Gold complexes inhibit mitochondrial thioredoxin reductase: consequences on mitochondrial functions

The effects of gold(I) complexes (auranofin, triethylphosphine gold and aurothiomalate), gold(III) complexes ([Au(2,2'-diethylendiamine)Cl]Cl(2), [(Au(2-(1,1-dimethylbenzyl)-pyridine) (CH(3)COO)(2)], [Au(6-(1,1-dimethylbenzyl)-2,2'-bipyridine)(OH)](PF(6)), [Au(bipy(dmb)-H)(2,6-xylidine)](PF(6))), metal ions (zinc and cadmium acetate) and metal complexes (cisplatin, zinc pyrithione and tributyltin) on mitochondrial thioredoxin reductase and mitochondrial functions have been examined. Both gold(I) and gold(III) complexes are extremely efficient inhibitors of thioredoxin reductase showing IC(50) ranging from 0.020 to 1.42 microM while metal ions and complexes not containing gold are less effective, exhibiting IC(50) going from 11.8 to 76.0 microM. At variance with thioredoxin reductase, auranofin is completely ineffective in inhibiting glutathione peroxidase and glutathione reductase, while gold(III) compounds show some effect on glutathione peroxidase. The mitochondrial respiratory chain is scarcely affected by gold compounds while the other metal complexes and metal ions, in particular zinc ion and zinc pyrithione, show a more marked inhibitory effect that is reflected on a rapid induction of membrane potential decrease that precedes swelling. Therefore, differently from gold compounds, the various metal ions and metal complexes exert their effect on different targets indicating a lower specificity. It is concluded that gold compounds are highly specific inhibitors of mitochondrial thioredoxin reductase and this action influences other functions such as membrane permeability properties. Metal ions and metal complexes markedly inhibit the activity of thioredoxin reductase although to an extent lower than that of gold compounds. They also inhibit mitochondrial respiration, decrease membrane potential and, finally, induce swelling.     

Thiol competition for Et3PAuS-albumin: a nonenzymatic mechanism for Et3PO formation

Thiols (RSH = 2,3,4,6-tetra-O-acetyl-beta-1-D-thioglucose, beta-1-D-thioglucose, and glutathione) can displace either the albumin or the triethylphosphine from the protein-gold complex, AlbSAuPEt3. The albumin is displaced in preference to triethylphosphine, but irreversible oxidation of the latter eventually shifts the equilibria toward Et3PO and AlbSAuSR. Albumin disulfide bonds are the probable oxidants. Neither O2 nor oxidized glutathione substantially enhanced the rate or extent of Et3PO formation. The labilization of the phosphine in AlbSAuPEt3 is attributed to a strong trans effect of the albumin thiolate, Cys-34. The 31P NMR chemical shifts of various thiolato(triethylphosphine)gold(I) complexes are correlated directly with the affinity of the thiols for gold and inversely with their pKSH values. Deacetylated auranofin (1-thio-beta-D-glucopyranosato-S) (triethylphosphine)gold(I) reacts with the mercaptalbumin and oxidized mercaptalbumin (putatively AlbSOH) forms of bovine serum albumin to form AlbSAuPEt3 with displacement of the thioglucose ligand.     

