Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00249 (Mutagen)
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The effects of altering glutathione (GSH) levels in the male reproductive tract have been studied in an attempt to establish a link between chemical-induced perturbations in glutathione and susceptibility of spermatozoa to chemical insult. Tissue GSH levels were enhanced by a treatment regimen of N-acetylcysteine (NAC) (250 mg/kg, 4 treatments at 2 h intervals). With this treatment, GSH levels in liver, testis, caput epididymis, and cauda epididymis were elevated to 126%, 110%, 178%, and 136% of control values. Sexually mature male rats were then treated with NAC and challenged with a dose of EMS (100 mg/kg) to determine if enhanced tissue GSH would protect against EMS-induced dominant lethal mutations. Pretreatment with NAC significantly decreased the post-implantation loss from 7.05 +/- 0.57 with EMS alone to 5.28 +/- 0.47. Conversely, a dominant lethal assay was conducted using different doses of phorone pretreatment to determine the relative contribution of hepatic versus reproductive tract GSH in protecting against EMS-induced dominant lethal resorptions. Doses of 100 mg/kg and 250 mg/kg phorone significantly lowered both hepatic and reproductive tract GSH while 25 mg/kg lowered only hepatic GSH. These three dose levels were used as pretreatments in a dominant lethal study followed by a challenge administration of EMS (50 mg/kg), which is a threshold dose of EMS for producing dominant lethal mutations. Comparison against controls demonstrated a significant potentiation of fetal resorptions in all groups receiving phorone pretreatment, including the 25 mg/kg pretreatment group which only lowered hepatic GSH prior to EMS challenge. The results of these experiments indicate that GSH reserves in the male reproductive tract are insufficient to protect developing spermatozoa from damage by alkylating agents in the absence of hepatic GSH.
Teratog Carcinog Mutagen 1992
PMID:Effects of reproductive tract glutathione enhancement and depletion on ethyl methanesulfonate-induced dominant lethal mutations in Sprague-Dawley rats. 135 63

Glutathione S-transferase (GST) isozymes from human fetal liver (16-18 weeks gestation) were purified by affinity chromatography followed by ion-exchange high performance liquid chromatography (HPLC). The purified isozymes were used to investigate toxicity of 1,2-dibromoethane(EDB) in an in vitro model of rat embryos in culture as passive targets. At least five isozymes of GST were found in the human fetal liver. Two anionic forms [pI values 5.5 (P-2) and 4.5 (P-3)] and one basic form [pI value 8.7 (P-6)] were clearly separated. The presence of two near-neutral forms was also identified. All the isozymes of the human fetal liver GSTs tested metabolized EDB (specific activities were 2.1, 7.0, and 2.0 mumol of GSH consumed/min/mg protein for P-2, P-3, and P-6 isozymes, respectively). Covalent binding of EDB to DNA and protein was 144% and 212% higher, respectively, with the P-3 anionic isozyme when compared to the P-6 basic isozyme of GST. No covalent binding to either protein or DNA was observed with the P-2 isozyme. EDB bioactivation by the GST isozyme P-3 (15 units; 1 unit = 1 nmol of GSH consumed/min) resulted in toxicity to cultured rat embryos. Significant reductions of crown rump length, yolk sac diameter, and the composite score of morphological parameters (Brown and Fabro method) were observed. The central nervous system, optic and olfactory systems, and the hind limb were most significantly affected. The results of this investigation suggest that EDB may be classified as a suspected developmental toxicant in humans.
Teratog Carcinog Mutagen 1992
PMID:A novel model to assess developmental toxicity of dihaloalkanes in humans: bioactivation of 1,2-dibromoethane by the isozymes of human fetal liver glutathione S-transferase. 136 1

Dichloromethane (DCM) vapour by inhalation is carcinogenic to rodents and is an in vivo rodent cell clastogen and a bacterial mutagen. It has been suggested that the bacterial mutagenicity of DCM is mediated by glutathione (GSH) conjugation. The involvement of endogenous and exogenous GSH in the conversion of DCM to a bacterial mutagen has been studied in a vapour phase protocol using wild-type and GSH-deficient (NG54; gsh) Salmonella typhimurium TA100 strains in the presence and absence of various rat liver fractions. The effect of the duration of exposure was also investigated in these Salmonella strains and in E. coli WP2 uvrA pKM101. Dose- and time-related increases in revertants occurred with all metabolic activation systems used (without exogenous metabolic activation; with Aroclor-induced rat liver S9, microsomes, or cytosol fractions), with minor quantitative differences among the 3 strains. Mutagenicity was marginally highest in the presence of cytosol at the highest DCM concentrations. Strain NG54 gsh, which contains approximately 25% of the TA100 level of GSH/microgram protein, was slightly less responsive to DCM-induced mutagenicity than TA100. Addition of 0.33 mumoles/plate of GSH had little effect on the mutagenic responses of TA100 or NG54 in the presence or absence of S9. In these 2 strains, exogenous S9 produced small increases in mutagenicity at the highest concentrations of DCM (2 and 4% v/v). These results suggest that if an interaction between DCM and GSH is required for the activation of DCM to a bacterial mutagen, it occurs at low levels of endogenous GSH and is not significantly affected by GSH supplementation.
Environ Mol Mutagen 1992
PMID:The role of glutathione in the bacterial mutagenicity of vapour phase dichloromethane. 139 12

