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PubMed2003

A bifunctional alkylating nitrogen mustard agent that utilizes barbituric acid as carrier drug with the potential for crossing the brain-blood barrier.

Barbituric acid is the parent compound of a large family of hypnotic barbiturates. A nitrogen mustard (N-mustard) group (-CH2CH2N[CH2CH2Cl]2) was placed onto the two nitrogen atoms at positions 1 and 3 of the pyrimidine ring. This N-mustard agent is a solid at 25 degrees C, stable at -10 degrees C for >10 weeks, and soluble in aqueous solvent at 37 degrees C and 25 degrees C. The partition coefficients miLog P and CLog P were calculated to be -0.93 and -1.441 for barbituric acid. The miLog P and CLog P for the N-mustard agent were 1.82 and 2.707, respectively. The N-mustard substituents significantly increased solubility in lipid by-layers. The N-mustard agent alkylated a nucleophilic primary amine (p-chloroaniline) at physiological conditions of pH 7.4 and 37 degrees C. Aliquots of reaction mixtures were withdrawn at known time periods to react with fluorescamine for determination of unreacted p-chloroaniline and calculation of rate constants. The alkylation of the primary amine was second order with rate = k2[Nu]2, (Nu is nucleophile) and rate constant k2 = 0.01358 L/(mole.min). The molecular dipole of barbituric acid and the N-mustard agent was calculated by SPARTAN software (wavefunction, Irvine, CA) to be 0.681 and 2.153 Debye, respectively. The brain/blood partition coefficient (Log BB) of the N-mustard agent was -0.399. Values of molecular polar surface area (TPSA) for barbituric acid and the N-mustard agent was 75.27 and 64.17, respectively. TPSA values indicate an expected intestinal absorbance to be 79% and 90%, respectively. The N-mustard agent showed zero violations of the Rule of 5, indicating good bioavailability.

Barbiturates↗

PubMed1975

Mustard meal in dairy rations.

Consumption of 0% mustard meal and 15% soybean meal, 7.5% mustard meal and 7.5% soybean meal, or 15% mustard meal and 0% soybean meal rations did not differ in palatability studies with 10 group-fed lactating cows when the mustard meal was treated with 3% caustic soda. Order of preference was for 0, 7.5, and 15% mustard meal rations when mustard meal was untreated. Twelve lactating cows were in each of two lactation trials to compare the three rations of untreated mustard meal. Milk, milk fat, and solids-not-fat, and milk protein did not differ for either trial. Protein-bound iodine of plasma for all cows were within the normal range. Three cows were placed on each of the three rations and received a minimum of 9 kg per day for 6 mo preparturition to determine goitrogenic effects. All cows gave birth to normal, vigorous calves. Limited organoleptic evaluations of milk indicated that untreated mustard meal may impart a detrimental flavor to milk, but a taste panel could not differentiate between milk from cows on the three rations of treated mustard meal. Twenty-one male and 43 female Holstein claves received either 0, 10, or 20% mustard meal starter rations from birth to 3 mo of age. Growth, feed consumption, or plasma protein-bound iodine did not differ.

Animal Feed↗

PubMed2006

Modulation of the expression of superoxide dismutase gene in lung injury by 2-chloroethyl ethyl sulfide, a mustard analog.

