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Title
Exogenous glutathione decreases cellular cadmium uptake and toxicity.
Author
Kang YJ
Address
Department of Pharmacology and Toxicology' University of North Dakota School of Medicine' Grand Forks 58203.
Source
Drug Metab Dispos, 20(5):714-8 1992 Sep-Oct
Abstract
The effect of intracellular glutathione (GSH) on cadmium metabolism and toxicity has been extensively investigated. However' little is known regarding the effect of extracellular GSH on cellular cadmium responses. Therefore' this study was conducted to investigate the effect of exogenously added GSH on cadmium toxicity in normal rat kidney fibroblasts (NRK-49F). Exponentially growing NRK-49F cells were arrested by serum deprivation and then stimulated with epidermal growth factor (EGF). CdCl2' at concentrations that range from 0.25 to 2 microM' was found to inhibit' in a dose-dependent fashion' the EGF-induced DNA synthesis (as Judged by [3H thymidine incorporation) in the cells. A long-term survival assay revealed that CdCl2 above 1 microM was toxic to the cells. Exogenous GSH had a dose-dependent antagonistic effect on cadmium inhibition of EGF-induced DNA synthesis' and 1 mM GSH was found to block completely cadmium inhibition of both EGF-induced DNA synthesis and cell survival. Exogenously added GSH did not increase intracellular GSH levels but decreased cadmium accumulation by the cells. This decrease was primarily caused by a reduced cadmium uptake. Further studies indicated that exogenous GSH would form a complex with cadmium outside of the cells preventing cellular cadmium uptake. This may explain the mechanism of action of the exogenous GSH in cytoprotection against cadmium. The results also suggested a practical potential for GSH as a cadmium chelator. If GSH were coadministered with a cadmium mobilizer and a gamma-glutamyl transpeptidase inhibitor' it could enhance cadmium excretion from the body.

Title
Effects of a hepato-protective agent and a hepato-secreting chelator on cadmium-induced nephrotoxicity in Syrian hamsters.
Author
Shibasaki T; Matsumoto H; Gomi H; Ohno I; Ishimoto F; Sakai O
Address
Second Department of Internal Medicine' The Jikei University School of Medicine' Nishi-Shimbashi' Minato-ku' Tokyo 105' Japan.
Source
Biol Trace Elem Res, 52(1):1-9 1996 Apr
Abstract
cadmium (Cd)-induced nephropathy in male Syrian hamsters was treated with D/L-penicillamine (D/L-p) or neomynophagen C (NMC). The subcutaneous inJection of CdCl(2)' 3 mg/kg' three times a week led to marked renal damage' ie.' increased proteinuria and the excretion of urinary N-acetyl-beta-D-glucosaminidase (NAG) as compared with the saline-inJected controls. Cd-treated hamsters that were inJected intraperitoneally with D/L-p' 0.1 mg/kg' five times a week' showed less renal damage' including a reduction in urinary protein from 3.60 + or - 0.42 to 1.77 + or - 0.7 mg/d. NMC-treated hamsters showed a reduced excretion of NAG (from 1.47 +/ - 0.34 to 0.91 + or - 0.68 u/d). The concentration of Cd in renal cortical tissue was reduced slightly (from 2.78 + or - 0.08 to 2.34 + or - 0.3 mg/g.prot) by NMC treatment' but not by D/L-p. The elevated malondialdehyde (MDA) in renal cortical tissue was unaffected by administering D/L-p or NMC. The concentration of glutathione (CSH) in the renal cortex was not elevated after administering Cd' but the ratio of the reduced to the oxidized GSH was elevated. The Cd induced liver dysfunction' as compared with untreated controls. The dysfunction was improved slightly by NMC administration' but not by that of D/L-p. Changes in renal morphology induced by Cd involving marked degeneration and necrosis of tubules as shown by light microscopy' were unaffected by treatment with D/L-p or NMC. We thus demonstrated the efficacy of D/L-p of NMC in treating the nephropathy induced by Cd in hamsters. The mechanism of therapeutic effect is not known.

