas of opiate research. This is understandable as, relative to doses required for their analgesic actions in humans, the cardiovascular effects of opiates are less noticeable and, indeed, undesirable. Early studies established that cardiovascular responses to morphine var­ ied among species; both autonomic and histamine-releasing properties con­ tributed to their hypotensive and bradycardic actions (1-5). Generally speaking, morphine was shown to produce prominent effects upon brain­ stem and hypothalamic centers that resulted in increased parasympathetic and decreased sympathetic tone (3-6). These effects upon autonomic out­ flow caused a depression of both heart rate and blood pressure. A resurgence of interest in opiate-cardiovascular interactions followed the discovery of endogenous opiate systems (for review see 7). A family of opioid peptides were found to be located at sites suggesting an autonomic action (8); also, opiate receptors were shown to be densely distributed in the brainstem and hypothalamus in close proximity to cardiovascular centers as well as endogenous opiate pathways (9, to). These anatomical findings

Mechanisms of calcium antagonist-induced vasodilation.

Abstract: Excitation-contraction coupling in smooth and cardiac muscle can be dis­ rupted by a number of organic compounds known collectively as Ca antago­ nists (CAts). In 1964, Fleckenstein (1) provided the first important clue regarding their possible mechanism of action when he noted that the cardiac effects of two of these agents, verapamil and prenylamine, were similar to those of Ca2+ removal from the extracellular space. A few years later, he proposed that CAts exerted their negative inotropic and coronary vasodila­ tor effects by blocking the entry of Ca2+ into the cells (2, 3). The vasodila­ tor and cardiac effects of CAts are having a great impact on cardiovascular medicine; consequently many reviews and monographs on this subject have appeared in the recent past (4--9). The purpose of this review is to provide an in-depth analysis of the mechanisms of action of CAts, rather than to compile an exhaustive survey of the literature. Only when we know how CAts interact with the processes that regulate Ca availability and sensitivity in smooth muscle can we understand why agents that "antagonize" the action of such a universal intracellular messenger can be effectively de­ ployed as selective therapeutic agents in cardiovascular medicine.

Agents that release histamine from mast cells.

Abstract: A fully differentiated mast cell, packed with 500 to 1000 granules, poised for secretion, wants only the appropriate stimulus to release the contained histamine, heparin, and hydrolytic enzymes into the connective tissue. Since the major storage site of histamine in mammalian tissues was located in the mast cell by Riley & West (1), the cell has been a major focus in the study of histamine release. The literature is abundant and there is no dearth of reviews (2-7) and books (8-10) on the mast cell and its histamine-releasing activities. We concentrate in this review on agents of more or less known structure capable of releasing histamine, and attempt to collect information on a range of agents and to evaluate succinctly the available information on their modes of action. The behavior of mast cells in response to a few agents has been studied in considerable detail, and we stress these as archetypes. The important category of IgE-mediated release has recently been reviewed in this series (11) and elsewhere (12, 13) and will not be considered here. Under usual conditions, virtually all of the histamine stored in mast cells is located in the cells' secretory granules (14, 15, 16). These granules in the rat consist of a matrix of heparin and a limited number of proteins (17) of which only two, both mast cell proteases, have been characterized substan­ tially (18, 19). Histamine and several acid hydrolases are weakly associated with the matrix by ionic bonding (20, 21); some unbound histamine may

Dmsa and dmps-water soluble antidotes for heavy metal poisoning

Abstract: This article reviews the pharmacological properties and the uses of two important antidotes for heavy metal poisoning. Meso-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-l-propanesulfonic acid, Na salt (DMPS) are relatively new antidotes-new, that is, to the western world. Although DMSA was introduced originally by Friedheim et al (1) to increase uptake of antimony during schistosomiasis therapy, Liang et al (77) at Shanghai in 1957 were the first to report its effectiveness as an antidote for heavy metal poisoning. The synthesis and some of the metal binding properties of DMPS were reported in 1956 by Petrunkin from Kiev (3). Shortly thereaf­ ter, DMPS became an official drug in the Soviet Union, where it is known as Unithiol (4). Between 1956 and 1975, DMSA and DMPS were studied extensively, at both the basic science and clinical levels, in the People's Republic of China, the Soviet Union, and Japan. Some of these investigations have been cited and can be found in an earlier review (5). In the USA and western Europe, however, these two compounds received very little attention until recently. A paper by Friedheim & Corvi (6) in 1975, dealing with DMSA for the treatment of mercury poisoning, and the recent production and availability of DMPS from Heyl & Co., Berlin, stimulated investigators to "rediscover" and study these two metal-binding agents. DMSA and DMPS are water soluble chemical analogs of dimercaprol (British Anti-Lewisite, BAL). In contrast to BAL, they have less toxicity, greater water solubility, and lim­ ited lipid solubility, and are effective when given orally.

