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G R Gale

Publications and source records attributed to G R Gale.

At least 37 records · Page 2Linked to original sources

Mechanistic aspects of the dithiocarbamate-induced mobilization of cadmium.

The examination of some of the species involved in the in vivo processes in which dithiocarbamates mobilize cadmium from its intracellular deposits indicates that several competing reactions occur. Rates of hydrolytic decomposition of a series of dithiocarbamates capable of mobilizing cadmium in vivo have been determined, and the solubility behavior and nuclear magnetic resonance (NMR) spectra of their cadmium complexes have been examined. Some of the dithiocarbamates most effective in this mobilization process are shown to undergo slow conversion to oxazolidine-2-thiones in the presence of cadmium. All of the cadmium complexes involved in the mobilization process are shown to undergo rapid ligand exchange. While dissociative mechanisms based on the turnover of metallothionein are inconsistent with the experimental data, at least two associative mechanisms are possible. These involve attack on the metallothionein by the dithiocarbamate itself or by a compound derived from it by known metabolic processes.

Animals↗

N,N-disubstituted dithiocarbamates as cadmium antagonists: N-(4-methoxybenzyl)-N-dithiocarboxy-D-glucamine.

The newly synthesized dithiocarbamate analog, N-(4-methoxybenzyl)-N-dithiocarboxy-D-glucamine (MeOBDCG) reduced whole-body cadmium levels 66% in cadmium-laden mice when given as 3 injections at 1.0 mmol/kg. Renal and hepatic Cd concentrations were reduced 78 and 85%, respectively. After 6 injections, the whole-body cadmium burden was reduced 71%, while renal and hepatic levels were lowered 84% and 91%, respectively. Mobilized cadmium was excreted almost exclusively by the fecal route. There was no evident toxicity consequent to treatment as judged by mouse body weights and by gross appearance of organs upon dissection. On a molar dose basis, MeOBDCG was more effective than N-benzyl-N-dithiocarboxy-D-glucamine (BDCG) in removing cadmium from both renal and hepatic deposits. An in-vitro assessment of the interaction of MeOBDCG, BDCG and N-methyl-N-dithiocarboxy-D-glucamine with murine cadmium-metallothionein (Cd-MT) revealed a direct relationship between the extent of cadmium depletion from Cd-MT and the relative in-vivo efficacies of the 3 analogs.

Animals↗

Mobilization of lead by esters of meso-2,3-dimercaptosuccinic acid.

An examination was made of the relative efficacies of 2,3-dimercapto-1-propanol (BAL) and three diesters ( [CH(SH)COOR]2; DMDMS, R = CH3; DEDMS, R = C2H5; and Di-PDMS, R = CH(CH3)2] of meso-2,3-dimercaptosuccinic acid (DMSA) in mobilizing freshly injected lead from mice. These diesters, like BAL, reduced the lead levels resulting from freshly injected lead in both the soft tissues (liver, kidneys, spleen, and brain) and the bone (tibia). After treatment with the dimethyl (DMDMS), the diethyl (DEDMS), and the diisopropyl (Di-PDMS) esters the lead content of each of the organs was significantly less than that present in the untreated controls. Each of the diesters reduced lead levels in the kidneys, liver, and spleen significantly below those levels found after BAL treatment. The action of the diesters in reducing brain lead levels was comparable to that of BAL. Di-PDMS was the most effective of these compounds and was significantly superior to BAL. Each of the esters was also significantly more effective than BAL in reducing the whole body level of lead.

Animals↗

Effect of chelating agent structure on the mobilization of cadmium from intracellular deposits.

An examination of the efficacy of several structural types of chelating agents in the removal of cadmium from its intracellular deposits in mouse liver and kidneys reveals that of the structural types examined, only dithiocarbamates and a vicinal dithiol were able to mobilize cadmium from such intracellular sites. Esters of L-cysteine, a macrocyclic thioether, and a disulfide of a dithiocarbamate were unable to cause any appreciable decrease in either renal or hepatic cadmium levels. Charged groups such as carboxylic acid groups reduce the efficacy as well as the toxicity of the structural types that can otherwise mobilize such cadmium. It was also found that the administration of a cadmium-binding polymer ip leads to only a very slight net excretion of cadmium, while the po administration of this polymer leads to no net additional cadmium excretion. Of the compounds newly reported here, some are approximately equal in cadmium-mobilizing efficacy to the most effective of previously reported compounds.