Title
A comparative study of the influence of vicinal dithiols and a dithiocarbamate on the biliary excretion of cadmium in rat.
Author
Jones MM; Cherian MG; Singh PK; Basinger MA; Jones SG
Address
Department of Chemistry' Vanderbilt University' Nashville' Tennessee
37235.
Source
Toxicol Appl Pharmacol, 110(2):241-50 1991 Sep 1
Abstract
The effect of two vicinal dithiols' 2'3-dimercaptopropan-1-ol (BAL) and N-(2'3-dimercaptopropyl)phthalamidic acid (DMPA)' and a dithiocarbamate' sodium N-(4-methoxybenzyl)-D-glucamine dithiocarbamate (MeOBGDTC)' on the biliary excretion of cadmium was examined in rats. Tissue cadmium levels were also determined following the measurements of biliary excretion of cadmium. At 30 min after the inJection of CdCl2.2.5H2O (1 mg/kg' iv) each rat was given 400 mumol/kg ip of one of the compounds' BAL' DMPA or MeOBGDTC. While all the compounds increased the biliary excretion of cadmium' the most effective was MeOBGDTC' whose administration resulted in a 580% increase in biliary cadmium content. The effectiveness of the MeOBGDTC may be due to the presence of both nonpolar and nonionizing polar groups attached to nitrogen. MeOBGDTC was able to mobilize cadmium to the bile even after the occurrence of the synthesis of metallothionein and the incorporation of the cadmium into it. An attempt was also made to determine the chemical nature of the Cd-MeOBGDTC complex present in the bile by comparing a newly synthesized authentic sample of Cd(MeOBGDTC)2 complex with the hot dioxane extract of the freeze-dried bile samples using thin-layer chromatography and proton NMR. The results suggested that cadmium excreted in the bile in part' is complexed to MeOBGDTC and glutathione.

Title
Nuclear magnetic resonance studies of the solution chemistry of metal complexes. 26. Mixed ligand complexes of cadmium' nitrilotriacetic acid' glutathione' and related ligands.
Author
Kadima W; Rabenstein DL
Address
Department of Chemistry' University of Alberta' Edmonton' Canada.
Source
J Inorg Biochem, 38(4):277-88 1990 Apr
Abstract
The complexation of glutathione and related ligands by the nitrilotriacetic acid complex of Cd2+ (Cd(NTA)-) has been investigated by 1H NMR as a model for the coordination chemistry of Cd2+ and GSH in biological systems. Related ligands included glycine' glutamic acid' cysteine' N-acetylcysteine' penicillamine' N-acetylpenicillamine' mercaptosuccinic acid' and the S-methyl derivative of glutathione. The nature of the complexes formed was deduced from 1H NMR spectra of Cd(NTA)- and the ligands. Mixed ligand complexes (Cd(NTA)L) and single ligand complexes (CdLx) are formed with the thiol ligands' whereas only mixed ligand complexes form with glycine' glutamic acid and S-methylglutathione. Formation constants of the mixed and the single ligand complexes were determined from NMR data. The results indicate that formation constants for binding of a thiolate donor group by Cd2+' either as the free ion or in a coordinately unsaturated complex' are in the range 10(5)-10(6).

Title
Comparative investigations on the effects of acute intraperitoneal cadmium, chromium, and mercury exposure on the kidney.
Author
Bomhard E; Maruhn D; Vogel O
Source
Uremia Invest, 9(2):131-6 1985-86
Abstract
Urinary excretion of lactate dehydrogenase (LDH), glutathione-S-transferase (GST), leucine arylamidase (LAS), gamma-glutamyltransferase (GGT), beta-galactosidase (GAL), beta-N-acetyl-D-glucosaminidase (NAG), sodium, and glucose were determined in female Sprague-Dawley rats the subsequent three days after intraperitoneal treatment with single doses of 4.5 mg CdCl2 X 1H2O/kg, 20 mg Na2CrO4/kg, and 0.75 mg HgCl2/kg body weight. Although the pathological effects were localized within the same part of the nephron (i.e., the proximal tubule), there were marked differences with regard to the extent and time course of the parameters affected. Treatment with cadmium resulted essentially in a marked decline in sodium and glucose excretion. The administration of chromate led to a slightly to moderately elevated excretion of the enzyme activities measured with the cytosolic LDH as the most increased enzyme (ca. 500% of controls on Day 3 postadministration). Median glucose excretion was unaffected whereas sodium excretion was transiently reduced. The maximum of enzyme excretion after HgCl2 was essentially the same on the first day postadministration and the amount of enzyme activity in urine up to 20 times higher compared to that after chromium. Sodium excretion was below that of controls on Days 2 and 3, whereas glucose excretion was markedly elevated (up to 8000% of controls). The results indicate that it is possible to discriminate with the use of selected urinary enzymes, substrates, and electrolytes various kinds of nephrotoxic actions not only in different but also within the same part of the nephron.