Tartrate-resistant acid phosphatase: a potential target for therapeutic gold

Gold compounds are disease-modifying agents for the treatment of rheumatoid arthritis. They act on the immune system but the mechanism is not fully understood. Gold has been shown to affect antigen processing by T-cells and also reduces expression of cytokines in macrophages. Tartrate-resistant acid phosphatase (TRAP), expressed by osteoclasts, macrophages and dendritic cells is an enzyme with roles in skeletal metabolism and the immune response. TRAP is able to degrade skeletal phosphoproteins including osteopontin, identical to the T-cell cytokine, Eta-1; we thus propose that TRAP regulates the Eta-1 pathway common to the immune system and skeleton. We compared the distribution of osteopontin and TRAP in sections of 18-day-old embryonic mice by immunohistochemistry. Both proteins occurred in the same locations. To determine whether gold compounds exert their effects by modification of TRAP activity, we examined the action of gold chloride and the prodrugs, aurothioglucose and aurothiomalate on the dephosphorylation of osteopontin by TRAP. Aurothioglucose and aurothiomalate had little effect on phosphatase activity; gold chloride was a potent non-competitive inhibitor (Ki < 47 x 10(-9) M). These findings indicate a possible molecular mechanism for the action of therapeutic gold and further implicate TRAP in the control of immunity.     

Ploidity and cell cycle progression during treatment with gold chloride, auranofin and sodium aurothiomalate. Studies on a human epithelial cell line and its sub-strains made resistant to the antiproliferative effects of these gold compounds

The possible influence of gold(III) chloride and the two gold(I)-containing anti-arthritic drugs, auranofin and sodium aurothiomalate, on cellular ploidity and cell cycle progression was investigated on cultured human epithelial cells. Four different cell lines were used: the parent line (HE) and three sub-strains which previously had acquired resistance to the antiproliferative effects of either 350 mumol gold chloride/l culture medium (HEAu350), 2 mumol auranofin/l (HEAF) or 300 mumol sodium aurothiomalate/l (HEMyo). DNA-histograms were obtained by flow cytometry examinations during a 9-days' exposure to either of these gold-containing compounds and concentrations. The HE, HEAF and HEMyo cells had similar ploidities, close to tetraploid. The HEAu350 cells had altered ploidity to distinct tetraploid. The distribution of the resistant cells with the cell cycle phases was not different from that of untreated HE cells. The HE cells, when treated with auranofin or sodium aurothiomalate, accumulated in the G2-phase of the cell cycle. In addition, a new cedecoploid peak appeared. No such changes were observed on gold chloride exposure or in HE controls grown without drug supplement. The effects of auranofin and sodium aurothiomalate on cell cycle progression of the HE cells possibly indicate a tendency to polyploidity, and furthermore that inhibition of cellular mitosis is one mechanism of the antiproliferative effect common to the two drugs.     

Gold sodium thiomalate toxicity in cadmium-sensitive and cadmium-resistant Chinese hamster ovary cells

Gold sodium thiomalate was incubated with one cadmium-sensitive cell line and two cadmium-resistant variants. The resistant lines have been reported to synthesize metallothionein (MT) in response to both cadmium and zinc, whereas the sensitive line does not. All cell lines showed a dose-dependent inhibition of growth as a result of gold sodium thiomalate treatment. However, daily comparisons of cell numbers indicate that the cadmium-resistant lines actually increase in number at the highest gold concentrations, whereas numbers of cells in the nonresistant line decrease. MT biosynthesis was measured by monitoring the incorporation of [35S )cysteine into low molecular weight protein. None of the cells synthesized MT in response to gold. When incubated with both zinc and gold, MT was synthesized by both of the cadmium resistant lines; however, the amount of MT synthesized was reduced in the presence of gold which appears to inhibit the uptake of [35S]cysteine by all the cell lines. Although MT is synthesized in the presence of zinc and gold sodium thiomalate, the MT does not have a significant effect on the ability of these cells to withstand high concentrations of gold.     

Decreased rate of uridine and glycerin uptake in L cells resistant to ethidium bromide

A comparison was made among rates of uptake of 3H-uridine, 3H-glycerol and 3H-D-xylose into mouse fibroblasts of line L sensitive to ethidium bromide (EB), and into EB-resistant cells obtained from this line by selection. Constants of uridine transport and phosphorylation were determined. For EB sensitive L cells Kt was 162 +/- 27 microM, Vt was 7.5 +/- 0.7 microM/sec. For EB resistant cells Kt was 178 +/- 27 microM, and Vt was 4.6 +/- 0.2 microM/sec. Thus, the transport rate of uridine in resistant cells was twice lower than in EB sensitive cells. The rate of uridine phosphorilation in EB resistant cells was by three times lower than in EB sensitive ones. The uptake of glycerol into resistant cells was also lowered. There was no difference in transport of 3H-D-xylose between sensitive and resistant cells. The data obtained may suggest some changes in plasma membrane in the EB resistant cells.     