Animals↗

Antipseudomonal effects of selected dithiocarbamates alone and in combination with gentamicin or aztreonam.

The antipseudomonal effects conferred by combinations of substituted dithiocarbamates, gentamicin or aztreonam (Azactam) were measured and compared to those produced by single agents alone in female BALB/C mice bearing overwhelming Pseudomonas aeruginosa infections. Dimethyldithiocarbamate (DMDTC), diethyldithiocarbamate (DEDTC), and sodium N-methyl-D-glucamine dithiocarbamate (NMGDTC) were chosen as representative substituted dithiocarbamates. All three dithiocarbamates rescued some cisplatin-immunosuppressed mice from pseudomonal infections but DMDTC and NMGDTC produced better results than DEDTC. Single daily injections of DMDTC at doses of 5 mg/kg/day or higher for a total of 7 days rescued 14 of 18 mice given 10(6) viable Pseudomonas aeruginosa by tail vein inoculation. Similar dose regimens of 10 mg/kg/day or higher NMGDTC for a total of 7 days rescued 15 of 18 mice. DEDTC at doses of 5 mg/kg/day or higher for 7 days rescued 7 of 18 mice. Combinations of DMDTC or NMGDTC with gentamicin failed to produce better results than each agent alone in mice immunosuppressed with methyl-prednisolone (Solumedrol) at the dose range evaluated in mice inoculated with 10(6) viable organisms via tail veins. Combinations of DMDTC and aztreonam were effective in mice immunosuppressed with methylprednisolone and given overwhelming numbers of viable Pseudomonas aeruginosa (10(7) or more, ip). Combinations of 6 mg/kg/day or higher of each agent with multiple daily injections rescued 11 of 18 mice. The results yielded by either agent alone were not impressive. Similar results were obtained when mice immunosuppressed with cisplatin were given ip injections of 10(8) or more viable bacteria. No mice were rescued by the use of DMDTC, NMGDTC, aztreonam or gentamicin only. Combinations of DMDTC (6 mg/kg) and aztreonam (6 mg/kg) with multiple daily injections for seven days rescued 11 of 20 infected mice while combinations of NMGDTC with aztreonam were less effective (3 of 20 rescued). The concurrent administration of DMDTC and aztreonam offers considerable promise in the treatment of overwhelming pseudomonal infections in mice and may prove to be of value in human patients as well.

Animals↗

Comparative effects of disulfiram and diethyldithiocarbamate on cadmium distribution in mice.

It has been reported that disulfiram (DSF) and diethyldithiocarbamate (DDTC) have similar actions on cadmium (Cd) distribution in maternal and fetal organs when given to pregnant mice prior to and again immediately after iv administration of Cd (Arch. Toxicol. 55, 161-167, 1984). We have now examined Cd distribution in mice in which virtually all of the Cd was bound to metallothionein (MT) in an attempt to simulate more closely the condition of low level, chronic Cd exposure. When DSF was incorporated into food and ingested by mice over a 4-hr period on each of four days, hepatic and pulmonary Cd levels were reduced significantly. When given ip at 500 mg/kg, DDTC lowered hepatic, renal, splenic, and pancreatic Cd levels, but increased Cd concentrations in brain, testes, heart, and lungs. When DSF was given at 500 mg/kg ip, it lowered hepatic, splenic, testicular, and pancreatic Cd levels, but increased Cd concentrations in heart and brain. In contrast to DDTC, DSF had no effect on pulmonary or renal Cd. When given as a bolus dose po for five days at 1.0 mmole/kg, DDTC lowered renal, splenic, testicular, and pancreatic Cd levels, but increased Cd concentrations in brain and heart. There was no effect on hepatic or pulmonary Cd. When given at the same dose po, DSF did not alter the Cd concentration of any organ assessed. We suggest that studies of interactions of various xenobiotics with Cd in vivo should be done with an animal model which simulates chronic Cd exposure rather than acute Cd intoxication.

Animals↗

Esters of meso-dimercaptosuccinic acid as cadmium-mobilizing agents.

