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PubMed1997

Survival of Escherichia coli cells exposed to iodoacetate and chlorodinitrobenzene is independent of the glutathione-gated K+ efflux systems KefB and KefC.

The KefB and KefC systems of Escherichia coli cells are activated by iodoacetate (IOA) and chlorodinitrobenzene (CDNB), leading to a rapid drop in the intracellular pH. However, survival of exposure to IOA or CDNB was found to be essentially independent of KefB and KefC activation. No correlation was found between the toxicity of the compound and its ability to elicit protective acidification via activation of KefB and KefC.

Antiporters↗
PubMed1981

Inhibition of Bacillus cereus spore outgrowth by covalent modification of a sulfhydryl group by nitrosothiol and iodoacetate.

Nitrosothiols with the general structure RSN==O were studied as a model system of bacteriostatic action toward outgrowing bacterial spores. With a Taft plot analysis, the influence of the structure of the R group on the inhibitory effectiveness of a series of nitrosothiols showed that effectiveness as an inhibitor of Bacillus cereus T outgrowth correlated with the electron withdrawal of R, but that size, shape, charge, hydrophobicity, and transportability had little influence. This was interpreted to mean that nitrosothiols do not traverse the membrane to act. The Taft plot together with competition data between nitrosothiol and iodoacetate indicated that the mode of nitrosothiol action is the covalent modification of a sulfhydryl group, probably to form RSN(OH)--SX, where --SX is derived from a sensitive spore sulfhydryl group. Cooperativity effects indicated that outgrowth inhibition is accompanied by a conformational change occurring upon sulfhydryl group modification, which is communicated among at least three to five subunits. Uptake of label during spore germination indicated that most of the sulfhydryl groups which can be modified are associated with the inhibitory event. These data suggest that this sulfhydryl group may be sufficiently unique that inhibitors designed to interfere specifically with it could have value as bacteriostatic agents.

Bacillus cereus↗
PubMed1984

Induction of metallothionein-I mRNA in cultured cells by heavy metals and iodoacetate: evidence for gratuitous inducers.

A mouse hepatocyte cell line selected for growth in 80 microM CdSO4 (Cdr80 cells) was used to test the role of metallothioneins in heavy metal detoxification. The cadmium-resistant (Cdr80) cells have double minute chromosomes carrying amplified copies of the metallothionein-I gene and accumulate ca. 20-fold more metallothionein-I mRNA than unselected cadmium-sensitive (Cds) cells after optimal Cd stimulation. As a consequence, the amount of Cd which inhibits DNA synthesis by 50% is ca. 7.5-fold higher in Cdr80 cells than in Cds cells. Cds and Cdr80 cells were compared in terms of their resistance to other heavy metals. The results indicate that although Zn, Cu, Hg, Ag, Co, Ni, and Bi induce metallothionein-I mRNA accumulation in both Cdr80 and Cds cells, the Cdr80 cells show increased resistance to only a subset of these metals (Zn, Cu, Hg, and Bi). This suggests that not all metals which induce metallothionein mRNA are detoxified by metallothionein and argues against autoregulation of metallothionein genes. Metallothionein-I mRNA is also induced by iodoacetate, suggesting that the regulatory molecule has sensitive sulfhydryl groups.

Animals↗
PubMed1985

Iodoacetic acid inhibition of calcium-dependent potassium efflux in red blood cells.

The metabolic inhibitor, iodoacetic acid (IAA), has commonly been used to increase Ca-dependent K efflux in red blood cells. It is thought that this effect of IAA involves the irreversible inhibition of glyceraldehyde-phosphate dehydrogenase (EC 1.2.1.12), resulting in the energy depletion of the cell. Without energy, active transport stops, and the K loss is enhanced both by increasing cellular Ca and by preventing K reuptake. The present study shows that in addition to this metabolic effect, which increases Ca-dependent K efflux, IAA also inhibits this efflux. This inhibition is irreversible and is not related to the ATP or Ca concentrations of the cells. The carboxymethylation of a specific protein band correlates with IAA inhibition of K efflux.

Cadmium↗
PubMed1991

Iodoacetate-induced contracture in rat skeletal muscle: possible role of ADP.

