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1.
Toxicon ; 110: 90-109, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26690979

ABSTRACT

Ureases are metalloenzymes that hydrolyze urea into ammonia and carbon dioxide. They were the first enzymes to be crystallized and, with them, the notion that enzymes are proteins became accepted. Novel toxic properties of ureases that are independent of their enzyme activity have been discovered in the last three decades. Since our first description of the neurotoxic properties of canatoxin, an isoform of the jack bean urease, which appeared in Toxicon in 1981, about one hundred articles have been published on "new" properties of plant and microbial ureases. Here we review the present knowledge on the non-enzymatic properties of ureases. Plant ureases and microbial ureases are fungitoxic to filamentous fungi and yeasts by a mechanism involving fungal membrane permeabilization. Plant and at least some bacterial ureases have potent insecticidal effects. This entomotoxicity relies partly on an internal peptide released upon proteolysis of ingested urease by insect digestive enzymes. The intact protein and its derived peptide(s) are neurotoxic to insects and affect a number of other physiological functions, such as diuresis, muscle contraction and immunity. In mammal models some ureases are acutely neurotoxic upon injection, at least partially by enzyme-independent effects. For a long time bacterial ureases have been recognized as important virulence factors of diseases by urease-producing microorganisms. Ureases activate exocytosis in different mammalian cells recruiting eicosanoids and Ca(2+)-dependent pathways, even when their ureolytic activity is blocked by an irreversible inhibitor. Ureases are chemotactic factors recognized by neutrophils (and some bacteria), activating them and also platelets into a pro-inflammatory "status". Secretion-induction by ureases may play a role in fungal and bacterial diseases in humans and other animals. The now recognized "moonlighting" properties of these proteins have renewed interest in ureases for their biotechnological potential to improve plant defense against pests and as potential targets to ameliorate diseases due to pathogenic urease-producing microorganisms.


Subject(s)
Metalloproteins/toxicity , Neurotoxins/toxicity , Urease/toxicity , Animals , Apoenzymes/genetics , Apoenzymes/metabolism , Apoenzymes/pharmacology , Apoenzymes/toxicity , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Bacterial Proteins/pharmacology , Bacterial Proteins/toxicity , Fungicides, Industrial/pharmacology , Fungicides, Industrial/toxicity , Humans , Insecticides/metabolism , Insecticides/pharmacology , Insecticides/toxicity , Isoenzymes/genetics , Isoenzymes/metabolism , Isoenzymes/pharmacology , Isoenzymes/toxicity , Metalloproteins/genetics , Metalloproteins/metabolism , Metalloproteins/pharmacology , Neurotoxins/genetics , Neurotoxins/metabolism , Neurotoxins/pharmacology , Plant Proteins/genetics , Plant Proteins/metabolism , Plant Proteins/pharmacology , Plant Proteins/toxicity , Recombinant Proteins/metabolism , Recombinant Proteins/pharmacology , Recombinant Proteins/toxicity , Urease/genetics , Urease/metabolism , Urease/pharmacology
2.
Metallomics ; 2(12): 811-8, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21085722

ABSTRACT

The accumulation and cytotoxicity of a 10 µmol L⁻¹ equimolar human serum albumin-cisplatin adduct (HSA-Pt) was investigated in suspension Ehrlich Ascites Tumor Cells (EATC) and adherent Ehrlich Lettré Ascites Cells (Lettré). HSA-Pt did not induce apoptosis nor was it taken up by the cells to any significant amount within 24 h incubation. The accumulation and cytotoxicity of HSA-Pt was compared to 10 µmol L⁻¹ cisplatin for which a larger accumulation and cytotoxicity were observed in EATC compared to Lettré. The experiment was performed with cell medium exchange every fourth hour as HSA-Pt and cisplatin were not stable in RPMI-1640 with 10% serum. The stability was determined using size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and after 4 h new platinum peaks were observed. These findings indicate that before conducting cell experiments, the stability of the compound in the cell medium should be investigated especially when long exposure times are applied. Furthermore, HSA-Pt was found to be stable in Hanks Balanced Saline Solution (HBSS) and in Phosphate Buffered Saline (PBS) at pH 5.3, 6.1 and 7.4. Thus, the shift in pH when HSA-cisplatin passes from blood (pH 7.4) to tumor tissue (pH 5-6) is not capable of releasing cisplatin from HSA.