Investigations on the effects of cobalt-alkyne complexes on leukemia and lymphoma cells: cytotoxicity and cellular uptake

Cobalt-alkyne complexes represent a new class of antiproliferative drugs with high activity on cell lines derived from human solid tumors. These promising results encouraged us to evaluate also their effects against leukemia and lymphoma cells. For this purpose, we selected three cobalt complexes with (2-propyn-1-yl)acetylsalicylate (Co-ASS), 2-propyn-1-ol (Co-Prop) and diphenylacetylene (Co-Diph) ligands and investigated their growth inhibiting properties on the LAMA-84, K-562, SD-1 leukemia and U-937 lymphoma cell lines. The cobalt complexes showed high effects on LAMA-84 cells (IC(50)=7.7-16.8 microM) after 48 and 72 h of incubation, but were inactive (K-562, U-937) or low active (SD-1) on the other cell lines. The proliferation of SD-1 cells was reduced by Co-Prop (IC(50)=18.6 microM) and Co-Diph (IC(50)=7.5 microM) only after a 72 h exposure. The antiproliferative effects did not correlate with the accumulation of the drugs into the tumor cells. The time dependent uptake during 24 h determined by atomic absorption spectroscopy was comparably the same in sensitive LAMA-84 and insensitive K-562 cells.     

Genotype‐by‐environment interactions due to antibiotic resistance and adaptation in Escherichia coli

Mutations that are beneficial in one environment can have different fitness effects in other environments. In the context of antibiotic resistance, the resulting genotype‐by‐environment interactions potentially make selection on resistance unpredictable in heterogeneous environments. Furthermore, resistant bacteria frequently fix additional mutations during evolution in the absence of antibiotics. How do these two types of mutations interact to determine the bacterial phenotype across different environments? To address this, I used Escherichia coli as a model system, measuring the effects of nine different rifampicin resistance mutations on bacterial growth in 31 antibiotic‐free environments. I did this both before and after approximately 200 generations of experimental evolution in antibiotic‐free conditions (LB medium), and did the same for the antibiotic‐sensitive wild type after adaptation to the same environment. The following results were observed: (i) bacteria with and without costly resistance mutations adapted to experimental conditions and reached similar levels of competitive fitness; (ii) rifampicin resistance mutations and adaptation to LB both indirectly altered growth in other environments; and (iii) resistant‐evolved genotypes were more phenotypically different from the ancestor and from each other than resistant‐nonevolved and sensitive‐evolved genotypes. This suggests genotype‐by‐environment interactions generated by antibiotic resistance mutations, observed previously in short‐term experiments, are more pronounced after adaptation to other types of environmental variation, making it difficult to predict long‐term selection on resistance mutations from fitness effects in a single environment.     

Studies on the angiotensin-converting enzyme and the kinin B2 receptor in the rabbit jugular vein: modulation of contractile response to bradykinin