Mustard gas exposure causes inflammatory lung diseases. Many inflammatory lung diseases are associated with oxidative stress. Reactive oxygen species (ROS) are involved in the maintenance of physiological functions. In tissues, it is therefore essential to maintain a steady-state level of antioxidant activity to allow both for the physiological functions of ROS to proceed and at the same time preventing tissue damage. We have recently reported that mustard gas exposure decreases the overall activity of superoxide dismutase (SOD). In the present study, we investigated the effects of mustard gas on each of the three isozymes: SOD-1 (Cu/Zn), SOD-2 (Mn), and SOD-3 (extracellular). Adult guinea pigs were intratracheally injected single doses of 2-chloroethyl ethyl sulfide (CEES) (2 mg/kg body weight) in ethanol. Control animals were injected with vehicle in the same way. The animals were sacrificed after 7 days, and lungs were removed after perfusion with physiological saline. Lung injury was established by measuring the leakage of iodinated-BSA into lung tissue. Mustard gas exposure caused a significant increase in the activity of SOD-1 (35%). However, the SOD-3 activity which is the predominant type in lung was significantly decreased (62%), whereas no change was observed in SOD-2 activity. Thus the decrease in the total activity of SOD was primarily due to the SOD-3 isozyme. Northern blot analysis indicated 3.5-fold increased expression of SOD-1 in mustard gas exposed lung, but no significant change in the expression of SOD-2 and SOD-3 was observed. Mustard gas exposure did not cause mutation in the coding region of SOD-1 gene while causing modulation in expression levels. The protein levels of SOD-1, SOD-2, and SOD-3 were not altered significantly in the mustard gas exposed lung. Our results indicate that the overall decrease in the activity of SOD by mustard gas exposure is probably mediated by direct inactivation of the SOD-3 gene or the enzyme itself. This decrease in the activity of SOD-3 may be due to the cleavage of active form of the protein to an inactive form. The existence of active and inactive forms of SOD-3 as a result of shifts in Cys-Cys disulfide bonding has been described in human, recently. Studies are underway in our laboratory to investigate whether mustard gas induced inactivation of SOD-3 in lung is similarly mediated by a change in Cys-Cys disulfide bonding.

Animals↗

PubMed1995

Nitrogen mustard drug resistant B-cell chronic lymphocytic leukemia as an in vivo model for crosslinking agent resistance.

Acquired resistance is a limiting factor in chemotherapy. We have employed nitrogen mustard resistant B-cell chronic lymphocytic leukemia (B-CLL) as a clinically relevant model to study this phenomenon. Resistance in B-CLL is associated with enhanced repair of nitrogen mustard crosslinks. In order to identify the repair pathway responsible for nitrogen mustard resistance, lymphocytes were screened for cross-resistance to a variety of DNA damaging agents. The MTT assay was used to measure the resistance of B-CLL lymphocytes to various DNA damaging agents, including nitrogen mustards, UV light, methyl methanesulfonate, and mitomycin C. We have shown that B lymphocytes from patients with nitrogen mustard resistant chronic lymphocytic leukemia reflect their clinical status. This assay allows us to classify lymphocytes as nitrogen mustard sensitive or resistant, based on in vitro observations. The resistant population was 5.6 and 4.1 fold more resistant to the nitrogen mustard analogs, chlorambucil and melphalan, respectively. Resistant lymphocytes displayed no increased resistance to either methyl methanesulfonate or UV light, indicating that neither classical base nor nucleotide excision repair is rate-limiting in resistance. Resistant lymphocytes were 6.0 and 2.2 fold more resistant to mitomycin C and cis-diamminedichloroplatinum (II), respectively, suggesting enhanced crosslink repair. Neither glutathione nor glutathione S-transferase levels correlated with resistance. The development of nitrogen mustard drug resistance in B-CLL appears to be associated with cross-resistance to other bifunctional alkylating agents which produce interstrand crosslinks. Our results indicate that resistance to nitrogen mustards in chronic lymphocytic leukemia is associated with enhanced repair of DNA crosslinks which may involve a recombination dependent system. This model should prove very useful in the elucidation of the molecular mechanisms of crosslink repair.

B-Lymphocytes↗

PubMed2002

Sulfur mustard-induced arachidonic acid release is mediated by phospholipase D in human keratinocytes.