Subject(s)
Cisplatin/toxicity , Cytotoxins/toxicity , Serum Albumin/toxicity , Cell Line, Tumor , Cisplatin/chemistry , Cisplatin/metabolism , Cytotoxins/chemistry , Cytotoxins/metabolism , Humans , Metalloproteins/metabolism , Metalloproteins/toxicity , Platinum/chemistry , Platinum/metabolism , Platinum/toxicity , Serum Albumin/chemistry , Serum Albumin/metabolism
3.
J Inorg Biochem ; 98(1): 133-43, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14659642

ABSTRACT

In this paper, we report the characterization of copper(II) complexes with two prion (PrP) protein peptide fragment analogues (VNITKQHTVTTTT), one with the N-terminus acetylated and the C-terminus amidated (PrP Ac180-193NH2) and the other with both the C- and N-termini free (PrP 180-193). Such peptide sequence almost entirely encompasses the PrPC's helix 2 in the C-terminal region. The stoichiometry, the binding modes and the conformational features of the copper(II) complexes with the above mentioned two peptides were investigated by electrospray ionization-mass spectrometry (ESI-MS), UV-visible (UV-Vis) spectrometry and electron paramagnetic resonance (EPR) spectrometry as well as by circular dichroism (CD) measurements. The binding site location of copper(II) in the structured region of the protein can be here suggested on the basis of our findings that show the involvement of His 187 residue. The similarity of the EPR parameters suggests that the anchoring imidazole residue drives the copper(II) coordination environment towards a common binding motif in different regions of the prion protein.


Subject(s)
Copper/chemistry , Metalloproteins/chemistry , Peptide Fragments/chemistry , Prions/chemistry , Amino Acid Motifs , Animals , Binding Sites , Cells, Cultured , Circular Dichroism , Electron Spin Resonance Spectroscopy , Hydrogen-Ion Concentration , Metalloproteins/metabolism , Metalloproteins/toxicity , Mice , Mice, Inbred Strains , Neurons/cytology , Neurons/drug effects , Peptide Fragments/metabolism , Peptide Fragments/toxicity , Polytetrafluoroethylene/chemistry , Prions/metabolism , Prions/toxicity , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Ultraviolet
4.
Int J Clin Pharmacol Ther Toxicol ; 31(2): 53-60, 1993 Feb.
Article in English | MEDLINE | ID: mdl-8458676

ABSTRACT

In this brief review the preclinical safety studies on iron protein succinylate (synonym: ITF 282) are presented. Iron protein succinylate is an iron-protein complex, in which iron is present in ferric form. It has been developed for oral iron-supplementation therapy and is characterized by a very favorable tolerability profile. The acute toxicity of iron protein succinylate to rodents is very low, indicating a substantial margin of safety with respect to accidental child poisonings. In chronic toxicity studies of 52-week duration in rats and dogs, there were no findings of toxicological significance. In particular, there were no alterations in hematological parameters and no histopathological findings consistent with iron overload damage. Some deposition of iron was noted in the spleen and liver of the treated dogs. A series of reproductive toxicology studies were performed to assess the effects on fertility (in the rat), peri- and postnatal reproductive function (in the rat) and fetal toxicity (in the rat and the rabbit). Treatment with iron protein succinylate did not result in any adverse effect on reproductive performance nor did it affect the incidences of malformations, visceral and skeletal anomalies or skeletal variants. There was no evidence of mutagenic activity in a comprehensive series of in vitro and in vivo mutagenicity studies. No secondary pharmacological effects of the product were noted in a wide range of single and repeated administration studies. Overall, the available toxicology and safety profile of this product offers ample assurances of the safety of iron protein succinylate in clinical use.


Subject(s)
Metalloproteins/adverse effects , Succinates/adverse effects , Animals , Female , Male , Metalloproteins/toxicity , Pregnancy , Succinates/toxicity
5.
Toxicon ; 26(4): 379-85, 1988.
Article in English | MEDLINE | ID: mdl-3136558

ABSTRACT

By comparative studies of the immunological properties of the metalloproteins (hemorrhagic factors and proteases) isolated from the venoms of Bothrops jaracaca, Bothrops neuwiedi and Bothrops moojeni, it was found that the hemorrhagic factors contain common antigenic determinants and the proteases were immunologically distinct entities. The rabbit antisera raised for the hemorrhagic factors not only neutralized the hemorrhagic activities of the respective factors but also activities of the other hemorrhagic factors. Although the homology among these proteins are not yet known, these studies have shown that the hemorrhagic factors must have a similar partial structure which includes the catalytic hemorrhagic active site.


Subject(s)
Crotalid Venoms/immunology , Hemorrhage/immunology , Peptide Hydrolases/immunology , Animals , Cross Reactions , Crotalid Venoms/toxicity , Immunodiffusion , Metalloproteins/immunology , Metalloproteins/toxicity , Peptide Hydrolases/toxicity , Species Specificity
6.
Toxicol Lett ; 16(1-2): 95-101, 1983 Apr.
Article in English | MEDLINE | ID: mdl-6340247

ABSTRACT

Influence of metallothionein (MT) isolated from rat liver on rat cerebellum in culture was investigated by comparison with that of CdCl2. Cd-MT at 0.2 X 10(-5) M as Cd significantly depressed the outgrowth of nerve fibers, fibroblasts and glial cells as compared to the control culture. In the range from 0.2 X 10(-5) M to 2.7 X 10(-5) M Cd, the toxicity of Cd-MT was the same as that of CdCl2. Above 5 X 10(-5) M Cd, however, the toxicity of Cd-MT was less than that of CdCl2. Cadmium added as CdCl2 was perfectly recovered at a region of higher Mr than MT on the Sephadex G-75 column. Cadmium added as Cd-MT was detected in part at the higher Mr region and in part at the MT region, depending on incubation time and Cd concentration in the medium. The toxic action of Cd-MT was proportional to the recovery level of Cd at the higher Mr region.