The dimethyl, diethyl, di-n-propyl, diisopropyl (Di-PDMS), and di-n-butyl esters of meso-2,3-dimercaptosuccinic acid were prepared by esterification of the parent acid and were subsequently purified and characterized. Their relative ability to mobilize cadmium from its aged (greater than 30 days) deposits was evaluated in mice in comparison with 2,3-dimercapto-1-propanol (BAL). All but the dimethyl ester were superior to BAL in reducing the hepatic cadmium levels, though none was superior in reducing renal cadmium levels. Their efficacy in reducing hepatic cadmium levels had the result that all except the dimethyl ester were significantly more effective than BAL in reducing total cadmium body burdens in mice. The most effective of these compounds, Di-PDMS, caused a reduction of whole body cadmium of 59% (i.e., to 41% of control values) under conditions where the corresponding reduction found for BAL was only 18% (i.e., to 82% of control value). The predominant route of excretion of cadmium subsequent to administration of these compounds is via the fecal route (greater than 99%). A synergistic effect was found in the reduction of whole body and kidney cadmium burdens when Di-PDMS was used in combination with trisodium calcium diethylenethriaminepentaacetate.

Animals↗

N-alkyl-N-dithiocarboxy-D-glucamine analogs as cadmium antagonists: synthesis and evaluation of the n-propyl, n-butyl, and n-amyl derivatives.

N-(n-Propyl)-, N-(n-butyl)-, and N-(n-amyl)-N-dithiocarboxy-D-glucamine were newly synthesized by (a) addition of each n-alkylamine to glucose, (b) high-pressure catalytic reduction of each glucosamine thus formed to the corresponding glucamine, and (c) reaction of the resultant secondary amines with CS2 to form the dithiocarboxy derivatives. Each compound was evaluated as an antagonist of acute cadmium (Cd) toxicity and as a complexing agent for intracellular metallothionein-bound Cd (Cd-MT) in mice. N-Benzyl-N-dithiocarboxy-D-glucamine (BDCG) was used as a positive control compound. Each congener afforded partial or complete protection against the lethal effects of 10.0 mg/kg CdCl2.2.5 H2O, and retarded accumulation of Cd in livers and kidneys when given 2 h after the acutely toxic dose of Cd. Each derivative was also effective in mobilizing Cd from MT-bound sites in livers and kidneys of mice which had received a sub-lethal dose of CdCl2 along with 109CdCl2 2 weeks earlier. Excretion of mobilized Cd was almost exclusively by the fecal route. Potency of the analogs, as well as the octanol/aqueous partition coefficients, increased with the overall length of the N-(n-alkyl) carbon chain. Each compound readily complexed Cd from partially purified Cd-MT in vitro. Serum Cd from mice treated with BDCG was associated principally with proteins of high molecular weight.

Animals↗

Meso-2,3-dimercaptosuccinic acid and sodium N-benzyl-N-dithiocarboxy-D-glucamine as antagonists for cadmium intoxication.

Orally administered meso-2,3-dimercaptosuccinic acid (DMSA) is an effective antagonist for acute oral cadmium chloride (1 mmol/kg) intoxication in mice when administered up to 8 h after cadmium ingestion. Administration of sodium N-benzyl-N-dithiocarboxy-D-glucamine (NaB) i.p. along with DMSA p.o. resulted in kidney and liver cadmium levels only marginally smaller than those obtained with DMSA alone. Both chelation treatment regimens permitted survival of 80% or more of the animals, in comparison to a survival rate of 40-50% in untreated animals. Intraperitoneally administered NaB by itself is a very effective antagonist for cadmium chloride administered intraperitoneally in either acute or chronic cadmium intoxication. A dose-response study was made of the mobilization of cadmium from the liver and kidney of cadmium-loaded mice by NaB; this showed that NaB is one of the most effective cadmium mobilizing agents developed to date. We have also confirmed the earlier report of Kojima and his co-workers of the ability of NaB to remove cadmium from animals which have been treated with cadmium over an extended period of time. NaB causes a very large increase in the biliary excretion of cadmium. Nuclear magnetic resonance (NMR) spectra of 113Cd in bile from treated animals and model solutions indicates that such cadmium is undergoing rapid ligand exchange.