The effects of iodoacetic acid (IAA) and ischemic contraction were studied in rat extensor digitorum longus muscles. Ischemic contraction of IAA-treated muscles produced contracture. The onset of contracture was not associated with a change in sarcolemmal electrical properties or reduction in intracellular [ATP]; however, [creatine phosphate] was reduced by 75% and free [ADP] was increased by 665%. Continued stimulation of IAA-treated fibers resulted in depolarization, loss of membrane excitability, further depletion of creatine phosphate, and reduction in [ATP]. The effects seen in IAA-treated muscle did not appear to result from a direct action of IAA on the surface membrane, contractile proteins, or excitation-contraction coupling. The contractures in IAA-treated muscle may have resulted from increased Ca sensitivity of the contractile proteins, increased myoplasmic [Ca], or both. Both effects may have resulted from increased [ADP]. In addition, the reduced acidification during ischemic contraction of IAA-treated fibers compared with control fibers may have further increased the Ca sensitivity of IAA-treated fibers compared with controls.

Adenosine Diphosphate↗
PubMedDate not supplied

Calcium independent contraction induced by iodoacetic acid in isolated cerebral arteries.

In helically-cut strips of cerebral arteries isolated from dogs and monkeys, the addition of 1 mM iodoacetic acid (IAA) produced contractions during an early period (5 to 10 min) and also a prolonged exposure (50 to 70 min). The early contraction was abolished by exposure to Ca++-free media containing EGTA, and significantly attenuated by treatment with procaine or dantrolene. Verapamil, lidocaine, ATP and pyruvate did not inhibit the contraction. On the other hand, the late contraction was not prevented by exposure to Ca++-free, EGTA-containing media and by treatment with procaine, dantrolene, lidocaine, ATP or pyruvate. Nitroglycerin and papaverine did not relax the IAA-contracted arteries. In dog and monkey mesenteric arteries and dog coronary, renal and femoral arteries, IAA elicited contractions after a prolonged exposure, which were not inhibited by soaking the preparations in Ca++-free, EGTA-containing media. Passive tensions developed by rapid stretch in Ca++-free media did not differ in IAA-treated and control arteries. During an early period of IAA actions, Ca++ appears to be released from intracellularly stored sites in the amount sufficient to produce significant contractions in cerebral, but not in peripheral arteries. It is concluded that the involvement of Ca++ in the late contraction induced by IAA is if any minimal, and such a contraction may be associated with functional alterations induced by the metabolic inhibitor in arterial tissues other than smooth muscle.

Adenosine Triphosphate↗
PubMed1984

Effect of iodoacetic acid on maintenance of pancreatic endocrine cells of the neonatal rat.

This report describes the specific cytotoxicity of iodoacetic acid (IAA) in selectively destroying the fibroblastoid cells and stimulating the in vitro function of neonatal B cells prepared from rat pancreases. Under culture conditions with a basal medium containing 5.5 mM D-glucose alone, the responses to insulin secretagogues tested were abolished by day 7 of culture. In contrast, the addition of 10 microM IAA enhanced either insulin release evoked by D-glucose (16.7 mM), L-leucine (10 mM) and 2-ketoisocaproate (10 mM) or the cellular insulin content to approximately twice the initial levels (day 0). L-Glutamine (10 mM) augmented the stimulatory effect of L-leucine or 2-ketoisocaproate. Moreover, the continuous application of IAA significantly increased the rates of glutamine oxidation in endocrine cells after 7 days of culture. On the other hand, the IAA-supplemented medium did not preserve the function of A cells. The phase-contrast microphotograph examination revealed the selective removal of fibroblasts from the monolayer cultures. This corresponded very closely with a remarkable reduction in culture DNA content.

Animals↗
PubMed1984

[Effects of sodium iodate, iodoacetic acid and ethambutol on electroretinogram and visual evoked potential in rats].

The effects of sodium iodate (SI), iodoacetic acid (IAA) and ethambutol (EB) on the electroretinogram (ERG) and the visual evoked potential (VEP) were examined in unrestrained rats. A single intravenous dose of SI at 25 mg/kg caused depression of amplitudes of the ERG a-wave and oscillatory potentials 24 hrs after dosing. Following these changes, the amplitude of the ERG b-wave decreased. The depression of the VEP was observed in parallel with the depression in amplitude of the ERG. A single intravenous dose of IAA, even at a dose of 60 mg/kg which induced death of the rats, did not cause any significant abnormality in the ERG and VEP. Repeated subcutaneous dose of EB at 500 mg/kg/day depressed the amplitude of the P1-N1 wave and prolonged the peak latency of the P1 and N1 waves of the VEP without affecting the ERG after administration for 5 to 6 weeks. These abnormalities of the VEP appeared almost in parallel with ataxic gait. Neither gross behavioral changes suggesting visual disturbances nor abnormal ocular fundus was revealed in any rat receiving SI or EB even when marked depression of the ERG and/or VEP was observed. These results indicate that SI damages retinal function and EB does the conduction pathways from the retina to the visual cortex. In addition, the simultaneous recordings of both the ERG and VEP in unrestrained rats were found to be useful for evaluating the visual toxicity, and to furnish useful information on the site of toxic action of drugs.