Sulfur mustard (2,2(')-dichloroethyl sulfide) is a chemical warfare agent that causes incapacitating skin blisters in humans 12-24h post-exposure following a variable asymptomatic phase. Recent reports demonstrate that inflammation plays a vital role in sulfur mustard toxicity. One of the key biochemical pathways involved in inflammation is the arachidonic acid cascade. In this report, we demonstrate that arachidonic acid is released in response to sulfur mustard and investigate the mechanisms of arachidonic acid release. Exposure to sulfur mustard caused a 5- to 8-fold increase in arachidonic acid release from human keratinocytes that had been radiolabeled with arachidonic acid. Maximal arachidonic acid release occurred between 12 and 24h. Several enzymatic pathways can lead to arachidonic acid release. Treatment with 2.0% (v/v) ethanol, an inhibitor of phospholipase D, decreased sulfur mustard-induced arachidonic acid release 40+/-7%. Additionally, 100 microM (+/-)-propranolol, an inhibitor of phosphatidic acid phosphohydrolase, blocked sulfur mustard-induced arachidonic acid release by 62+/-3%. These findings suggest that arachidonic acid release is mediated by phospholipase D and phosphatidic acid phosphohydrolase in human keratinocytes following sulfur mustard exposure. Due to the 12-24h delay in arachidonic acid release following sulfur mustard exposure, delayed therapeutic intervention may be possible. Indeed, we found that the addition of 100 microM (+/-)-propranolol up to 18 h after sulfur mustard exposure was still able to block arachidonic acid release by 30+/-3%.

Arachidonic Acid↗

PubMed1983

Isophosphoramide mustard, a metabolite of ifosfamide with activity against murine tumours comparable to cyclophosphamide.

Isophosphoramide mustard was synthesized and was found to demonstrate activity essentially comparable to cyclophosphamide and ifosfamide against L1210 and P388 leukaemia. Lewis lung carcinoma, mammary adenocarcinoma 16/C, ovarian sarcoma M5076, and colon tumour 6A, in mice and Yoshida ascitic sarcoma in rats. At doses less than, or equivalent to, the LD10, isophosphoramide mustard retained high activity against cyclophosphamide-resistant L1210 and P388 leukaemias, but was less active against intracerebrally-implanted P388 leukaemia while cyclophosphamide produced a 4 log10 tumour cell reduction. It was also less active (one log10 lower cell kill) than cyclophosphamide against the B16 melonoma. Metabolism studies on ifosfamide in mice identified isophosphoramide mustard in blood. In addition, unchanged drug, carboxyifosfamide, 4-ketoifosfamide, dechloroethyl cyclophosphamide, dechloroethylifosfamide, and alcoifosfamide were identified. The latter 4 metabolites were also identified in urine from an ifosfamide-treated dog. In a simulated in vitro pharmacokinetic experiment against L1210 leukaemia in which drugs were incubated at various concentrations for various times, both 4-hydroxycyclophosphamide and isophosphoramide mustard exhibited significant cytoxicity at concentration times time values of 100-1000 micrograms X min ml-1, while acrolein was significantly cytotoxic at 10 micrograms X min ml-1. Treatment of mice with drug followed by L1210 cells demonstrated a shorter duration of effective levels of cytotoxic activity for isophosphoramide mustard and phosphoramide mustard in comparison with cyclophosphamide and ifosfamide. Isophosphoramide mustard and 2-chloroethylamine, a potential hydrolysis product of isophosphoramide mustard and carboxyifosfamide, were less mutagenic in the standard Ames test than the 2 corresponding metabolites of cyclophosphamide [phosphoramide mustard and bis(2-chloroethyl)amine].

Adenocarcinoma↗

PubMed2006

Ifosfamide metabolites CAA, 4-OH-Ifo and Ifo-mustard reduce apical phosphate transport by changing NaPi-IIa in OK cells.