Suicidal destruction of cytochrome P-450 during oxidative drug metabolism.

Abstract: Cytochrome P-450 enzymes catalyze three general types of oxidative reac­ tions: (0) insertion of an oxygen atom into the sigma bond between a hydrogen and a heavier atom (hydroxylation), (b) addition of an oxygen atom across the two ends of a 'IT-bond (epoxidation), and (c) addition of an oxygen atom to a nonbonding electron pair (oxidation). A limited number of reductive reactions are also catalyzed by cytochrome P-450 monooxyge­ nases under appropriate conditions. All cytochrome P-450 enzymes appear to operate by closely related catalytic mechanisms that hinge on activation of molecular oxygen by the prosthetic heme iron atom, although the hemo­ proteins differ, among other things, in their size, amino acid sequence, cellular and organ location, and substrate specificity. Some cytochrome P-450 enzymes, such as the sterol hydroxylases located both in the adrenal gland and in the liver, are primarily engaged in the metabolism or biosyn­ thesis of critical physiological substrates, whereas others are primarily de­ voted to the metabolism of lipophilic drugs and other xenobiotics. The cytochrome P-450 class of enzymes is subject to a variety of regulatory mechanisms that are in tum meshed to the regulation of tributary pathways, such as that of hepatic heme biosynthesis. Therefore, the inhibition or destruction of cytochrome P-450 enzymes by exogenous substrates is of concern not only because it can alter the metabolism of other substances but also because it can interfere with essential physiological processes. Cytochrome P-450 enzymes Can be inhibited by competition between substrates for residence in the active site; by generalized destruction, usually associated with lipid peroxidation; by catalytic activation of substrates to

The Treatment of Acetaminophen Poisoning

Abstract: Acetaminophen has become a very popular over-the-counter analgesic in some countries and as a result it is used increasingly as an agent for self-poisoning. Without treatment only a minority of patients develop severe liver damage and 1 to 2% die in hepatic failure. Until Mitchell and his colleagues discovered the biochemical mechanisms of toxicity in 1973 there was no effective treatment. They showed that the metabolic activation of acetaminophen resulted in the formation of a reactive arylating intermediate, and that hepatic reduced glutathione played an essential protective role by preferential conjugation and inactivation of the metabolite. Early treatment with sulphydryl compounds and glutathione precursors has been dramatically effective in preventing liver damage, renal failure, and death following acetaminophen overdosage. It seems likely that these agents act primarily by stimulating glutathione synthesis. Inhibition of the metabolic activation of acetaminophen is another potential therapeutic approach that has not yet been put to the test clinically. The clinical management of acetaminophen poisoning has been transformed and it is particularly gratifying to have effective treatment based on a well established biochemical mechanism of toxicity. It is likely that effective treatment will be developed for toxicity caused through similar mechanisms by other agents.

Purinergic Neurotransmission and Neuromodulation

Abstract: Conflicting views abound on the peripheral neurotransmitter and neuromodulator roles of purine compounds. Substantial organ- and species-related variations have become apparent. There is, however, a body of compelling evidence for such roles, if not so broad and ubiquitous as those envisioned (7) for the central nervous system. The variations may in part be attributable to the neuroeffector synaptic geometry. The transmitter concentration found at the postsynaptic membrane drops precipitously with increase in the synaptic cleft (85). Where the cleft is narrow, a purine may serve as the primary or sole transmitter (purinergic nerve) and presynaptic modulator. Alternatively, from nonpurinergic (e.g. adrenergic) nerves a purine may be released, possibly ATP by exocytosis, to act as a cotransmitter. It may also serve as pre- and post-synaptic modulator, potentially with a contribution from postsynaptic release (Figure 1). The purine could conceivably diffuse and affect other varicosities. Where the cleft is wide, the postsynaptic concentration of the neurogenic purine may be too low to permit a transmitter or postsynaptic modulator function. The concentration of the nonpurine transmitter may also be insufficient to elicit a significant postsynaptic purine release. The neuronally released purine may, however, presynaptically exert inhibition of transmitter release much as in a narrow cleft. It seems, therefore, that the origin of synaptic purines and their function, be it transmitter, cotransmitter, or modulator, are dictated at least in part by the characteristics of the purine pools, purinergic receptors, and synaptic configuration, which await further assessment.