Animals↗
PubMed1987

Effect of iodoacetic acid upon cochlear potentials.

Lotz et al. reported that perilymphatic application of 5 X 10(-3) M iodoacetic acid (IAA) in the guinea pig does not influence the first-order cochlear microphonics (CM1) under aerobic conditions. However, in ischemia the rate of decline of the second-order microphonics (CM II, also called postmortem CM) was significantly increased by IAA. The authors concluded that glycolysis plays no role in maintaining the CMI, but that it is responsible for supporting the CMII. In carefully controlled experiments we found that in the respiring guinea pig, perilymphatic application of 5 X 10(-3) M IAA produced a rapid and pronounced effect upon both the endolymphatic potential and the CM. In particular, the CM dropped to less than 0.5% of its initial level within 40 min, due to IAA, whereas it took 120 min to drop to the same level in total ischemia (without IAA). We therefore reject the above-mentioned proposition that IAA is ineffective upon cochlear potentials under aerobic conditions; moreover, we find that even under aerobic conditions, the CM drops well below the usual CM II level substantially faster than under anaerobic conditions (without IAA). Other important findings, including an anoxia-sensitive negative component of the endolymphatic potential due to severe intoxication with IAA, and the effects of pretreatment of the organ of Corti with low concentrations of IAA upon the CM II are discussed.

Aerobiosis↗
PubMed1992

Structural and metabolic changes in articular cartilage induced by iodoacetate.

The chemically induced injury to articular cartilage, caused by two successive intra-articular injections of sodium iodoacetate, has been used in studies on the effects of anti-inflammatory and of potentially chondroprotective agents. It has been assumed that the injurious effects are caused by inhibition of the glycolytic pathway. In the present study this inhibition has been shown to be greater than expected from in vitro studies, and to influence equally other oxidative pathways. However, the response is clearly not a simple one in that some of the surface chondrocytes, and synovial lining cells in close proximity to the cartilage, show virtually no inhibition.

Animals↗
PubMed1985

Alterations of ultrastructure and elemental composition in cultured neonatal rat cardiac myocytes after metabolic inhibition with iodoacetic acid.

The purpose of this study was to document changes in cellular fine structure and elemental composition, and their relationship to progression of cell injury, in cultured neonatal rat cardiac myocytes in which impaired energy metabolism was produced by the metabolic inhibitor, iodoacetic acid (IAA). In order to quantitate changes in the concentrations of elements and their subcellular distribution in individual myocytes, electron probe x-ray microanalysis was performed on freeze-dried cryosections of rapidly frozen cells. After 1 hour of exposure to IAA, ATP level was not significantly reduced. Most cells exhibited minimal ultrastructural alterations and had normal elemental profiles, whereas some cells (10 to 25%) had increased sodium and calcium in mitochondria and cytoplasm. After exposure to IAA for 1.5, 2, or 4 hours, the ATP level was reduced to below one third of control, and remained decreased 24 hours after removal of IAA, indicating irreversible depression of this variable. After exposure to IAA for 1.5 hours no longer, many cells showed severe ultrastructural alterations, including contraction or swelling of mitochondria and distortion of the cristae, myofibrillar hypercontraction, and formation of fluid-filled blebs. At 1.5 and 2 hours, approximately 75% or more of the myocytes had increased sodium and calcium and decreased potassium and magnesium in mitochondria, nuclei, and cytoplasm. Thus, the development of an increased calcium concentration in cytoplasm as well as mitochondria of most myocytes was a feature of this transitional period. These data indicate that progressive alterations in the levels and distribution of elements accompany the development of severe ultrastructural changes and irreversible injury in response to impaired energy metabolism in cultured myocytes. These elemental alterations include accumulation of calcium in cytoplasm and mitochondria of myocytes in this model.