Renal Fanconi syndrome occurs in about 1-5% of all children treated with Ifosfamide (Ifo) and impairment of renal phosphate reabsorption in about 20-30% of them. Pathophysiological mechanisms of Ifo-induced nephropathy are ill defined. The aim has been to investigate whether Ifo metabolites affect the type IIa sodium-dependent phosphate transporter (NaPi-IIa) in viable opossum kidney cells. Ifo did not influence viability of cells or NaPi-IIa-mediated transport up to 1 mM/24 h. Incubation of confluent cells with chloroacetaldehyde (CAA) and 4-hydroperoxyIfosfamide (4-OH-Ifo) led to cell death by necrosis in a concentration-dependent manner. At low concentrations (50-100 microM/24 h), cell viability was normal but apical phosphate transport, NaPi-IIa protein, and -mRNA expression were significantly reduced. Coincubation with sodium-2-mercaptoethanesulfonate (MESNA) prevented the inhibitory action of CAA but not of 4-OH-Ifo; DiMESNA had no effect. Incubation with Ifosfamide-mustard (Ifo-mustard) did alter cell viability at concentrations above 500 microM/24 h. At lower concentrations (50-100 microM/24 h), it led to significant reduction in phosphate transport, NaPi-IIa protein, and mRNA expression. MESNA did not block these effects. The effect of Ifo-mustard was due to internalization of NaPi-IIa. Cyclophosphamide-mustard (CyP-mustard) did not have any influence on cell survival up to 1000 microM, but the inhibitory effect on phosphate transport and on NaPi-IIa protein was the same as found after Ifo-mustard. In conclusion, CAA, 4-OH-Ifo, and Ifo- and CyP-mustard are able to inhibit sodium-dependent phosphate cotransport in viable opossum kidney cells. The Ifo-mustard effect took place via internalization and reduction of de novo synthesis of NaPi-IIa. Therefore, it is possible that Ifo-mustard plays an important role in pathogenesis of Ifo-induced nephropathy.

Acetaldehyde↗

PubMedDate not supplied

Synthesis and alkylation activity of a nitrogen mustard agent to penetrate the blood-brain barrier.

Nitrogen mustard agents are widely used for the clinical treatment of cancers. A nitrogen mustard (N-mustard) agent was synthesized utilizing nicotinic acid as the carrier of the alkylating substituent (-OCH2CH2N(CH2CH2Cl)2) that forms an ester group (R-C(O)-OR) on a heterocyclic ring. The N-mustard agent is a solid at room temperature and is stable for more than 6 weeks when stored at -10 degrees C. To determine the kinetics of alkylation activity a nucleophilic primary amine compound (4-chloroaniline) was placed in aqueous solution with the mustard agent at physiological pH 7.4 (pH of blood) and 37 degrees C. The alkylation reaction was found to be second-order with rate equation: rate = k2[N-mustard][Nu], where Nu = nucleophile and k2 = 0.0415 L/(mol x min). Pharmacological descriptors calculated showed values indicating a strong potential of penetrating the blood-brain barrier. The partition coefficient (Log P) of the mustard agent is 1.95 compared with 0.58 for nicotinic acid. Values of descriptors such as dipole, polar surface area, Log BB, molar refractivity, parachor, and violations of Rule of 5 were found to be 5.057 Debye, 42.44 A2, 0.662, 72.7 cm3, 607.7 cm3, and 0.0 for the N-mustard agent. Value of polar surface area for the mustard agent (42.44 A2) predicts that >90% of any amount present in the intestinal tract will be absorbed.

Algorithms↗

PubMed2002

Combined effects of mustard flour, acetic acid, and salt against Esherichia coil O157:H7 stored at 5 and 22 degrees C.