Title
Protective effects of GSH' vitamin E' and selenium on lipid peroxidation in cadmium-fed rats.
Author
Rana SV; Verma S
Address
Department of Zoology' Ch. Charan Singh University' Meerut' India.
Source
Biol Trace Elem Res, 51(2):161-8 1996 Feb
Abstract
Increased intake of Cd results in its retention and in peroxidative damage in soft tissues. Coadministration of antioxidants' viz.' glutathione (GSH)' alpha-tocopherol' and Se' restricted the uptake and distribution of Cd in liver and kidney of rats. Moreover' no rise in malondialdehyde was recorded. Although possible antioxidative mechanisms manifested by GSH' alpha-tocopherol' and Se have been discussed' it is hypothesized that GSH functions as a Cd chelator. glutathione yielded favorable effects in comparison to Se and alpha-tocopherol.

Title
Effect of arsenicals on biliary excretion of endogenous glutathione and xenobiotics with glutathione-dependent hepatobiliary transport.
Author
Gyurasics A; Varga F; Gregus Z
Address
Department of Pharmacology' University Medical School of P]ecs'
Hungary.
Source
Biochem Pharmacol, 41(6-7):937-44 1991 Mar 15-Apr 1
Abstract
Sodium arsenite (25-100 mumol/kg' i.v.) and arsenate (75-300 mumol/kg' i.v.) inJected into anaesthetized rats increased the biliary excretion of endogenous non-protein thiols (NPSH) in a dose-dependent fashion up to 24- and 31-fold' respectively. Simultaneously with NPSH' glutathione (GS) excretion was increased to a similar extent suggesting that the increment in biliary thiol output originated from enhanced hepatobiliary transport of GS. After administration of labelled arsenicals' biliary excretion of 74As and NPSH followed similar time-courses. Biliary excretion of 74As was more efficient after arsenite than arsenate administration corresponding to the greater potency of arsenite compared to arsenate to increase biliary output of NPSH. Coadministered sulfobromophthalein (BSP) inhibited the biliary excretion of 74As and prevented the arsenical-induced increase in biliary NPSH. Thus' hepatobiliary transport of arsenic apparently proceeds coordinately with that of GS. However' excretion of each molecule of arsenic compound generates transport of several molecules of GS. Though mercuric' methylmercuric' cadmium and zinc ions are thought to be excreted into bile as complexes with GS' the marked arsenical-induced increase in GS excretion only doubled the biliary excretion of inorganic mercury and hardly influenced the transport of other metals into bile. This finding suggests that arsenicals markedly enhance biliary excretion of GS with a free thiol group but barely or not at all that of GS with a thiol group blocked by a firmly bound metal ion. Both arsenicals diminished the biliary excretion of BSP-glutathione conJugate after BSP administration presumably because they impaired conJugation of BSP with GSH due to decreased GS availability. It is assumed that arsenite' and arsenate after reduction to arsenite' forms an unstable complex with GS that is efficiently transported into bile resulting in increased biliary output of GS. It is demonstrated that arsenite-induced perturbation of hepatobiliary disposition of endogenous GS differentially affects biliary excretion of xenobiotics with GS-dependent hepatobiliary transport.