Asbestos: Mechanisms of Toxicity and Carcinogenicity in the Respiratory Tract

Abstract: "Asbestos" is a generic name for a group of minerals well·known for their adverse effects on the respiratory system. After prolonged periods of inhala· tion, asbestos produced fibrosis of the lung (i.e. asbestosis) and two types of malignancies. Mesothelioma, a tumor of the serosal cells lining the pleural and peritoneal cavities, is an extremely rare cancer in the general population but can account for as many as one in thirty of the malignancies found in asbestos workers (1). The second type of cancer produced by asbestos is bronchogenic carcinoma, a tumor of the epithelial cells lining the upper airways. This cancer occurs with a high incidence in both asbestos workers and smokers in the general population (2). This review considers new experimental approaches, developed mainly in the past decade, that have been aimed at elucidating the mechanisms of asbestos toxicity. First, we review the physicochemical properties of asbes­ tos that relate to biological activity. Subsequently, we discuss the various

The Activity of Sulfonamides and Anions Against the Carbonic Anhydrases of Animals, Plants, and Bacteria

Abstract: For nearly thirty years after the discovery of carbonic anhydrase in red cells and tissues of the animal kingdom (1), susceptibility to inhibition by sul­ fonamides was found to be about the same, whatever the enzyme source. Although no systematic studies were done, tissues as different as human red cells and clam mantle showed similar susceptibility to sulfonamide inhibi­ tion (reviewed in 2); at the time isozymes were not in the forefront, and there seemed to be no special problem at hand. It was found that the plant enzyme was different, requiring some 103-fold greater concentration of acetazolamide, for example, than the 10-8 M needed for 50% inhibition of the animal enzymes thus far studied (3). The first example of very different behavior in animal tissues was discov­ ered accidentally in this laboratory. We found that rats did not respond to acetazolamide in terms of the alterations in hepatic electrolyte excretion known for dog and man (4). After an initial rude dismissal of the possibility that the rat liver enzyme might be different (in all other carbonic anhydrase systems rats behaved normally), we found that this was indeed the case. In male rat liver the KI for acetazolamide was 1()4 times higher than the "standard value." The universe had been disturbed (5), at least a microcosm of it. Meanwhile, work was being done on the differing properties of the two isozymes in primate red cells (and those of certain other species) (6), now designated carbonic anhydrases I and II, the latter having nearly lO-fold

LOCALIZATION OF METABOLIC ACTIVATION AND DEACTIVATION SYSTEMS IN THE LUNG: Significance to the Pulmonary Toxicity of Xenobiotics

Abstract: The lung is a complex organ with a great deal of histological and biochemical heterogeneity. The distribution of systems responsible for the metabolic activation of lung toxins and/or their detoxification can vary substantially from one cell-type to another. This suggests that localized damage by xenobiotics requiring metabolic activation can, at least in part, be attributed to the localization of such systems. Recent advances in the isolation of different lung cell-types in reasonably pure fractions have allowed for investigation of the metabolic capabilities of some individual cell-types. A more complete understanding of the mechanisms of pulmonary metabolic activation and deactivation of toxic chemicals and drugs may contribute to our knowledge of the underlying causes of various pathological processes such as cellular necrosis, fibrosis, emphysema, and cancer, any of which may arise from the interaction of chemical toxins with lung tissue. We hope that this review has drawn attention to some of the newer and less understood aspects of pulmonary activation/deactivation of toxic drugs and chemicals.