Administration, Oral↗

Mobilization of aged in vivo cadmium deposits by diethyl dimercaptosuccinate.

Diethyl dimercaptosuccinate (DEDMS) was prepared and found to be capable of mobilizing cadmium from mice one month after they had been given an injection (i.p.) of 0.03 mg CdCl2.2.5H2O containing 1.0 microCi of 109 CdCl2. When pure, DEDMS is a waxy solid with a melting point of 61-62 degrees C which is soluble in warm peanut oil. Its LD50 value (i.p.) in mice is approximately 2.6 mmol/kg, a value which allows it to be given at a higher dosage than other known lipid-soluble dithiols. This compound is especially effective in reducing hepatic and whole body levels of cadmium; it is not as effective as 2,3-dimercaptopropanol (BAL) in reducing renal cadmium levels.

Animals↗

Dithiocarbamate treatment of chronic cadmium intoxication in mice.

The dithiocarbamate analogs, N-benzyl-N-dithiocarboxy-D-glucamine (BDCG) and N-cyclohexyl-N-(2-hydroxy-3-sulfonatopropyl)dithiocarbamate (CAPSO-DTC), were evaluated as cadmium (Cd) antagonists in mice which had received repetitive injections of Cd to effect accumulation of substantial levels of metallothionein-bound Cd in kidneys and livers. BDCG was highly effective in lowering whole body Cd stores and renal Cd concentrations. While the percent of renal Cd mobilized decreased with increasing Cd concentrations, the total amount of Cd mobilized increased. CAPSO-DTC was also effective in reducing whole body Cd levels, but appeared to have less affinity for renal Cd than did BDCG. Treatment of Cd-laden mice with BDCG provoked only a modest elevation of serum creatinine levels, suggesting that the complex of Cd with BDCG may be less nephrotoxic than the complex of Cd with EDTA or dimercaprol. The log of the percent reduction of renal Cd by BDCG was found to be a linear function of the pretreatment renal Cd concentration, and reductions of whole body Cd burdens correlated closely with reductions of liver and kidney Cd concentrations. It was suggested that a Cd complexing agent of the dithiocarbamate class may have ultimate application in a provocative methodology to estimate body or organ Cd stores based upon the amount of Cd excreted following a standard dose of the chelator.

Animals↗

Mobilization of cadmium in mice by combined treatment with N-benzyl-N-dithiocarboxy-D-glucamine and diesters of meso-2, 3-dimercaptosuccinic acid.

Mice which had received a non-lethal injection of cadmium (Cd) as CdCl2 nine days prior to therapy were treated with N-benzyl-N-dithiocarboxy-D-glucamine (BDCG) alone or in combination with either di(iso-butyl)dimercaptosuccinate (DiBDMS) or di(iso-amyl)-dimercaptosuccinate (DiADMS). Seven injections of BDCG (1.0 mmole/kg), DiBDMS (0.4 mmole/kg), and DiADMS (0.4 mmol/kg) reduced whole body Cd burdens 50%, 54% and 37%, respectively; coadministration of BDCG + DiBDMS and BDCG + DiADMS produced respective reductions of 65% and 61%. Seven injections of BDCG lowered renal Cd concentrations an average of 82%, but reduced hepatic Cd concentrations only 53%. The DMSA diesters were more effective in lowering hepatic Cd than in reducing the levels of Cd in the kidneys. The respective hepatic and renal Cd reductions were 50% and 20% after treatment with DiADMS, and were 73% and 30% after treatment with DiBDMS. Coadministration of BDCG with DiADMS reduced hepatic and renal Cd concentrations 74% and 82%, respectively, while BDCG co-administered with DiBDMS yielded respective reductions of 80% and 82%. It is suggested that combined use of these newer Cd complexing agents in studies of experimental Cd poisoning may now permit resolution of the issue of reversibility of Cd-induced nephrotoxicity.

Animals↗

Interaction of caffeine with acetaminophen in mice: schedule dependency of the antagonism by caffeine of acetaminophen hepatotoxicity and the effects of caffeine metabolites, allopurinol, and diethyl ether.