The rabbit jugular vein (rbJV) was used as a bioassay system to validate some early and new hypothetical interactions between the angiotensin-converting enzyme (ACE) and the B2 receptor, which may be influenced by ACE inhibitors (ACE-I). These involve the potentiation of the contractile effect of bradykinin (BK) and BK analogues, which are inactivated by ACE (e.g., [Hyp3, Tyr(Me8)]-BK (R556)), the prevention of BK-induced B2 receptor desensitisation, and the restoration of receptor sensitivity in tissues desensitised with B2 receptor agonists. Enzymatic degradation studies performed in vitro and in vivo revealed that BK and R556 are readily degraded by rabbit ACE whereas [Phe8psi(CH2-NH)Arg9]-BK (R379) is totally resistant. BK, R556, and R379 contracted endothelium-denuded veins with similar potencies (pEC50 range 8.10-8.50). Tissues pretreated with ACE-I showed an increase in pEC50 values for BK and R556 but not for R379. ACE-I (captopril, enalaprilat) were unable to prevent B2 receptor desensitisation induced by BK (1 microM). ACE-I partially restored B2 receptor-mediated contraction in tissues initially exposed to BK but not to R379. These effects were antagonised by HOE 140 (0.1 microM) but were unaffected by AcLys[Dbeta-Nal7, Ile8]-desArg9BK (R715) (1 microM) or by Losartan (1 microM). In conclusion, the potentiation of BK and its analogues relates exclusively on prevention of their metabolism, B2 receptor desensitisation is not affected by ACE-I, and restoration of tissue responsiveness to BK by ACE-I may be attributed to changes in BK concentrations in the vicinity of the B2 receptor.     

Sensitivity and resistance in human metastatic melanoma to the new chloroethylnitrosourea anti-tumor drug Fotemustine

Fotemustine is a novel chloroethylnitrosourea derivative currently used in Phase III clinical trials for disseminated metastatic melanoma. This drug has been shown to inhibit enzymes in the ribonucleotide reduction pathway (i.e., thioredoxin reductase, glutathione reductase and ribonucleotide reductase). 14C chloroethyl-labelled Fotemustine covalently labels the thiolate active sites of thioredoxin reductase and glutathione reductase yielding 14C chloroethyl-thioether enzyme-inhibitor complexes. Enzyme activities can be restored by a reduced thioredoxin or reduced glutathione mediated beta-elimination of the chloroethyl group. 14C Fotemustine has been used to determine its reactivity and metabolism in drug sensitive and resistant melanoma metastases and in cultures of sensitive and resistant clones of human melanoma cells. Melanoma metastases from four different patients who were treated with Fotemustine could be labelled with radioactive drug only under reducing conditions with NADPH as electron donor and DTNB as substrate. FPLC analysis of these extracts revealed two radioactive proteins (I) glutathione reductase and (II) an unidentified protein with 95 and 50 kDa subunits. A similar labelling pattern was also found in extracts of Fotemustine sensitive melanoma cells (Cal 1). Fotemustine resistant tumors were melanotic and contained more glutathione reductase than thioredoxin reductase, whereas sensitive tumors were clinically amelanotic with more thioredoxin reductase than glutathione reductase. Fotemustine resistant melanoma cells (Cal 7) showed a slower uptake of 14C-label with 34% less isotope intracellularly in 1 h compared to sensitive melanoma cells (Cal 1). These results strongly indicate (I) the induction of alternate electron donors thioredoxin reductase or glutathione reductase for ribonucleotide reduction determines tumor and melanoma cell responses to the drug and (II) Fotemustine transport and the intracellular redox status seems to regulate resistance in melanoma cells and tissues.     

Autometallographic demonstration of gold in the adrenal gland of rats exposed to sodium aurothiomalate

The presence of gold was investigated in sections of the adrenal glands from rats which had been exposed to intraperitoneal sodium aurothiomalate (32 to 120 mg). Gold was histochemically detected in cortical endocrine cells, chromaffin cells and in fibroblasts and macrophages of both the cortex and medulla. Invisible traces of gold were silver enhanced by autometallography making them readily visible at both the light and electron microscopic levels. The intracellular staining intensity was dose-dependent. In general, the number as well as the staining intensity of individual cells, were highest in the zona glomerulosa and zona reticularis. In gold-containing cells the silver-amplified deposits were present in lysosomes.     

