Preparations of two new beta-adrenergic blocking drugs, Zami 1305 [1-(2-nitro-3-methyl-phenoxy)-3-tert-butylaminopropan-2-ol] and Zami 1327 [1-(6-nitro-3-methyl-phenoxy)-3-tert-butylaminopropan-2-ol], were found to be contaminated by expoxides which are direct acting mutagens on TA 100 and TA 1535 in the Salmonella/microsome mutagenicity test. Because of the suggested correlation between mutagenicity and carcinogenicity of a chemical [10,11], beta-adrenergic blocking agents contaminated by mutagenic expoxide impurities may be a health hazard.

Adrenergic beta-Antagonists↗

PubMed1980

Psychotropic drugs: evaluation of mutagenic effect.

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Anti-Anxiety Agents↗

PubMed1978

Mutagenicity of diallate, sulfallate, and triallate and relationship between structure and mutagenic effects of carbamates used widely in agriculture.

In an investigation of the mutagenic properties of 20 carbamate herbicides and fungicides by use of the Salmonella/microsome mutagenicity test as developed by Ames et al. (Mutation Res., 31: 347-364, 1975), we have found that three thiocarbamate compounds, diallate, sulfallate and triallate, are mutagenic in the presence of a liver microsomal fraction on strains TA1535 and TA100. This indicates that the metabolic products of these thiocarbamates are causing base-pair substitutions. Since the 2-chloro-allyl group is common to the three mutagenic compounds but is not common to the 17 nonmutagenic compounds, a metabolic derivative of this group is probably responsible for the mutagenic activity.

Animals↗

PubMedDate not supplied

Species variability in platelet aggregation response to different agonists.

Conflicting data on platelet function in animal species are reported in the literature. In this study, the response of buffalo, horse, pig and sheep platelets to different agonists was assessed. Blood samples were collected from the jugular vein of six healthy subjects of each species and platelet-rich plasma was obtained by centrifugation. Platelet aggregation responses to increasing doses of adenosine 5'-diphosphate (ADP), arachidonic acid, collagen, platelet activating factor (PAF) and ristocetin were measured by a turbidimetric method. Horse platelets were the most responsive to ADP, collagen and PAF, whereas sheep platelets were the most responsive to ristocetin. The response to arachidonic acid varied least between species. PAF was the most effective agonist, inducing a maximum aggregation response at a concentration of 1 micro M for platelets of each species. Conversely, concentrations of ristocetin higher than 1mg/ml induced a maximum aggregation response only with sheep and horse platelets. The different responses of platelets from the four animal species to various agonists may reflect either (1). structural differences (including composition of the platelet membrane and presence of specific agonist receptors), or (2). activation of distinct signalling pathways by the agonist.

Adenosine Diphosphate↗

PubMedDate not supplied

Adhesive properties of platelets from different animal species.

The use of large animals (e.g., pig and sheep) in human medicine, and the need to develop new therapeutic strategies for domestic animal diseases related to platelet disorders, require better characterization of the physiology of animal platelets. In this study, the ability of platelets from buffaloes, horses, pigs and sheep to adhere to immobilized autologous fibrinogen was compared with that of human platelets. Blood samples were collected from the jugular vein of six healthy subjects of each species and platelet-rich plasma (PRP) was obtained by centrifugation. Platelets, isolated by further centrifugation of PRP, were washed by gel-filtration on Sepharose-2B, counted and added to the wells of 96-well plates pre-coated with autologous fibrinogen. After different times of incubation, non-adherent platelets were removed, and the number of adherent platelets was assessed by measuring endogenous acid phosphatase activity. Horse platelets showed the strongest ability to adhere to autologous immobilized fibrinogen, being 1.7-, 3.1- and 2.3-fold more active than human, buffalo and porcine platelets, respectively. Sheep platelets were unable to adhere to autologous immobilized fibrinogen. Platelet activation by adenosine 5-diphosphate (ADP) increased both human and animal platelet adhesive response. ADP-stimulated sheep platelets were able to adhere to autologous immobilized fibrinogen, albeit to a lesser extent than platelets from the other animal species. The observed interspecies variability in adhesive properties of platelets may reflect structural differences, or differences in the availability of the fibrinogen receptor (glycoprotein IIb/IIIa) on the platelet surface.