Title
Studies on the efficacy of lipoate and dihydrolipoate in the alteration of cadmium2+ toxicity in isolated hepatocytes.
Author
M uller L; Menzel H
Address
Institute of Toxicology' University of D usseldorf' F.R.G.
Source
Biochim Biophys Acta, 1052(3):386-91 1990 May 22
Abstract
Lipoate (thioctic acid) is presently used in therapy of a variety of diseases such as liver and neurological disorders. However' nothing is known about the efficacy of lipoate and its reduced form dihydrolipoate in acute cadmium (Cd2+) toxicity which involves severe liver disturbances. Therefore' we investigated the effects of these redox compounds on Cd2(+)-induced inJuries in isolated rat hepatocytes. The cells were coincubated with 150 microM Cd2+ and either 1.5-6.0 mM lipoate or 17-89 microM dihydrolipoate for up to 90 min and Cd2+ uptake as well as viability criteria were monitored. Both exposure regimens diminished Cd2+ uptake in correspondence to time and concentration. They also ameliorated Cd2(+)-induced cell deterioration as reflected by the decrease in Cd2(+)-induced membrane damage (leakage of aspartate aminotransferase)' by the lessening of the Cd2(+)-stimulated lipid peroxidation (TBA-reactants) and by the increase in Cd2(+)-depleted cellular glutathione (GSH + 2 GSSG). Half-maximal protection was achieved at molar ratios of 9.9 to 19 (lipoate vs. Cd2+) and 0.25 to 0.74 (dihydrolipoate vs. Cd2+)' indicating a 19.5 to 50.6 lower protective efficacy of lipoate as compared to dihydrolipoate. Lipoate induced an increase in extracellular acid-soluble thiols different from glutathione. It is suggested that dihydrolipoate primarily protects cells by extracellular chelation of Cd2+' whereas intracellular reduction of lipoate to the dihydro-compound followed by complexation of both intra- and extracellular Cd2+ contributes to the amelioration provided by lipoate.

Title
Influence of selenium supplement on cadmium metabolism in human
Author
Wei HJ
Source
Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao, 11(3):185-9 1989 Jun
Abstract
38 subjects were randomly divided into 2 groups of 19 each. Group 1 consumed a selenium supplement (150 micrograms/d X 21) and Group 2 received only placebo(glucose). After supplementation, blood Se levels and plasma GSH-Px activities in Group 1 increased from 76 to 100 ng/ml (P less than 0.05) and 0.082 to 0.122 e.u./ml (P less than 0.01) respectively. All measured Se, GSH-Px values in Group 2, and high concentrations of lipid peroxides (greater than 4 nmol/ml as malonaldehyde) in both groups remained approximately the same. Se supplementation resulted in a marked decrease of RBC cadmium (Cd) from 32.3 to 25.4 micrograms/g Hb (P less than 0.001). Urinary and fecal Cd in 5 subjects of each group were analyzed every 4 days, and the results demonstrated that Cd was mainly excreted in feces after Se supplementation. One week after discontinuing of Se treatment, Cd content in urine and feces decreased to control levels. Theoretical evidence for chemoprevention of lung cancer with Se in this area was thus provided.

Title
glutathione transferases in the urine: sensitive methods for detection of kidney damage induced by nephrotoxic agents in humans.
Author
Sundberg A; Appelkvist EL; Dallner G; Nilsson R
Address
Clinical Research Center' Karolinska Institute' Huddinge Hospital' Stockholm' Sweden.
Source
Environ Health Perspect, 102 Suppl 3():293-6 1994 Sep
Abstract
With the aid of immunohistochemical methods the localization of the various isoenzymes of glutathione S-transferase was investigated. The alpha isoenzyme was present solely in the proximal tubular cells of the human kidney' while the pi form was restricted to the distal convoluted tubules' the thin loop of Henle' and the collecting ducts. Damage to the epithelial cell membranes results in the increased excretion of these enzymes with the urine. The alpha and pi isoenzymes have been isolated in a highly purified form and used for the production of polyclonal antisera. Subsequently' radioimmunological and ELISA techniques were developed for quantitation of these proteins in the urine; the methods exhibited a high specificity and were sufficiently sensitive to determine nanogram quantities or less. Disease affecting tubular function' cyclosporine A treatment' administration of nephrotoxic antibiotics' and exposure to cadmium all resulted in characteristic changes in the pattern of the glutathione transferase isoenzymes present in urine. Such effects were seen also in patients who had previously been exposed to nephrotoxic agents' but in whom conventional tests for kidney function were apparently normal. Thus' it appears that radioimmunologic or immunochemical quantitation of alpha and pi forms of the enzyme can be used as sensitive and relatively simple markers for the early detection of toxic effects with respect to the renal tubuli.