We examined the relationship between intracellular levels of glutathione (GSH), glutathione-S-transferase (GST) activity, and the kinetics of DNA cross-links induced by the bifunctional alkylating drugs melphalan (MLN), chlorambucil (CLB), and mechlorethamine (HN2) in a rat mammary carcinoma cell line (WT) and in a subline selected in vitro for primary resistance to MLN (MLNr, 16-fold resistance). MLNr cells exhibit a 2-fold increase in intracellular GSH concentration and an approximately 5-fold increase in GST activity as compared with the parent cells. They are cross-resistant to a variety of drugs, including CLB (6-fold) and HN2 (14-fold). Treatment of WT cells with 30 microM MLN or CLB induced a significant accumulation of DNA-DNA cross-links for up to 8 h, which decreased over a 24-h period. In MLNr cells, no significant cross-link formation was induced by either MLN of CLB at any time between 0 and 24 h. Doses of up to 100 microM MLN failed to induce cross-links in MLNr cells. Formation of cross-links was observed immediately after treatment with HN2 in both cell lines and was followed by a subsequent decrease during a 24-h incubation in drug-free medium. At an equimolar concentration (30 microM), the numbers of HN2-induced cross-links were significantly lower in MLNr cells than in WT cells. However, treatment of MLNr cells with 60 microM HN2 resulted in cross-link levels similar to those obtained using 30 microM HN2 in WT cells. The 35% decrease in MLN accumulation observed in MLNr cells could not entirely explain the absence of cross-links, since thin-layer chromatographic analysis demonstrated that both cell lines accumulate a significant amount of MLN and metabolize it to the same extent. Significant amounts of MLN were also detected in nuclei isolated from WT and MLNr cells that had been treated with 30 microM [14C]-MLN. Intracellular depletion of GSH by a nontoxic concentration of L-buthionine-(S, R)-sulfoximine (BSO, 100 microM; about 70% GSH depletion) significantly sensitized MLNr cells to MLN and increased cross-link formation. A nontoxic concentration (50 microM) of ethacrynic acid (EA, an inhibitor of GST showing some specificity for Yc/Yp subunits) also sensitized MLNr cells to MLN and increased cross-link formation. Our data demonstrate that both EA and BSO are effective modulators of nitrogen mustard cytotoxicity in tumor cells resistant to alkylating drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Nitrogen mustard-DNA interaction in melphalan-resistant mammary carcinoma cells with elevated intracellular glutathione and glutathione-S-transferase activity. 150 71

The alkylating anticancer drugs, mechlorethamine (HN2), chlorambucil, cyclophosphamide, carmustine and lomustine readily induced cytotoxicity in isolated rat hepatocytes. Hepatocyte glutathione (GSH) was depleted rapidly following addition of the drugs. Lipid peroxidation ensued following GSH depletion and before cytotoxicity occurred. Furthermore, cytotoxicity was delayed by the antioxidants butylated hydroxyanisole (BHA) and alpha-tocopherol, the ferric iron chelator desferoxamine or the radical trap 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) even when added 10 min later. HN2 was much less toxic to hepatocytes under nitrogen and caused much less lipid peroxidation than under aerobic conditions. Cytotoxicity induced by HN2 was also prevented by choline, suggesting that a choline carrier is responsible for HN2 uptake in the hepatocytes. Various sulfur compounds acted as antidotes for HN2 cytotoxicity. Thiosulfate was still effective when added 30 min after HN2. Depletion of GSH in the hepatocytes markedly increased their susceptibility to HN2. However, BHA, desferoxamine or TEMPO protected these hepatocytes from HN2. This suggests that antioxidants could prove useful in preventing the increased risk of hepatotoxicity if GSH-depleting agents are used to overcome tumor resistance to nitrogen mustards.
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PMID:Hepatocyte toxicity of mechlorethamine and other alkylating anticancer drugs. Role of lipid peroxidation. 159 84

Biopsy samples and cultured cells derived from them were obtained from 39 patients with malignant glioma and were analyzed for 1) glutathione (GSH) content; 2) sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or nitrogen mustard (HN2) treatment and 3) the effect of buthionine sulfoximine (BSO) treatment on BCNU and/or HN2 cytotoxicity. The average GSH concentration of biopsy specimens was lower than those of cultured cells (2.36 +/- 0.44 vs. 11.42 +/- 2.32 nmol/10(6) cells). While some of the tumor specimens were sensitive to either BCNU or HN2, the majority were resistant to both. However, 8 of 23 tumors tested showed enhanced sensitivity to BCNU following treatment with BSO. Five of 17 tumors were similarly sensitized to HN2 by BSO. These results suggest that BSO chemosensitization may be of value for certain patients and that screening assays may help identify treatment-sensitive individuals.
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PMID:Glutathione levels and chemosensitizing effects of buthionine sulfoximine in human malignant glioma cells. 174 83