Adenosine Triphosphate↗
PubMed1989

Reactive thiols in type II iodothyronine 5'-deiodinases: inactivation by iodoacetate.

Although all iodothyronine 5'-deiodinases require thiol cofactors for activity, the type II variant has been suspected to contain no reactive thiol groups because of its resistance to inactivation by iodoacetate (IAC). We report here that, under suitable stoichiometric conditions for the alkylation reaction, the type II enzyme is substantially inactivated by IAC. The reaction follows pseudo-first-order kinetics with an inactivation rate constant of 0.08 min-1. Moreover, the enzyme is inhibited by hydroxyethyl disulfide and propylthiouracil. These reagents, but not thyroxine, also protect the enzyme from inactivation by IAC, The data suggest that IAC interacts with an essential thiol group in the active center domain.

Animals↗
PubMed1986

Effects of iodoacetic acid on cytoskeleton and adhesiveness of the chick RPE cells in vitro.

The retinotoxic, sulfhydryl-binding drug, iodoacetic acid (IAA), affects embryonic chick retinal pigmented epithelial (RPE) cells grown in primary cultures in a reversible, dose-dependent manner. A dose of 5 X 10(-4) M which produces drastic cell shape changes in about 90 min was chosen to study the effects of IAA on the organization of cytoskeleton and adhesiveness in RPE cells. After treatment of cells with IAA microtubules depolymerize and F-actin becomes redistributed from numerous stress fibers to knob-like aggregates. Vinculin is released from focal contacts and adhesions into the cytosol and, at the same time, adhesiveness of the RPE cells to substratum decreases. Since RPE in vitro is susceptible to the action of IAA, it seems possible that also in vivo some of the retinotoxic effects of IAA might be attributed to its damaging influence on the RPE. Thus, the retinotoxic effects of IAA in vivo cannot be solely attributed to the selective degeneration of photoreceptors by this agent.

Animals↗
PubMed1983

Effect of ethylenediamine-tetra-acetate, sodium, iodoacetate and potassium cyanide on the release of cobalophilins from polymorphonuclear granulocytes during phagocytosis.

The influence of ethylenediamine-tetra-acetate (EDTA, 10(-3) M, 10(-5) M and 10(-7) M), sodium iodoacetate (CH2 . I. COONa, 10(-4) M and 10(-6) M) and potassium cyanide (KCN, 10(-2) M, 10(-3) M and 10(-5) M) on the release of cobalophilins (vitamin B12 binding proteins) from polymorphonuclear granulocoytes (PMN) was studied. The agents mentioned above reduced the release of cobalophilins from resting and functionally stimulated granulocytes. This effect increased with the growth of concentration of these agents in the sample. The inhibitory effect of EDTA, CH2 . I. COONa and KCN on phagocytosis-activated cobalophilins release occurred irrespective of the time of granulocytes stimulation. This could be observed in these experiments, where granulocytes were first affected by these chemical agents and then stimulated functionally, as well as in those samples where EDTA, CH2 . I . COONa, and KCN influenced the cells after incubation with latex particles. The inhibitory effect of EDTA was diminished in the presence of a higher concentration of calcium ions in an incubation medium. On the contrary, CH2 . I . COONa reduced the release of cobalophilins from PMN during phagocytosis irrespective of the concentration of calcium ions in the medium.

Adult↗
PubMed1993

Prolonged effect of iodoacetate on articular cartilage and its modification by an anti-rheumatic drug.

The intra-articular injection of iodoacetate into the knee joint of rats produced changes in the articular cartilage which resembled those of osteoarthritis. It caused virtually total loss of many of the oxidative enzymes, indicating inhibition of the main oxidative pathways. Treatment with an anti-rheumatic drug had little early effect but ultimately led to partial restoration of these pathways. The reduced progression of cartilage degradation induced by this drug was accompanied by some unusual histological features.

Animals↗
PubMed1996

ATP depletion by iodoacetate and cyanide in renal distal tubular cells.