Title
Role of metallothionein in metal detoxification and metal tolerance in protein calorie malnutrition and calcium deficient monkeys (Macaca
mulatta).
Author
Nath R; Paliwal VK; Prasad R; Kambadur R
Address
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Source
EXS, 52():631-8 1987
Abstract
A monkey model has been set up for protein calorie malnutrition and calcium deficiency. Oral exposure of 5ppm Cd/kg body wt./day for 24 weeks led to increased excretion of Cd, metallothionein (MT) and zinc. Rehabilitation of PCM monkeys for one year resulted in gradual reduction and finally complete disappearance of urinary metallothionein. During Cd exposure, the accumulation of Cd and induction of MT was significantly higher in liver, kidney and intestine. MT was also induced in heart, lung and testis of Cd exposed PCM and calcium deficient monkeys. Metallothionein from liver has been resolved into three isoforms, viz MTa, MTb and MTc on DEAE-Sephadex A 25 ion exchange column. MTc is the major isoform in Cd-treated, normal and protein calorie malnourished monkeys whereas MTb is the major isoprotein in the cadmium treated calcium deficient monkeys. The iso-metallothioneins varied in their metal composition in the nutritional stress conditions and showed different capacities to reactivate apo-enzymes viz. alkaline phosphatase, ceruloplasmin, superoxide dismutase and glutathione peroxidase. Thus, metallothionein plays a key role in metal metabolism during cadmium toxicity under nutritional stress conditions.

Title
Toxic heavy metal ions activate the heme-regulated eukaryotic initiation factor-2 alpha kinase by inhibiting the capacity of hemin-supplemented reticulocyte lysates to reduce disulfide bonds.
Author
Matts RL; Schatz JR; Hurst R; Kagen R
Address
Department of Biochemistry' Oklahoma State University' Stillwater
74078-0454.
Source
J Biol Chem, 266(19):12695-702 1991 Jul 5
Abstract
Addition of toxic heavy metal ions (Cd2+' Hg2+' and Pb2+) to hemin-supplemented rabbit reticulocyte lysate brings about the activation of the heme-regulated eukaryotic initiation factor 2 alpha kinase (HRI) and the inhibition of protein chain initiation. In this report we examined the effects of monothiol and dithiol compounds' metal ion-chelating agents' and metallothioneins (MT) on metal ion-induced inhibition of protein synthesis. The dithiol compounds dithiothreitol and 2'3-dimercaptopropane sulfonic acid prevented and relieved the inhibition of protein synthesis caused by Cd2+ and Hg2+ in hemin-supplemented lysates' but the monothiol compounds 2-mercaptoethanol' cysteamine' D-(-)penicillamine' and glutathione had no effect. The inhibition of protein synthesis caused by Cd2+ was reversed by the addition of excess EDTA but not by the addition of excess nitrilotriacetic acid. Toxic heavy metal ions inhibited the capacity of hemin-supplemented lysate to reduce disulfide bonds. Addition of excess EDTA to Cd(2+)-inhibited lysates restored the capacity of the lysate to reduce disulfide bonds and inhibited the phosphorylation of eukaryotic initiation factor eIF-2. MTs and their apoproteins (apoMTs) inhibited the activation of HRI and protected protein synthesis from inhibition by Cd2+' Hg2+' and Pb2+. Addition of apoMTs to heavy metal ion-inhibited lysates restored the capacity of lysates to reduce disulfide bonds. The restoration of the lysate`s thioredoxin/thioredoxin reductase activity was accompanied by the inactivation of HRI and the resumption of protein synthesis' indicating that apoMTs can "detoxify metal ions already bound to proteins. Several observations presented in this report suggest that the binding of metal ions to the alpha-domain of MT is responsible for the ability of MT to sequester bound metal in a non-toxic form. Addition of glucose 6-phosphate or NADPH had no effect on protein synthesis in metal ion-inhibited lysates' and NADPH concentrations in Cd(2+)-inhibited and hemin-supplemented control lysates were equivalent. The data suggest that the metal ions cause the inhibition of protein synthesis by binding to vicinal sulfhydryl groups present in some critical protein(s)' possibly the dithiols present in the active site of thioredoxin and (or) thioredoxin reductase' which leads to the activation of HRI.

 

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