The cytotoxic and genotoxic effects of glutaraldehyde were studied in vitro in the human TK6 lymphoblast cell line and in primary cultures of rat hepatocytes. TK6 lymphoblasts were exposed to glutaraldehyde for 2 hr in serum-free GSH-free media. Cytotoxic effects were observed at concentrations as low as 10 microM with only 10% cell survival at 20 microM. Alkaline elution studies indicated that glutaraldehyde-induced DNA-protein crosslinking increased linearly over the concentration range from 0 to 25 microM. Glutaraldehyde-induced mutations were assessed at the thymidine kinase locus over the same concentration range and reached a plateau at 10 microM of about six times the background mutant frequency. At equivalent levels of DNA-protein crosslinks and cytolethality, glutaraldehyde was mutagenic at approximately a one-seventh lower concentration than the rodent nasal carcinogen formaldehyde (Craft et al.; Mutation Research 176:147-155, 1987). Glutaraldehyde induced a marginal increase in unscheduled DNA synthesis in the in vitro hepatocyte DNA repair assay, but only at the two highest concentrations of 50 and 100 microM, indicating the induction of some DNA excision-repair activity. These data demonstrate that glutaraldehyde exhibits DNA-reactive genotoxic activity that may involve, at least in part, DNA-protein crosslinking in these cell culture models. These findings suggest the need to examine the potential carcinogenic activity of glutaraldehyde in appropriate inhalation studies.
Environ Mol Mutagen 1991
PMID:Evaluation of the genotoxic potential of glutaraldehyde. 190 74

EDB significantly depressed GSH in caput and cauda epididymis, but not in testis, 2 hours following injection. This depression was dose-related. EDB enhanced EMS-induced dominant lethal mutations at mating weeks 2 and 3 (of 6). At mating week 2 the fetal death rate was increased two-fold, while at week 3, the fetal death rate had increased to nearly three-fold greater than the EMS-only controls. Enhancement of fetal death rate was confined to postimplantation loss. As with EMS alone, the EDB potentiation of EMS-induced mutations was limited to postmeiotic stages of spermatogenesis. EDB also enhanced alkylation of rat spermatozoa by labeled EMS. Depression of GSH in reproductive tissues is correlated with a potentiation of dominant lethal mutations, as well as an increase in the binding of EMS to sperm heads.
Teratog Carcinog Mutagen 1990
PMID:Potentiation of ethyl methanesulfonate-induced germ cell mutagenesis and depression of glutathione in male reproductive tissues by 1,2-dibromoethane. 198 7

1. The activities of enzymes participating in the regeneration of reduced glutathione (GSH), and their subcellular distribution were studied in cultured rat adrenal cells. 2. It has previously been shown that the adrenocorticolytic agent 7-hydroxymethyl-12-methylbenz[a]anthracene (7-hydroxymethyl-12-MBA) causes a drastic and selective oxidation of mitochondrial GSH in rat adrenal cells. Treatment of the adrenal cells with 7-hydroxymethyl-12-MBA, resulted in a minor decrease in the content of cytochrome c oxidase, nicotinamide nucleotide transhydrogenase, isocitrate dehydrogenase and cytosolic GSH reductase, whereas the activity of lactate dehydrogenase and citrate synthase was unaffected. None of these effects were considered to be responsible for the massive oxidation of mitochondrial GSH induced by 7-hydroxymethyl-12-MBA. 3. 1,3-Bis-(2-chloroethyl)-1-nitrosourea (BCNU) was used to obtain rat adrenal cells cultures with inactivated cytosolic and mitochondrial GSH reductase. The oxidation of mitochondrial GSH, induced by 7-hydroxymethyl-12-MBA, was not dramatically enhanced by the inactivation of GSH reductase, indicating that this enzyme was not rate-limiting in the regeneration of GSH. 4. Fractionation of rat adrenal cells with increasing concentrations of digitonin resulted in an earlier release of citrate synthase in cells treated with 7-hydroxymethyl-12-MBA compared with controls. These results may indicate damage to mitochondrial membranes as a result of 7-hydroxymethyl-12-MBA treatment.
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PMID:Effect of 7-hydroxymethyl-12-methylbenz[a]anthracene and 1,3-bis-(2-chloroethyl)-1-nitrosourea on enzyme activities and oxidation of glutathione in cultured rat adrenal cells. 254 26

Day 9.5 rat embryos were exposed in culture to xanthine/xanthine oxidase generated active oxygen species. Growth and development were assessed after 46 hr of culture. The treatment induced abnormalities of the neural suture, the severity of which increased in a dose-related manner with the concentration of substrate or enzyme. Glutathione (10 mM) or catalase (50 micrograms/ml) either partially or completely abolished the effects of xanthine/xanthine oxidase, whereas the addition of superoxide dismutase (50 micrograms/ml) or desferrioxamine (1mM) did not reduce the number of malformed embryos. These findings suggest that hydrogen peroxide and/or hydroxyl radicals are responsible for the effects of xanthine and xanthine oxidase.
Teratog Carcinog Mutagen 1986
PMID:Malformations induced in cultured rat embryos by enzymically generated active oxygen species. 288 69


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