James J. Kocsis

Arachidonic acid-induced human platelet aggregation and prostaglandin formation☆

Abstract Arachidonic acid and several of its salts caused aggregation of platelets in platelet-rich plasma. Other fatty acids did not cause aggregation when tested under similar conditions. Platelet aggregation induced by arachidonic acid was inhibited by adenosine, β naphthol, non-steroidal anti-inflammatory agents, unsaturated fatty acids and albumin. At concentrations too low to cause aggregation, arachidonic acid enhanced aggregation induced by collagen, ADP or epinephrine. Arachidonic acid caused platelets to form PGE 2 and PGF 2α . However, it failed to induce prostaglandin synthesis or platelet aggregation in plateletrich plasma obtained one hour after the ingestion of a therapeutic dose of aspirin. This effect of aspirin persisted for several days. The significance of these findings in relation to hemostasis and thrombosis is discussed.

Arachidonic Acid Causes Sudden Death in Rabbits

Injection of sodium arachidonate (1.4 milligrams per kilogram) into the marginal ear veins of rabbits caused death within 3 minutes. Histological examination showed platelet thrombi in the microvasculature of the lungs. Rabbits were protected from the lethal effects of arachidonic acid by pretreatment with aspirin. Fatty acids closely related to arachidonic acid did not cause death.

Prostaglandin D2 inhibits the aggregation of human platelets.

Abstract Prostaglandin D2, heretofore considered to be biologically inactive, was found to be more than twice as potent as prostaglandin E1 as an inhibitor of aggregation in human citrated platelet-rich plasma. It was much less potent than prostaglandin E1 in rabbit or rat platelet-rich plasma. This prostaglandin, or a derivative of it, may prove to be of greater value than prostaglandin E1 in maintaining the viability of stored platelets and as an antithrombotic agent.

Formation of an Intermediate in Prostaglandin Biosynthesis and Its Association with the Platelet Release Reaction

A compound that could be converted to prostaglandin F(2alpha) by mild chemical reduction was formed by human platelets in response to arachidonic acid, collagen, or L-epinephrine. It was present in maximal amounts at about 1 min after addition of arachidonic acid or collagen to platelet-rich plasma. Its initial formation appeared to precede platelet aggregation by these agents and was closely correlated with the release of adenine nucleotides and radioactive 5-hydroxytryptamine from platelets. Moreover, the compound was itself found outside the platelets. This compound is probably an endoperoxide intermediate in prostaglandin biosynthesis and may be a trigger for the platelet release reaction.

Current Concepts of Chronic Benzene Toxicity

AbstractThe maladies that have beset mankind throughout history may in general be classified as parasitic (infections, infestations, etc.), nutritional/endocrine disease (hyper- or hypofunctional endocrine organs, etc.), or traumatic injury (accidents, war, etc.). With the development of an industrial society, new forms of disease arose in which people succumbed to illness induced by exposure to toxic materials in the course of their labor. Occupational diseases have been with us for many centuries,1, 2 but the incidence of industrial toxicity increased markedly with the advent of the industrial revolution. Although efforts to protect workers against job-related illness have been vigorous in recent years, economic necessity compels the continued use of hazardous chemicals, and benzene is an excellent case in point. It has been estimated by the National Institute for Occupational Safety and Health that about 2, 000, 000 persons in the national work force have potential exposure to benzene.

Effects of toluene on the metabolism, disposition and hemopoietic toxicity of [3H]benzene.

Abstract The administration of [3H]benzene to mice resulted in the decreased incorporation of 59Fe into red cells and the accumulation of benzene and its metabolites in bone marrow and other tissues. Toluene protected against the benzene-induced depression of red cell 59Fe uptake and reduced the levels of benzene metabolites in bone marrow without affecting the level of benzene in this tissue. The results of this study suggest that toluene exerted its protective effect by inhibiting benzene metabolism and that a metabolite of benzene probably mediates the observed hemopietic toxicity of benzene.

Formation of Prostaglandins during the Aggregation of Human Blood Platelets

Prostaglandins E(2) and F(2alpha) were formed in response to ADP, L-epinephrine, or collagen by human platelets suspended in plasma containing citrate anticoagulant and stirred at 37 degrees C. The prostaglandins formed by platelets in response to collagen were rapidly released and the amounts formed were proportional to the amount of collagen added. The formation of the prostaglandins was associated with the single wave of aggregation induced by collagen or the second wave of aggregation induced by epinephrine. The above findings are discussed with reference to published studies on the biochemical changes occurring during platelet aggregation. It is suggested that the formation and release of prostaglandins is associated with the secretion of endogenous ADP and 5-hydroxytryptamine.

Partial hepatectomy reduces both metabolism and toxicity of benzene.

Removal of 70--80% of the liver reduced both the metabolism and the toxicity of benzene in rats. Metabolism was evaluated by measuring the levels of urinary metabolites in both sham-operated and partially hepatectomized rats given 2200 mg/kg [3H]benzene sc. Toxicity was evaluated by measuring the incorporation of 59Fe into circulating erythrocytes according to the method of Lee et al. The observation that partial hepatectomy decreases benzene metabolism and protects against benzene toxicity indicates that the liver may play a primary role in the development of benzene-induced bone marrow toxicity. The fact that benzene administration also reduces the ability of the liver to regenerate after partial hepatectomy suggests that the regenerating liver may serve as a model system in lieu of the bone marrow for studying the mechanism by which benzene inhibits cell proliferation.

Duration of inhibition of platelet prostaglandin formation and aggregation by ingested aspirin or indomethacin.

Abstract Platelet prostaglandin production was abolished in platelet-rich plasma taken from 4 adult subjects one and 6 hours after ingestion of aspirin or indomethacin. The second wave of epinephrine-induced platelet aggregation was also abolished. Sodium salicylate did not produce these effects. While the effects of aspirin persisted for as long as 2 to 3 days those of indomethacin lasted less than 24 hours.

Benzene metabolism in mouse liver microsomes

Abstract Mouse liver microsomes metabolized benzene more rapidly than microsomes prepared from rat and rabbit liver. Treatment of mice with benzene increased the metabolism of benzene in vitro without increasing cytochrome P-450 concentrations. Conversely, treatment of mice with phenobarbital increased cytochrome P-450 values but did not increase benzene metabolism. Benzene metabolism was inhibited by compounds known to interact with the mixed function oxidase system, e.g., aniline, metyrapone, aminopyrine, SKF-525A and cytochrome c , but not by KCN or 3-amino-1,2,4-triazole. CO also inhibited benzene metabolism and the Warburg partition coefficient was similar to that obtained for other drugs metabolized by cytochrome P-450. Addition of benzene to mouse liver microsomes yielded a type I binding spectrum. Induction with benzene increased the magnitude of the type I spectral change ( ΔE max ) by a factor approximately equal to the increase in benzene metabolism. The evidence suggests that benzene metabolism is mediated by the mixed function oxidase and binding of benzene to cytochrome P-450 is a significant factor in determining the rate of benzene metabolism.