Biosynthesis of the Enkephalins and Enkephalin-Containing Polypeptides

Abstract: The biochemical characterization of the enkephalins and the enkephalin-containing polypeptides and their biosynthesis has reached an advanced state. From the structural data showing great similarities between human and beef proenkephalin there is strong evidence for physiological roles for some of the extended enkephalins and for at least two of the ECPs. If, like the different hormones contained within proopiocortin, the different ECPs in proenkephalin perform different coordinate functions, their cosecretion with the catecholamines from the adrenal gland suggests that these functions play a role in the response to stress. It appears that proenkephalin represents another multi-hormone precursor, like proopiocortin, that is processed by proteolysis to yield a variety of peptides active in both the endocrine and nervous systems. The research effort must now turn toward resolving the nature of the physiologic functions these peptides perform.

Transport of organic anions and cations in isolated renal plasma membranes

Abstract: The transepithelial transport in proximal renal tubular cells has been well documented for both organic anions and cations, previously referred to as acids and bases. The latter nomenclature is incorrect as quaternary nitro­ gen-containing compounds are not chemical bases in the strictest sense. The sequence of movement of organic ions is transport across the basolateral membrane, accumulation in the cells, followed by efflux from the cell across the brush border into the tubular fluid (see 1-6), The techniques for demonstrating these phenomena are numerous and have been outlined in reviews by Torretti & Weiner (7) and Rennick (8). They include such in vivo techniques as renal clearance, Sperber technique, stop-flow, retrograde intraureteral injection, and micropuncture. In vitro transport has been studied in renal slices and isolated renal tubules. Collec­ tively these techniques have established that the two systems are separate and distinct and that both groups of compounds are actively secreted by "carrier"-mediated transport. Both anions and cations are capable of being transported "uphill" (movement against a concentration gradient). Each system is saturable, inhibitable by metabolic inhibitors, demonstrates com­ petition between compounds within the same class, and demonstrates bidi­ rectional transport. While all of these findings have generated a great deal of information about the overall sequence of events, they have failed to yield specific information on the relative contributions of the brush border and basolat­ eral membranes to the overall transepithelial phenomena. Therefore, this review emphasizes the contributions made as well as the questions raised

New Peripherally-Acting Oral Analgesic Agents

Abstract: Aspirin was recognized as an analgesic and anti-inflammatory agent even before the advent of modern medicine. It still remains the standard agent in this class; however, many new drugs are seriously challenging its position for both analgesia and anti-inflammatory indications. This review surveys the recent work on the analgesic efficacy and side effects of several new peripherally-acting, orally administered analgesic agents. It focuses on sin­ gle-dose clinical assays using a variety of pain models as this type of study has proven most useful for relative efficacy comparisons.

Prostaglandins and Nonsteroidal Antiinflammatory Drugs in Dysmenorrhea

Abstract: Recognition of a relationship between elevated levels of prostaglandins (PG) and dysmenorrhea represented a major advance. The PGs of most importance in primary dysmenorrhea are assumed to be PGF2alpha and PGE2. Oral contraceptives (OCs) which disrupt the normal sequence of hormonal dominance in the endometrium and reduce menstrual PG production were the therapeutic agent for dysmenorrhea until the introduction of nonsteroidan antiinflammatory drugs (NSAIDs) with PG synthetase in the mid-1970s. 4 groups of NSAIDs have been evaluated: 1) indomethacin 2) the fenamates 3) the arylpropionic acids and 4) aspirin. Ibuprofen and naproxen 2 arylpropionic acids are commonly used to treat dysmenorrhea and have fewer side effects than the other agents. The clinical effectiveness of NSAIDs is ascribed to their inhibition of PG synthestase activity; however little is known about the pharmacology of these drugs. Reduction of menstrual PG release by ibuprofen or naproxen sodium was shown to produce good to excellent relief in 80% of treatment cycles in a clinical trial in contrast to placebo therapy which afforded little or no relief. Moreover in individual subjects there was a positive correlation between the severity of dysmenorrhea and levels of menstrual PG released during the corresponding period. A causal relationship between uterine contractions and dysmenorrheic pain has been demonstrated by other investigators. A current shortcoming of NSAIDs is their lack of specificity. They are assumed to be nonselective agents affecting PG synthesis in all body tissues and inhibiting PG synthesis indiscriminately. Future research efforts should be directed toward development of a more uterine-selective agent that would produce fewer side effects.

Structure-activity relationships of dopamine agonists.