Subject(s)
Cadmium/toxicity , Cerebellum/drug effects , Metalloproteins/toxicity , Metallothionein/toxicity , Animals , Cadmium Chloride , Culture Techniques , Fibroblasts/drug effects , Male , Microscopy, Phase-Contrast , Nerve Fibers/cytology , Nerve Fibers/drug effects , Neuroglia/drug effects , Rats , Rats, Inbred Strains
10.
Arch Environ Contam Toxicol ; 8(1): 85-95, 1979.
Article in English | MEDLINE | ID: mdl-533310

ABSTRACT

Metallothioneins with differing Cd/Zn ratios were prepared in vitro from rat liver zinc-thionein by replacing zinc with cadmium and were injected intraperitoneally to female rats. The distribution of cadmium, zinc, and copper in the kidney supernatant fraction was determined using a Sephadex G-75 column. The distribution pattern of cadmium and zinc changed dramatically within 24 hr after the injection. The changes were explained by the degradation and re-synthesis of metallothionein in the kidneys. The necrotic changes of renal tubular lining cells were correlated to the amount of cadmium in the metallothionein but not to the amount of metallothionein (protein).


Subject(s)
Cadmium/toxicity , Kidney/metabolism , Metalloproteins/toxicity , Metallothionein/toxicity , Zinc/toxicity , Animals , Cadmium/metabolism , Female , Metallothionein/metabolism , Rats , Time Factors , Zinc/metabolism
12.
J Toxicol Environ Health ; 2(4): 963-75, 1977 Mar.
Article in English | MEDLINE | ID: mdl-857047

ABSTRACT

In protecting the body against the noxious effects of dietary cadmium ions, cadmium is bound to metallothionein in the proximal intestine, and subsequently excreted into the lumen with desquamation of the epithelium. The purpose of this study was to determine the extent to which cadmium in the form of intestinal cadmium-thionein is absorbed from the intestinal lumen and to appraise the toxicity of cadmium-thionein on the intestinal mucosa. With open-ended duodenal perfusion, equivalent amounts of cadmium administered as CdCl2 or cadmium-thionein entered the mucosa, but significantly less cadmium from the perfusate of cadmium-thionein passed into the body. Exposure of the mucosa to CdCl2 for 1 hr led to minor abnormalities in the form of broadening of villi with pseudostratification of epithelium, and swelling of mitochondria, whereas cadmium-thionein produced extensive necrosis of absorptive cells. The results suggest that cadmium-thionein may play a paradoxical role, providing protection against the cadmium ion in the intracellular milieu, but promoting cadmium toxicity when it is present in sufficient amounts in the lumen of the intestine.


Subject(s)
Cadmium/toxicity , Metalloproteins/toxicity , Metallothionein/toxicity , Animals , Cadmium/analysis , Cadmium/metabolism , Diet , Electrophoresis, Polyacrylamide Gel , Intestinal Absorption , Intestines/pathology , Metallothionein/chemical synthesis , Metallothionein/metabolism , Mice , Mice, Inbred C57BL
13.
Arch Pathol ; 99(4): 192-7, 1975 Apr.
Article in English | MEDLINE | ID: mdl-1115684

ABSTRACT

Cadmium-induced metallothionein may have a paradoxical role in the pathogenesis of cadmium toxicity. Mice are protected from cadmium-induced testicular necrosis by metallothionein, but in this experiment it was shown that cadmium-metallothionein complex injected into mice results in higher cadmium levels in renal cortex and more severe renal tubular cell injury than a comparable dose of cadmium chloride administered by the same route. Also, an injection of 1.1 mg/kg of body weight or more of cadmium bound to metallothionein was fatal to male CGA mice within seven days whereas five times this dose of cadmium administered as cadmium chloride was needed to produce a similar effect. A reason for the difference in renal effects of these two forms of cadmium has not been determined but may be related to differences in absorption or transport by renal tubular lining cells.


Subject(s)
Cadmium/toxicity , Kidney/drug effects , Metalloproteins/toxicity , Animals , Cadmium/metabolism , Chlorides/toxicity , Dose-Response Relationship, Drug , Kidney/pathology , Kidney/physiopathology , Kidney Cortex/drug effects , Kidney Tubules/drug effects , Male , Mice , Necrosis , Poisoning/pathology , Poisoning/physiopathology , Testis/drug effects , Time Factors
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