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Comparative and environmental genotoxicity of antimony and arsenic.

Antimony and arsenic compounds are known to have a genotoxic potential. Soil contamination with these elements can be due to the presence of natural ore sources of fahlore (gray copper). As a result, human and animal populations may be highly exposed. The sister chromatid exchange (SCE) test is an adequate tool for the sensitive detection of antimony and arsenic genotoxicity. We used this assay to investigate the coergism of the two elements in vitro to gain data for the assessment of a putative risk from coexposure. The combinative effect of antimony and arsenic in the SCE test appeared subadditive. Additionally, the SCE served to determine the genotoxic potential in extracts of contaminated fahlore soil samples gained under mildly acidic conditions. The genotoxicity observed was very low because antimony and arsenic predominated in the pentavalent, non-genotoxic state, but, the partial antagonism observed in the in vitro experiments could be an additional explanation for the low genotoxicity.

Adult↗
PubMed2003

Functional identification of ion binding sites at the internal end of the pore in Shaker K+ channels.

The inner end of the pore in voltage-gated K+ channels is the site of conformational changes related to gating and contains binding sites for permeant ions and pore-blocking molecules including quaternary ammonium ions and drugs. In order to determine the location and affinity of ion binding sites we probed the Shaker K+ channel with the quaternary ammonium analogue, tetrabutyl antimony (TBSb), a compound that is sufficiently electron dense to have been observed to occupy the cavity site in the bacterial K+ channel, KcsA. TBSb has K+ channel blocking properties analogous to those of tetrabutyl ammonium (TBA), and kinetics slow enough to be reliably measured. In the presence of external TEA, the internal TBSb on-rate decreased with increased internal K+ concentration as if these permeant ions prevented TBSb access to its site in the pore. The TBSb off-rate in low K+ was increased with external TEA addition and then reduced with increased internal K+. We found several differences between the behaviour of internal TBSb and TEA suggesting these molecules bind to distinct but interacting sites in the pore. We also found several differences in how K+ and Rb+ ions occupy sites in the inner end of the pore. These data suggest the presence of three sites in the inner end of the pore: (1) a site near the cytoplasmic end that binds TEA and K+ (but not Rb+) ions; K+ ions binding to this site inhibit TBSb exit from the pore; (2) a TBSb site slightly more into the pore that is rarely occupied by K+ or Rb+ ions; (3) a site further into the pore that has a high affinity for K+ and Rb+ ions; occupancy of this site by these permeant ions increases the TBSb off-rate. These results provide information on the fine-structure of ion interactions with the inner end of the pore in K+ channels.

Animals↗
PubMed2003

Arsenic methylation by micro-organisms isolated from sheepskin bedding materials.

Sudden infant death syndrome (SIDS) has been associated with the volatilization of arsenic, antimony or phosphorus compounds from infants' bedding material by micro-organisms, the so-called 'toxic gas hypothesis'. The volatilization of arsenic by aerobic micro-organisms isolated from new sheepskin bedding material, as well as on material used by a healthy infant and by an infant who perished of SIDS, was examined. Three fungi were isolated from a piece of sheepskin bedding material on which an infant perished of SIDS, which methylated arsenic to form trimethylarsenic(V) species, precursors to volatile trimethylarsine. These three fungi were identified as Scopulariopsis koningii, Fomitopsis pinicola and Penicillium gladioli by their 26S-ribosomal RNA polymerase chain reaction products. These fungi were not previously known to methylate arsenic. The volatilization of arsenic by these three fungi was then examined. Only P. gladioli volatilized arsenic and only under conditions such that the production of sufficient trimethylarsine to be acutely toxic to an infant is unlikely. S. brevicaulis grew on the sheepskin bedding material and evolved a trace amount of trimethylarsine. Known human pathogens such as Mycobacterium neoaurum and Acinetobacter junii were isolated from used bedding.

Animals↗
PubMed1998

Multiple exposure to arsenic, antimony, and other elements in art glass manufacturing.

Art glass manufacturing is one of the most interesting examples of exposure to complex mixtures. Among the raw materials used are silica sand, borax, carbonates, nitrates of Ca, Na, K, and a great number of compounds that are mainly oxides of As, Sb, Al, Zn, Cr, Ni, Sn, Se, Cd, Mn, Cu, Co, Fe, Nd, Er, Eu, and La. In six art glass factories that use As or Sb as fining agents, the exposure to these elements was investigated in 32 workers by means of environmental and biological monitoring. Analysis was conducted by atomic absorption spectrometry (AAS) and inductively coupled plasma mass spectrometry (ICP-MS). The results confirmed that As, which is the main carcinogen in glass production, reaches high air concentrations and is generally above the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value-time-weighted average (TLV-TWA) of 10 micrograms/m3. When partly substituted by antimonial compounds, As air concentrations dropped dramatically, while the air levels of Sb (which is considered less toxic but is classified as a class 2B carcinogen by IARC) were relatively low and below the ACGIH TLV-TWA of 500 micrograms/m3. Exposure to As and Sb also differed in the three types of jobs investigated: As was high in oven chargers, Sb was higher in batch mixers, and both elements were low in makers-formers. Eleven to 18 elements were detected: arsenic, Al, Ba, Sb, Pb, and Zn were the elements most frequently measured (in tens, and in some cases hundreds, of micrograms/m3), followed by B, Li, Mn, Se, Sn, Sr, Ce, La, and Nd (in micrograms or in some cases tens of micrograms/m3. The results of biological monitoring for As, Sb, and other elements were in agreement with environmental monitoring data. We concluded that multiple detection of elements is a useful tool (or the evaluation of exposure to complex mixtures such as those used in the art glass industry and that such detection also allows a more accurate evaluation of related epidemiological data.