Hexavalent chromium uptake by sensitive and tolerant mutants of Schizosaccharomyces pombe

Lysine and leucine auxotrophic, heterothallic (h+, h-) strains of Schizosaccharomyces pombe were used to obtain chromium (VI)-sensitive and -tolerant mutants by ultraviolet radiation-induced and nitrosoguanidine-induced mutagenesis. The minimal inhibitory concentrations of K2Cr2O7 on YEA media were 225 microM for the wild-type strain CW-6, 125 microM for the sensitive mutant CS-6.51 and 275 microM for the tolerant mutant CT-6.66. The mutants exhibited cross-sensitivity of various patterns to Cd2+, Cu2+, Ni2+, Zn2+ and VO3-(4). Cr(VI) was added to the actively growing cultures and the total chromium (TOCr) content of the cells was determined. The sensitive mutant exhibited a high bioaccumulation ability, with a dry biomass of 810 micrograms g-1 after 30 min, while the tolerant mutant had a significantly lower ability than the wild-type strain. In PIPES buffer, washed, lysine-starved biomasses were treated with 75 microM Cr(VI) and after 2 h, the TOCr and the organically bound chromium (OBCr) were determined. Under these conditions, the sensitive and tolerant mutants had the same TOCr content, 50% of which was OBCr. The wild-type strain exhibited a lower TOCr content than that of its mutants and only 35% of this was OBCr. The Cr(VI)-sensitivity was due to a significantly increased uptake of Cr(VI).     

Sensitivity of soil bacteria isolated from the alienated zone around the Chernobyl Nuclear Power Plant to various stress factors

Seventy strains of chemoorganotrophic bacteria isolated by our group in 1993-1994 from soil sampled in the zone around the Chernobyl Nuclear Power Plant (ChNPP) were studied with respect to their sensitivity to various stress factors damaging DNA. Bacillus subtilis, B. cereus (both spores and vegetative cells), Methylobacterium extorquens, M. mesophilicum, and unidentified pigmented bacteria were found to be the most resistant to ultraviolet (UV) radiation, exhibiting LD90 values of 40 to more than 211 J/m2. The same bacteria, as well as Bacillus polymyxa, were tolerant to hydrogen peroxide (lethal concentrations of H2O2 ranged from 0.3 to 1.0 M); i.e., UV-resistant strains were also tolerant to hydrogen peroxide and vice versa. Fluorescent pseudomonads were the most sensitive to both UV radiation and H2O2, showing LD90 from 6 to 18 J/m2 and a lethal concentration of H2O2 lower than 0.1 M. All of the soil samples collected in the alienated zone around the ChNPP, where the radioactivity of the soil had decreased from 1000 to 2 microCi/kg soil over the period from 1987 to 1995, contained not only resistant bacteria but also a small number of bacteria sensitive to UV radiation and H2O2.     

Characterization of cadmium-resistant bacteria for its potential in promoting plant growth and cadmium accumulation in Sesbania bispinosa root

The cadmium (Cd) resistant bacteria were isolated from soils of Damanganga river, Vapi, and identified 11 potential Cd resistant bacteria based on 16S rDNA sequences. The Cd resistant bacteria belonged to four different genera: Providencia spp., Morganella sp., Stenotrophomonas sp., and Bacillus spp. The assessment of plant growth-promoting (PGP) parameters revealed that the Cd tolerant bacteria showed one or more PGP properties. Further, a pot experiment was conducted to elucidate the effects of Cd resistant bacteria on the plant growth and the uptake of Cd by Sesbania bispinosa. The bacterized seedlings recorded 36.0–74.8% and 21.2–32.9% higher root and shoot lengths, respectively, in Cd amended soil compared with control. The Cd mobilization in the root of S. bispinosa by microbial inoculants ranged from 0.02 ± 0.01 to 1.11 ± 0.06 ppm. The enhanced concentrations of Cd accumulation in S. bispinosa roots correspond to the effect of the bacterial strains on metal mobilization in soil. The present observations showed that the Cd resistant strains protect the plants against the inhibitory effects of Cd, probably due to the production of PGP properties. The present results provided a new insight into the phytoremediation of Cd contaminated soil.     