Administration of caffeine (CAF) to mice as early as 6 hr prior to injection of a hepatotoxic but nonlethal dose of acetaminophen (ACM) significantly antagonized the hepatotoxic action of ACM as judged by serum levels of alanine aminotransferase (ALT) activity. Administration of CAF after ACM produced complete antagonism only when CAF was given no later than 1 hr after ACM. Administration of CAF daily for 3 days prior to injection of ACM enhanced ACM toxicity markedly, but little or no toxicity ensued when CAF-pretreated mice received ACM followed immediately by CAF. The four primary metabolites of CAF, 1,3-dimethylxanthine (theophylline), 3,7-dimethylxanthine (theobromine), 1,7-dimethylxanthine (paraxanthine), and 1,3,7-trimethyluric acid were effective and virtually complete antagonists of ACM-induced hepatotoxicity when given immediately after ACM, as were the secondary metabolites, 1-methylxanthine and 1,3-dimethyluric acid. Allopurinol, which reduces theophylline clearance, increases the rate of oxidative N-demethylation of theophylline to 1-methylxanthine, and inhibits conversion of 1-methylxanthine to 1-methyluric acid, was also a dose-dependent antagonist of ACM-induced hepatotoxicity. The hepatotoxic response of mice to ACM is exaggerated by a brief period of diethyl ether anesthesia; CAF given immediately after ACM to previously anesthetized mice suppressed this response and maintained serum ALT levels at control values. It is suggested that CAF and its primary metabolites compete with ACM for biotransformation by the cytochrome P-450 mixed function oxidase system, thereby reducing the rate of formation of the hepatotoxic ACM metabolite.

Acetaminophen↗

Amphipathic dithiocarbamates as cadmium antagonists: N-cyclohexyl-N-sulfonatoalkyl derivatives.

Disodium salts of the substituted dithiocarbamates (DTCs) N-cyclohexyl-N-(2-sulfonatoethyl) DTC, N-cyclohexyl-N-(3-sulfonatopropyl) DTC, and N-cyclohexyl-N-(2-hydroxy-3-sulfonatopropyl) DTC were synthesized and assessed as complexing agents for reducing organ concentrations of cadmium (Cd) in mice. At least one week after mice were given 0.03 mg of CdCl2.2.5 H2O containing 1.0 microCi of 109CdCl2 ip they were treated ip with various doses of each DTC. Administration of 4.44 mmoles/kg of each analog q2dx4 produced about a 60% reduction in the whole-body Cd burdens. There was approximately a 50% reduction of renal Cd concentrations and a greater than 90% reduction of hepatic Cd. There was no significant effect on the Cd levels in pancreas, spleen, testes, or brain. Mobilization of organ Cd stores led to excretion of Cd principally in the feces; treatment with 2.22 mmoles/kg of each analog qdx3 promoted a cumulative excretion of 32-40% of the administered metal. Rational design of potential Cd complexing agents is discussed with reference to the relative aqueous and lipid solubilities of the N,N-substituents on DTC congeners.

Animals↗

Effects of caffeine on biotransformation and elimination kinetics of acetaminophen in mice.

Coadministration of caffeine (CAF) with acetaminophen (ACM) to mice prolonged the blood half-life of ACM, increased moderately the fraction of ACM excreted as the glucuronide conjugate, and decreased slightly the fraction excreted as the sulfate conjugate. CAF exerted more profound effects on fractions of ACM metabolites which are formed as a consequence of biotransformation via cytochrome P-450-dependent pathway(s); urinary excretion of ACM-mercapturate was reduced ca. 44%, ACM-cysteine was reduced ca. 24%, and the methylthio metabolites were reduced ca. 30%. The apparent rate constants (K') for ACM metabolite formation were suppressed markedly by CAF. Following CAF coadministration with ACM, the K' values for the sulfate-, mercapturate-, cysteine-, and methylthio metabolites were decreased approximately 35%, 56%, 42%, and 47%, respectively. It was concluded that the protective action of CAF against ACM-induced hepatic injury in mice is mediated by a decrease in the rate of formation of N-acetyl-p-benzoquinoneimine, the reactive metabolite of ACM.

Acetaminophen↗

Acetaminophen-induced hepatotoxicity: antagonistic action of caffeine in mice.