Acid Phosphatase↗

PubMedDate not supplied

Enhancement by cysteinyl thiols of acetyltransferase-mediated, but not of sulfotransferase-mediated, binding of a pyrolysate-derived N-hydroxyarylamine, 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole, to DNA.

The effect of thiols on the activation of a pyrolysate-derived N-hydroxyarylamine, 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (N-hydroxy-Glu-P-1), was studied in vitro. In hepatic cytosol of rats, [3H]-N-hydroxy-Glu-P-1 bound covalently to calf thymus DNA in the presence of acetyl CoA or 3'-phosphoadenosine-5'-phosphosulfate (PAPS). The extent of the binding of N-hydroxy-Glu-P-1 in a PAPS-dependent system was decreased by the addition of 10 mM glutathione, N-acetyl-L-cysteine, 2-mercaptoethanol or dithiothreitol. However, acetyl CoA-dependent binding of N-hydroxy-Glu-P-1 was stimulated by the addition of 10 mM N-acetyl-L-cysteine (3 fold), L-cysteine (2 fold) or glutathione (1.2 fold), but not 10 mM 2-mercaptoethanol or L-methionine. After hydrolysis of the modified DNA, no difference was detected in the physicochemical properties of the nucleoside adduct formed in the acetyl CoA-supported system with and without thiols. These results indicate that thiols with a cysteine residue are able to affect the activation of carcinogenic heterocyclic arylamines selectively by the modulation of the acetyltransferase-mediated, but not the sulfotransferase-mediated, pathway.

Acetyl Coenzyme A↗

PubMedDate not supplied

Glutathione depletion induced in rat liver fractions by seven pesticides.

Glutathione (GSH) plays a central role in the chemical detoxication. Xenobiotics which induce GSH depletion, either via GSH conjugation or via oxidation of GSH to glutathione disulfide (GSSG), alter the mechanism of natural cellular defence against toxicants. The aim of this study was to evaluate the ability of seven widely used pesticides (Alachlor, Atrazine, Benomyl, Captan, Linuron, Methyl Parathion and Propanil) and/or of their metabolites to deplete GSH in rat liver fractions. In our experimental conditions, Atrazine, Linuron and Propanil failed to interact with rat liver GSH. Conversely, Alachlor, Benomyl and Methyl Parthion were able to deplete GSH in rat liver, probably by forming GSH conjugates. The fungicide Captan rapidly reduced the rat liver concentration of GSH by converting it to the oxidized form GSSG. But a longer incubation of Captan with rat hepatic enzymes produced the formation of metabolites which depleted GSH via conjugation. Our results suggest that exposure to the pesticides Alachlor, Benomyl, Captan and Methyl Parathion may induce an alteration of natural mechanisms of defence against toxicants in mammals, including humans.

Amino Acid Sequence↗

PubMedDate not supplied

Multiple binding mode of reversible synthetic thrombin inhibitors. A comparative structural analysis.

The central role of the serine protease thrombin in hemostasis and thrombosis brought many scientists to develop highly potent and selective thrombin inhibitors. Thrombin-inhibitor complexes have extensively been studied in order to understand structure-function relationships, and to design new inhibitors that can be used with broader efficacy over existing antithrombotic agents. In this paper, we summarize in a comparative manner the state of the art on reversible thrombin inhibitors and we discuss some structural aspects of thrombin-inhibitor interaction, which account for the different affinity and potency of these molecules. We also report here our approach to develop a new class of synthetic, multisite-directed thrombin inhibitors, named hirunorms, designed to mimic the distinctive binding mode of hirudin. We emphasize here that, despite the high specificity of thrombin action, the interaction of inhibitors in its active site may occur with quite different mechanisms.

Amino Acid Chloromethyl Ketones↗