A 1H nmr study of the interaction of aurothiomalate ("Myocrisin") with human red blood cells in vitro

The results of 1H spin-echo Fourier transform (SEFT) nuclear magnetic resonance (nmr) experiments suggest that some aurothiomalate binds intracellular glutathione (GSH) when added to suspensions of red cells in vitro. When added to red cell lysates, a specific binding of gold to cysteine of GSH is observed together with release of thiomalate. Gold binding to GSH can be reversed by addition of dimercaptopropanol sulfonate. Spectra are compared to those of an aurothiomalate-GSH model system. The relationship of these findings to the mechanism of action of Myocrisin is discussed.     

Glutamate release from adult primary sensory neurons in culture is modulated by growth factors.

The aim of this study was to examine possible modulatory effects of some trophic molecules, i.e. nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF), on potassium (K(+))-, bradykinin (BK)- or capsaicin (CAPS)-evoked release of glutamate (GLU) from dorsal root ganglion (DRG) neurons in vitro. BK (0.5 and 1 microM) induced a dramatic and significant increase in glutamate release. Neither CAPS nor K(+) (60 mM) produced any significant increase of GLU release vs. basal levels during a 5-min stimulation. The BK-evoked release of GLU was almost completely blocked by HOE 140, a selective BK2-receptor antagonist at high doses. Basal release of GLU was significantly reduced in cultures grown in the presence of bFGF, whereas BDNF and NGF had no significant effect. Incubation with growth factors generally decreased the BK-stimulated GLU release, an effect most pronounced for bFGF, which completely blocked BK-stimulated release. The rise in intracellular [Ca(2+)] following stimulation with BK (100 nM-1 microM), potassium (60 mM) or ATP (10 microM) was also studied using a Ca(2+)-sensitive indicator, Fura-2, in cultures grown in basal medium with or without bFGF. None of the bFGF-treated cells exhibited strong Ca(2+) responses to BK or ATP stimulation, while 10-20% of the responding cells grown in basal medium exhibited strong responses. The K(+)-induced increase of [Ca(2+)] did not vary between the different groups.The present findings suggest that sensory neurotransmission involving glutamate may be modulated by growth factors and that regulation of intracellular Ca(2+) homeostasis may be a contributing factor.     

Identification of rice varieties with high tolerance or sensitivity to lead and characterization of the mechanism of tolerance

Pb inhibits plant growth. To study Pb tolerance in rice (Oryza sativa), we screened 229 varieties for Pb tolerance or sensitivity. Three-day-old seedlings were treated for 12 d with 20 microM Pb solution. Based on the dry weight of the root, three Pb-tolerant (var CH-55, var KH-2J, var Kumnung) and three Pb-sensitive (var Aixueru, var C-9491, var Milyang23) rice varieties were selected. The root biomasses of the tolerant varieties were approximately 10-fold higher than those of the sensitive ones. The greatest morphological difference between the two groups was in the growth of the adventitious roots, as tolerant lines were able to develop adventitious roots after 6 d of Pb treatment, whereas sensitive ones did not develop any even after 15 d. The growth of adventitious roots in the tolerant varieties was dependent on a mechanism, whereby Pb was altered to a form that cannot be taken up by the tissue, because (a) the solution in which the tolerant varieties of rice had grown still contained Pb but nevertheless did not affect the root growth of new rice seedlings, and (b) the adventitious roots of tolerant seedlings developed in Pb solution contained little Pb. The oxalate content in the root and root exudate increased upon Pb treatment in the tolerant varieties, whereas the opposite was observed for the sensitive ones. Oxalate added to the growth solution ameliorated the inhibition of root growth by Pb. These results suggest that compounds such as oxalate secreted from the root may reduce the bio-availability of Pb, and that this may constitute an important Pb tolerance mechanism in the tolerant rice varieties studied here.     