The combined effects of acetic acid and mustard flour were investigated to ascertain their impact on Escherichia coli O157:H7 stored at 5 and 22 degrees C. Samples were prepared with various concentrations of acetic acid (0, 0.25, 0.5, 0.75, and 1% [vol/vol]) combined with 10% (wt/vol) Baltimore or Coleman mustard flour and 2% (fixed; wt/vol) sodium chloride. An acid-adapted mixture of three E. coli O157:H7 strains (10(6) to 10(7) CFU/ml) was inoculated into prepared mustard samples that were stored at 5 and 22 degrees C, and samples were assayed periodically for the survival of E. coli O157:H7. The numbers of E. coli O157:H7 were reduced much more rapidly at 22 degrees C than at 5 degrees C. E. coli O157:H7 was rapidly reduced to below the detection limit (<0.3 log10, CFU/ml) after 1 day at 22 degrees C, whereas it survived for up to 5 days at 5 degrees C. There was no synergistic or additive effect with regard to the killing of E. coli O157:H7 with the addition of small amounts of acetic acid to the mustard flour. When stored at 5 degrees C, mustard in combination with 0.25 (M-0.25), 0.5 (M-0.5), and 0.75% (M-0.75) acetic acid exerted less antimicrobial activity than the control (M-0). The order of lethality at 5 degrees C was generally M-0.25 = M-0.5 < M-0.75 = M-0 < M-1. The addition of small amounts of acetic acid (<0.75%) to mustard retards the reduction of E coli O157:H7. Statistical reduction in populations of E. coli O157:H7 (P < 0.05) was enhanced relative to that of the control (mustard alone) only with the addition of 1% acetic acid. This information may help mustard manufacturers to understand the antimicrobial activity associated with use of mustard flour in combination with acetic acid.

Acetic Acid↗

PubMed1999

Sequence selectivity, cross-linking efficiency and cytotoxicity of DNA-targeted 4-anilinoquinoline aniline mustards.

We have investigated the sequence selectivity, DNA binding site characteristics, interstrand cross-linking ability and cytotoxicity of four 4-anilinoquinoline aniline mustards related to the AT-selective minor groove-binding bisquaternary ammonium heterocycles. The compounds studied include two full mustards that differ in alkylating power, a half mustard and a quaternary anilinoquinolinium bismustard. We have also compared their cytotoxicity with their precursor diols and their toxicity and cross-linking ability with the classical alkylating agents melphalan and chlorambucil. We find that the anilinoquinoline aniline mustards weakly and non-specifically alkylate guanines in the major groove and that they bind strongly to AT-rich sequences in the minor groove, where they alkylate both adenines and guanines at the N3 position. The most preferred sites are classical minor groove binder AT-tracts to which all four ligands bind equally well. The remaining sites are AT-rich, but include GC base pairs, to which the ligands bind with preferences depending on their structure. The full mustards alkylate at the 3' ends of the binding site in an orientation that depends on the spatial disposition of the purines within the two strands. Generally speaking guanines are found to be much less reactive than adenines. The anilinoquinoline aniline mustards are interstrand cross-linking agents that are 60- to 100-fold more effective than melphalan, with the quaternary compound being the most efficacious. However, the type of binding site at which the cross-links occur is not clear, since distamycin challenge fails to antagonize them fully. The full mustards are 20- to 50-fold more cytotoxic than their diol precursors, are more cytotoxic than the half mustard and are 20- to 30-fold more active than melphalan and chlorambucil. The quaternary ligand is the most potent. Given the evidence to hand, it appears that antitumour activity correlates with capacity to cause interstrand cross-links at classical or near-classical AT-minor groove binder sites, rather than with ability to discriminate between the subsets of potential anilinoquinoline aniline mustard binding sites.

Alkylation↗

PubMed1975

The alkylation of hemoglobin S by nitrogen mustard. High resolution proton nuclear magnetic resonance studies.

Sickle cell hemoglobin (Hb S) treated with nitrogen mustard (bis(beta-chloroethyl)methylamine hydrochloride) gives two reaction products, one labile and one stable. After dialysis against buffer solution, the remaining stable product is found to inhibit the polymerization of deoxyhemoglobin S. High resolution proton nuclear magnetic resonance has been used to study the structure and function of this stable product and to investigate the nature of the binding sites of nitrogen mustard to the hemoglobin molecule. The NMR results suggest that the nitrogen mustard treatment of Hb S does not alter the heme environment or the subunit interfaces of the hemoglobin molecule. Moreover, the NMR spectra have also shown that the nitrogen mustard reacts with the beta2 histidines of the hemoglobin molecule and have suggested that several other surface amino acid residues of the hemoglobin molecule are also affected by the nitrogen mustard alkylation. These NMR findings are in good agreement with the data obtained from biochemical studies of nitrogen mustard-treated Hb S. The NMR spectra also indicate that nornitrogen mustard (which is also effective in inhibiting sickling) binds with the hemoglobin molecule in a manner identical with nitrogen mustard. Sulfur mustard, on the other hand, produces no observable changes in the aromatic proton resonances, which is consistent with the fact that it does not inhibit the polymerization of deoxy-Hb S.