Suspensions of proximal tubular and distal tubular (DT) cells from rat kidney were treated with iodoacetate and potassium cyanide (IAA+KCN) as a model to assess injury from ATP depletion. Cells were also incubated under N2/CO2 to assess if they respond similarly to ATP depletion due to hypoxia. Based on cytotoxic effects of IAA (lactate dehydrogenase [LDH] release, protein sulfhydryl depletion) and inhibition of lactate formation, 20 microM IAA was chosen with 1 mM KCN to inhibit cellular ATP generation. DT cells exhibited significantly greater LDH release due to both IAA + KCN and hypoxia than PT cells. Mechanisms of cellular injury and the ability of various strategies to protect against (IAA+KCN)-induced injury were then studied in isolated renal DT cells to investigate factors responsible for the enhanced susceptibility of this renal cell population, about which little metabolic and toxicological information is known. IAA+KCN produced marked depletion of ATP, only minimal changes in cellular content of glutathione, but significantly decreased cellular content of glutathione disulfide, suggesting generation of a proreductant environment. Extracellular acidosis (pH 6.2 vs. 7.4) completely prevented the increase in LDH release during 2-hr incubations with IAA+KCN and partially prevented ATP depletion. Similarly, preincubation with glutathione, glycine, ATP, or adenosine significantly protected DT cells from injury. Complete restoration of cellular ATP content was not required for protection, although viability correlated better with cellular content of total adenine nucleotides. These studies are the first to explore cellular energetics and cytotoxicity in renal DT cells and demonstrate that these cells are highly sensitive to injury from ATP depletion due to either IAA+KCN or hypoxia.

Acidosis, Renal Tubular↗
PubMed1997

Mono-iodoacetate-induced experimental osteoarthritis: a dose-response study of loss of mobility, morphology, and biochemistry.

OBJECTIVE: To characterize the dose-responsiveness of morphologic and biochemical chondral changes relative to mobility in mono-iodoacetate (MIA)-induced osteoarthritis (OA) in rats. METHODS: Rat mobility was assessed by biotelemetry. Articular lesions were characterized by macroscopic and histologic examinations. Cartilage proteoglycan metabolism was evaluated by the 1,9-dimethylmethylene blue dye binding assay and by radiosulfate incorporation in patellar cartilage. RESULTS: Spontaneous locomotor activity was rapidly, transiently, and dose-dependently decreased after MIA injection into rat knees (primary response). Thereafter, only high doses (0.3 mg and 3.0 mg) led to a secondary progressive long-term loss of spontaneous mobility on day 15, when subchondral bone was exposed. These 2 doses resulted in significant changes in cartilage proteoglycan concentration at day 15 and a strong inhibition of anabolism in the peripheral patellae by day 2, contrasting with the effects of lower doses (0.01, 0.03, and 0.1 mg). CONCLUSION: When a sufficient dose of MIA is used, this model can easily and quickly reproduce OA-like lesions and functional impairment in rats, similar to that observed in human disease. These parameters, as well as proteoglycan metabolism, could serve as indicators for studying chondroprotective drugs, or for evaluating the ability of imaging techniques to detect and evaluate chondral lesions.

Animals↗
PubMed2001

Chemical modification of transducin with iodoacetic acid: transducin-alpha carboxymethylated at Cys(347) allows transducin binding to Light-activated rhodopsin but prevents its release in the presence of GTP.

Modification of transducin (T) with iodoacetic acid (IAA) inhibited its light-dependent guanine nucleotide-binding activity. Approximately 1 mol of [(3)H]IAA was incorporated per mole of T. Cys(347), located on the alpha-subunit of T (T(alpha)), was identified as the major labeled residue in the [(3)H]IAA-modified holoenzyme. In contrast, Cys(135) and Cys(347) were modified with [(3)H]IAA in the isolated T(alpha). IAA-modified T was able to bind tightly to photoexcited rhodopsin (R*), but GTP did not promote the dissociation of the complex between alkylated T and R*. In addition, R* protected against the inhibition of T by IAA. A comparable inactivation of T and analogous interactions between T and R* were observed when 2-nitro 5-thiocyanobenzoic acid (NTCBA) was used as the modifying reagent (J. O. Ortiz and J. Bubis, 2001, Effects of differential sulfhydryl group-specific labeling on the rhodopsin and guanine nucleotide binding activities of transducin, Arch. Biochem. Biophys. 387, 233-242). However, while carboxymethylated T was capable of liberating GDP in the presence of R*, NTCBA-modified T was unable to release the guanine nucleotide diphosphate upon incubation with the photoactivated receptor. Thus, IAA-labeling stabilized a T:R* complex intermediate carrying the empty nucleotide pocket conformation of T. On the other hand, NTCBA-modified T seemed to be "locked" in the GDP-bound state of T, even in the presence of R*.

Animals↗