Adriamycin tolerance in human mesothelioma lines and cell surface NADH oxidase

Adriamycin tolerant human mesothelioma cell lines derived from a single tumor prior to either chemotherapy or radiation therapy and a susceptible cell line were investigated. Not only was growth resistant to low doses of adriamycin but an unusual pattern of resistance was encountered in which cells seemed to better tolerate high adriamycin doses than intermediate doses. The differential growth susceptibility of the tolerant lines compared to A549 lung carcinoma and the bimodal dose response correlated with differences in the specific activity of a plasma membrane-associated NADH oxidase (NOX). Plasma membrane fractions of high purity were isolated by aqueous two-phase partition and assayed directly. The NADH oxidase activity of the plasma membranes for the susceptible cell line was maximally inhibited by 1 microM adriamycin whereas the NADH oxidase activity of the tolerant lines was less and was maximally inhibited by 0.1 microM adriamycin with 1 and 10 microM adriamycin being less inhibitory than 0.1 microM adriamycin. The findings suggest a relationship between the growth response to adriamycin of the adriamycin tolerant mesothelioma lines and the activity of the plasma membrane-associated NADH oxidase activity of the cell surface in these cell lines.     

Isolation and partial characterization of human cell mutants differing in sensitivity to killing and mutation by methylnitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine

Isogenic variants resistant to alkylating agents have been isolated from the human lymphoblast cell line TK6. The cell lines may be divided into four classes on the basis of resistance to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The sensitive TK6 parental line shows a 37% survival after 45-min exposure to 0.04 microM MNNG; the three classes of more resistant mutants show 37% survival after 45-min exposure to 2 microM (MF lines), 6 microM (MT lines), and greater than or equal to 10 microM (MX line) MNNG. A representative MF line, MF1, is resistant to both killing and mutation by MNNG or N-methyl-N-nitrosourea. An MT clone, MT1, is highly resistant to killing but hypermutable by MNNG. The MT1 line, like the parental TK6, does not remove O6-methylguanine adducts from the DNA. Our data are consistent with the hypothesis that the MT1 line possesses a nonexcision pathway of defense against killing by alkylating agents. Rather than preventing alkylation of DNA or removing alkylated adducts, the MT1 cells appear to be tolerant of the adducts that are not removed from the DNA.     

Effects of aurothiomalate and gold(III) complexes on spontaneous motility of isolated human oviduct

Organic gold complexes have different biological activity, depending on their potential for interactions with key functional molecules.The aim of this study was to investigate potential of several newly synthesized organic gold complexes to influence spontaneous motility of the Fallopian tubes.The effects of [Au(bipy)Cl(2)](+) (dichloride(2,2'-bipyridyl)aurate(III)-ion), aurothiomalate, [Au(DMSO)(2)Cl(2)]Cl and DMSO on spontaneous motility of Fallopian tubes were tested on the isolated tube segments in vitro. Aurothiomalate (from 2.9?×?10(-9) to 4.9?×?10(-4)?M/l), [Au(bipy)Cl(2)]Cl (from 3.3?×?10(-9) to 4.2?×?10(-5)?M/l) and DMSO (from 1.9?×?10(-8) to 1.0?×?10(-5)?M/l) did not affect spontaneous contractions of the isolated Fallopian tube ampulla, while [Au(DMSO)(2)Cl(2)]Cl (from 2.9?×?10(-9) to 4.2?×?10(-5)?M/l) showed concentration-dependent increase (stimulation) of spontaneous contractions of the isolated Fallopian tube isthmus, and remained without effect on the isolated ampulla.The drugs designed as organic gold complexes with weaker bonds between the gold itself and organic part of a molecule could adversely affect motility of the Fallopian tubes, and theoretically fertility of women taking such drugs in their reproductive age.