Adult↗

PubMed2000

The mutagenic spectrum of acridine-linked aniline nitrogen mustards in AS52 cells: implications of DNA targeting with high selectivity for adenine or guanine bases.

The mutational spectra generated in AS52 cells at the gpt gene locus by aniline mustards were studied by the isolation of resistant clones and sequencing of the altered gene. A set of four aniline mustards (both mono- and bifunctional) linked to a DNA-affinic 9-aminoacridine (9-AA) carrier was used, together with the untargeted mustards chlorambucil (CHL) and its half-mustard, and the DNA binding carrier, 9-AA. Both 9-AA and CHL were weak cytotoxins, with the DNA-targeted mustards being markedly (10-40-fold) more dose potent, and the bifunctional ones somewhat more toxic than the monofunctional ones. 9-AA produced a different spectrum of mutations to the spontaneous background, with more minor addition events and less base pair substitutions, and showing for the first time that frameshift events so characteristic of 9-AA in bacteria or bacteriophage also occur in mammalian cells. The mutational spectra of the DNA-targeted mustards were quite different both from this and from the lesions caused by the untargeted mustards, which cause largely transition mutations at AT sites (despite a clear preference for formation of N(7)-guanine adducts). There were very few transition mutations, suggesting that the initial O(6)-alkylguanine/O(4)-alkylthymine lesions considered to give rise to these are relatively rare. There was also a lower incidence of complete deletions, usually attributed to DNA cross-links. For the short chain length targeted mustards, which form initial stable adducts largely (95%) at guanine N(7) sites, base pair substitution mutations, predominantly transversions, involved AT and GC base pairs equally. In contrast, the longer chain length targeted mustards, which form >90% of initial adducts at adenine N(1) sites, generated also formed transversion mutations, but these overwhelmingly (24/27) involved AT base pairs.

Aminacrine↗

PubMed2000

Sensitivity to nitrogen mustard relates to the ability of processing DNA damage in Chinese hamster ovary cells.

The hallmark of the excision repair pathways is the removal of DNA adducts by excision of the damaged nucleotides. In the course of repair, transient DNA strand breaks occur, which can be measured by the Comet assay. We have investigated the processing of DNA damage, mediated by nitrogen mustard, in wild-type AA8 Chinese hamster ovary cells, and in UV5, UV20 and UV41 DNA repair deficient cell lines. Whereas DNA repair could not be detected by unscheduled DNA synthesis at nitrogen mustard doses below 10 microM, processing of nitrogen mustard-mediated DNA damage was observed by the Comet assay at a 100-times lower concentration. Wild-type Chinese hamster ovary AA8 cells were able to process nitrogen mustard-mediated DNA damage within 4-24 hr depending on the dose of nitrogen mustard (0.1-10 microM). None of the repair-deficient cell lines was able to completely process the DNA damage induced by 10 microM nitrogen mustard. At nitrogen mustard doses that conferred 10% colony forming ability, the repair-deficient cells had an altered processing of nitrogen mustard-mediated DNA damage: In the AA8, UV20, and UV41 cells, the amplitude of strand breaks peaked early (within 4 hr), the level of strand breaks in the nitrogen mustard exposed UV20 and UV41 cells did not return to the baseline of the unexposed reference culture, and the peak in strand breaks in the UV5 cell line occurred after 4 hr. Our results indicate that the single cell gel electrophoresis (Comet) assay is suitable for assessing repair capability of DNA alkylations.