Studies of interactions in mice between acetaminophen (ACM) and caffeine (CAF) revealed that CAF given immediately after ACM antagonized the acute toxicity of ACM and reduced the severity of ACM-induced hepatic necrosis as assessed grossly and microscopically. It also attenuated the elevations of SGOT and SGPT levels following ACM administration. CAF reduced significantly the magnitude of ACM-induced mobilization of cadmium from hepatic cadmium-metallothionein stores and the extent of binding of 3H-ACM to hepatic proteins. CAF did not restore hepatic GSH levels toward control values in ACM-treated mice; administration of CAF alone led to a reduction of hepatic GSH concentrations. It was concluded that the antagonistic action by CAF of ACM toxicity in mice is not mediated through a salutary effect on endogenous hepatic sulfhydryl levels. The significance of these observations was discussed in terms of possible interactions at the level of ACM and CAF biotransformation and the potential for interactions of CAF with other xenobiotics.

Acetaminophen↗

Effects of 5,8-dideazaisopteroylglutamate (IAHQ) on L1210 leukemia in mice when given alone and in combination with methotrexate, probenecid, or verapamil.

The folate analogue 5,8-dideazaisopteroylglutamate (IAHQ; NSC-289517) inhibits the growth of a variety of human tumor cells in vitro such as colon, breast and osteosarcoma. Since IAHQ has only modest activity against L1210 leukemia in mice, it was tested in combination with methotrexate (MTX), probenecid, or verapamil in an effort to enhance efficacy. Single drug or drug combinations were administered every other day 3 or 5 times beginning on day 1 following the administration of 10(6) L1210 cells per animal. The combination of IAHQ (100 mg/kg) plus MTX (10 mg/kg) produced a decrease in mean survival time compared to that of MTX alone, regardless of whether the drugs were initiated on the same day or whether either one was started 2 days prior to the other. IAHQ (150 mg/kg) plus verapamil (5, 10, or 20 mg/kg) did not alter significantly the results produced by IAHQ alone. However, the combination of IAHQ (150 mg/kg) plus probenecid (250 mg/kg) augmented the increase in mean survival time above that produced by IAHQ alone by 82% (p = less than 0.001). The results suggest that probenecid could be used to enhance the effectiveness of IAHQ against solid tumors such as colon adenocarcinoma.

Animals↗

Effects of acetaminophen on cadmium metabolism in mice.

Acetaminophen (ACM) administration to mice of the (C57BL/6 X DBA/2)F1 strain produced a typical hepatic centrilobular necrosis similar to that observed in rodents and humans. To determine the effects of this drug-induced necrosis on cadmium (Cd) metabolism, mice were given a sublethal dose of CdCl2 . 2.5 H2O containing 109CdCl2 and maintained for a period of time sufficient for Cd-metallothionein (Cd-MT) to be synthesized and distributed. Subsequent administration of ACM ip or po evoked a marked redistribution of Cd from livers to kidneys of mice, and increased the amount of Cd excreted in urine and feces. There were only minimal or no effects on Cd concentrations in other organs assessed. The effect of ACM on Cd redistribution was antagonized by administration of cysteine, a glutathione precursor, and was enhanced by pretreatment with phenobarbital, a potent inducer of the cytochrome P-450 mixed-function oxidase system. Pretreatment of mice with ACM 6 or 24 hr prior to Cd administration caused aberrations of the normal Cd distribution pattern, but no effect was noted when Cd administration was delayed for 48 hr after ACM injection, indicating recovery of the mechanisms of Cd-MT synthesis and sequestration. Sephadex G-75 gel filtration chromatography of serum from ACM-treated mice showed that most of the Cd was associated with high-molecular-weight proteins, and only a minor portion was present as Cd-MT. Cd excreted in urine was predominantly in a low-molecular-weight form, but there was evidence of two minor components of higher molecular weight, neither of which eluted as Cd-MT. Cd excreted in feces was insoluble following homogenization in 0.25 M sucrose solution. Cd in livers and kidneys of ACM-treated mice eluted as Cd-MT. It was concluded that persons who have a moderately high Cd burden may be at risk of Cd nephrotoxicity if they incur hepatic necrosis subsequent to ACM abuse.

Acetaminophen↗