Antimony↗
PubMed2005

Development of antischistosomal drugs in China, with particular consideration to praziquantel and the artemisinins.

Remarkable achievements have been made in the control of schistosomiasis in China, with chemotherapy playing a seminal role. From the early 1950s through the early 1980s, Chinese scientists made considerable progress in discovery and development of compounds with antischistosomal properties, including antimonials, non-antimonials and various effective principles stemming from traditional herbs. However, only few compounds entered clinical testing, while others were abandoned mainly due to their toxicity and poor efficacy. The advent of praziquantel in the 1970s changed the landscape of research and development of drugs for treatment and morbidity control of schistosomiasis. The main Chinese contributions to enhance the understanding of the antischistosomal drug praziquantel are reviewed here, including issues of metabolism, antibody-dependency, host immune factors, stage-specific susceptibility and resistance. Over the past 25 years, researchers from China successfully developed artemether and artesunate, two derivatives from the antimalarial artemisinin, as promising drugs against Schistosoma japonicum. Laboratory investigations showed that the artemisinins display their highest activity against the juvenile stages of the parasite. These findings were consistently confirmed in randomised controlled trials; repeated oral administration of artemether or artesunate was safe and efficacious in the prevention of patent S. japonicum infections. The key findings are reviewed here, and emphasis is placed on how it stimulated research outside of China on other human schistosome species.

Animals↗
PubMed1991

Changing response to diamidine compounds in cases of kala-azar unresponsive to antimonial.

Two hundred and forty patients of kala-azar unresponsive to antimonial were treated with pentamidines in a dose of 4 mg/kg body weight on alternate days for 20 injections. Of these, 175 were treated with pentamidine isethionate and 65 with pentamidine methane sulphonate (Lomidine). Clinical and parasitological cure were significantly higher with lomidine as compared to pentamidine isethionate. However, cardiovascular, gastrointestinal and metabolic toxicity including hyperglycaemia were more marked with lomidine. Mortality rate was also significantly (P less than .05) higher with lomidine therapy. Significantly lower clinical and parasitological cure and higher relapse rate were observed in the present study compared with an earlier study in which pentamidine was used in the same doses for 10-12 injections only.

Adult↗
PubMed2006

Mechanisms of drug action and drug resistance in Leishmania as basis for therapeutic target identification and design of antileishmanial modulators.

The control of Leishmania infections relies primarily on chemotherapy. The arsenal of drugs available against Leishmania infections is limited and includes pentavalent antimonials, pentamidine, amphotericin B, miltefosine, paromomycin, allopurinol, and few other drugs at various stages of their development process. Knowledge about action and resistance mechanisms involved may allow the development of new drugs that minimise or circumvent drug resistance or may identify new targets for drug development. The aim of this review is to propose some chemical topics to design new modulators from the mechanisms of action of drugs and resistance mechanisms to drugs used in the clinic against Leishmania infections. Thus, different classes of ABC transporters extrude antimonials in Leishmania resulting in drug-resistant phenotypes. Compounds interfering with thiol and polyamine metabolism could be designed to inhibit the antimonial detoxication and therefore, such compounds could be used in combination with antimonials. New diamidines could be synthesized in regard to their ability to inhibit topoisomerase II. The challenge for amphotericin B is to be absorbed by oral route requiring labile physico-chemical modifications. New sesquiterpens and flavonoids have to be developed as reversant of antimonial resistance. Although some studies have focused on developing inhibitors against these resistant phenotypes, new efficient modulators that are able to inhibit drug efflux are needed.

ATP-Binding Cassette Transporters↗
PubMed1991

[Clinical and hygienic aspects of the effect of antimony ore on workers in the Far North].

The clinical and hygienic studies performed at the antimonite ore extraction mines in Yakutia revealed that the workers were exposed to high concentrations of polymetallic dusts, containing chromium dioxide, antimony, arsenic and their compounds. 11% of the workers exhibited dust bronchitis, changes in the blood and immune reactivity indices which were due to reactions of adaptation to the Far North climatic conditions and the occupational factors' toxic effects.

Air Pollutants, Occupational↗
PubMed1997

Genotoxicity of selected metal compounds in the SOS chromotest.

Knowledge concerning the genotoxicity of inorganic metal compounds in the SOS chromotest is limited. Up to now, only Cr(VI), Sn(II) and the platinum antitumor compound cisplatin(II) were shown to be genotoxic in this test system. However, for Cr(VI) and Sn(II), a positive reaction could only be achieved in cytotoxic dose ranges. The aim of the present study was to provide additional data concerning metal salt genotoxicity in the SOS chromotest. Therefore, 14 metal/metalloid salt compounds of platinum, palladium, rhodium, arsenic, antimony and chromium were tested. Four platinum salts, K2PtCl4, cis-Pt(NH3)2Cl2 (cisplatin), trans-Pt(NH3)2Cl2 (transplatin) and PtCl4 as well as two rhodium compounds tested, K2RhCl5 and (NH4)3RhCl6, could be shown to be genotoxic in the chromotest using the tester strain Escherichia coli PQ37. A moderate genotoxicity was shown by the two Cr(VI) compounds K2CrO4 and K2Cr2O7. All palladium compounds and all the other metal salts tested were unable to induce a significant SOS response.

Alkaline Phosphatase↗