Abstract: In the several years since Blaschko (1) suggested neurohormonal activity for dopamine, several types of chemical compounds have been found to possess dopamine-like actions. This review surveys classes of structures in which putative dopamine agonism has been reported, and cites struc­ ture-activity correlations. Detailed stereochemical aspects of dopamine ago­ nists have been addressed elsewhere (2). A serious problem in dopamine structure-activity studies arises from the large variety of animal models and in vivo and in vitro pharmacological assays utilized to assess dopaminergic effects. Comparable test data in the same animal species using the same biological endpoint and the same crite­ ria for assessment of activity/potency are not available for many agents. Thus, it is frequently not possible to make valid comparisons of actions and potencies among compounds described in the literature, and a caveat must be expressed with respect to the validity of many attempted structure­ activity correlations.

Recent Developments in Mass Spectrometry for the Analysis of Complex Mixtures

Abstract: Analytical chemists faced with complex problems such as food or drug analysis, chemical dump site analysis, or incorporation of xenobiotics and natural toxins into the food chain, require increasingly sophisticated analytical tools. Recent developments in mass spectrometry may be applied to some of these analytical problems. Negative chemical ionization mass spectrometry and to a lesser extent tandem mass spectrometry have passed the stage of expensive curiosities and are now vital screening tools. Negative chemical ionization is a powerful new method for the analysis of complex environmental samples for trace levels of both oxidizing and alkylating agents. Since these compounds comprise a large number of substances known to cause cancer or other environmental health problems, it seems likely that use of NCIMS will continue to grow. Tandem mass spectrometry has several advantages for the analysis of specific organic compounds in complex mixtures. Target compounds can be isolated and identified almost instantaneously at detection limits comparable and identified almost instantaneously at detection limits comparable to GC-MS with minimum sample preparation. A major deterrent to MS/MS is price ($400,000 or more). Also, the operator must know something about the sample and what to look for. Complete characterization of a sample by MS/MS is impractical. In the past, application of mass spectrometry to the determination of molecular weight and structure of polar (or thermally labile) compounds was severely limited. The limitations are due to inability to vaporize samples or to prevent thermal decomposition. The development of desorption chemical ionization, fast atom bombardment, secondary ionization mass spectrometry, and 252Cf plasma desorption mass spectrometry was in an attempt to rectify this situation. Each of the ionization techniques has advantages and limitations. With continued research into actual ionization/desorption process and continued instrumentation development (perhaps with a lower price tag), many of these techniques will become commonplace.

Central control of prolactin and estrogen receptors in rat liver--expression of a novel endocrine system, the hypothalamo-pituitary-liver axis.

Abstract: The many and complex functions of the liver require extensive control mechanisms. Consequently, several liver functions seem to be regulated by the endocrine system. The initial event by which most hormones exert their effects is via association with a specific receptor present in the target tissue (for review see 1, 2). These hormonal receptors are characterized by a narrow ligand specificity and a high-affinity, low-capacity binding. Receptor

Beta receptor blocking agents in the secondary prevention of coronary heart disease

Abstract: In the western world coronary heart disease (CHD) constitutes the single most common cause of death from middle age on in both men and women (1). This fact remains despite a recent decline in mortality from the disease in some countries including the USA (2). The magnitude of the problem has induced planning and realization of a number of trials aimed at reducing mortality and new events. The natural history of CHD is usually divided into two major parts separated by the initial manifestation of the disease. During the period preceding the initial clinical manifestation certain factors have been found to be statistically significantly associated with increased risk of an initial event, i.e. primary risk factors. Measures aimed at these factors are usually included under a common heading, primary prevention. In an analogous way factors associated with increased risk of a second or further events are termed secondary risk factors, and measures aimed at a reduction of these late complications are grouped under the heading secondary prevention. Coronary heart disease has three major clinical manifestations: angina pec­ toris, acute myocardial infarction, and sudden cardiac death, listed in as­ cending order of clinical urgency. Despite widespread availability of cardiopulmonary resuscitation, in some areas few victims of sudden cardiac death had been exposed to secondary prevention, and for a number of reasons, despite the high prevalence of the symptom, there have been very few systematic studies or controlled trials of secondary prevention in angina pectoris. An acute myocardial infarction constitutes a clinical �vent that defines a subcategory of the population that, in addition to be�ng easy to find, has