Alkylating Agents↗

PubMed1994

Regulation of rat brain synaptosomal [3H]hemicholinium-3 binding and [3H]choline transport sites following exposure to choline mustard aziridinium ion.

Choline uptake by cholinergic nerve terminals is increased by depolarization; the literature suggests that this results from either the appearance of occult transporters or the increased activity of existing ones. The present experiments attempt to clarify the mechanism by which choline transport is regulated by testing if the preexposure of synaptosomes to choline mustard aziridinium ion prevents the stimulation-induced appearance of hemicholinium-3 binding sites and/or choline transport activity. Choline mustard inhibited irreversibly most of the "ground-state" (basal) high-affinity choline transport but only 50% of "ground-state" hemicholinium-3 binding sites. Exposure of both striatal and hippocampal synaptosomes to the mustard, before stimulation, inhibited K(+)-stimulated increases in choline transport and of [3H]-hemicholinium-3 binding. We conclude that the mechanism by which choline transport is regulated involves the increased activity of a pool of transport sites that are occluded to hemicholinium-3 but are available to choline mustard aziridinium ion, and presumably to choline, before stimulation. However, the concentration of mustard needed to inhibit the stimulation-induced increase of [3H]-hemicholinium-3 binding and choline transport was lower for striatal synaptosomes than for hippocampal synaptosomes. In the absence of extracellular Ca2+ or presence of high Mg2+ levels, the choline mustard did not prevent the appearance of extra striatal hemicholinium-3 binding sites. Also, high Mg2+ levels removed the ability of the mustard to inhibit K(+)-stimulated increases of either [3H]-hemicholinium-3 binding or choline transport by hippocampal synaptosomes. In contrast, the preexposure of hippocampal synaptosomes to the mustard in the presence of a calcium ionophore (A23187) reduced the concentration of inhibitor needed to prevent the activation of [3H]hemicholinium-3 binding and choline uptake. Thus, we conclude that the ability of the choline mustard to alkylate the pool of choline transporters that are activated by stimulation appears dependent on the entry of extra-cellular Ca2+.

Animals↗

PubMed2002

Selenium assimilation and volatilization from selenocyanate-treated Indian mustard and muskgrass.

Selenocyanate (SeCN(-)) is a major contaminant in the effluents from some oil refineries, power plants, and in mine drainage water. In this study, we determined the potential of Indian mustard (Brassica juncea) and muskgrass (a macroalga, Chara canescens) for SeCN(-) phytoremediation in upland and wetland situations, respectively. The tolerance of Indian mustard to toxic levels of SeCN(-) was similar to or higher than other toxic forms of Se. Indian mustard treated with 20 microM SeCN(-) removed 30% (w/v) of the Se supplied in 5 d, accumulating 554 and 86 microg of Se g(-1) dry weight in roots and shoots, respectively. Under similar conditions, muskgrass removed approximately 9% (w/v) of the Se supplied as SeCN(-) and accumulated 27 microg of Se g(-1) dry weight. A biochemical pathway for SeCN(-) degradation was proposed for Indian mustard. Indian mustard and muskgrass efficiently degraded SeCN(-) as none of the Se accumulated by either organism remained in this form. Indian mustard accumulated predominantly organic Se, whereas muskgrass contained Se mainly as selenite and organic Se forms. Indian mustard produced volatile Se from SeCN(-) in the form of less toxic dimethylselenide. Se volatilization by Indian mustard accounted for only 0.7% (w/v) of the SeCN(-) removed, likely because the biochemical steps in the production of dimethylselenide from organic Se were rate limiting. Indian mustard is promising for the phytoremediation of SeCN(-) -contaminated soil and water because of its remarkable abilities to phytoextract SeCN(-) and degrade all the accumulated SeCN(-) to other Se forms.

Biodegradation, Environmental↗

PubMed1984

An evaluation of irreversible inhibition of synaptosomal high-affinity choline transport by choline mustard aziridinium ion.

Choline mustard aziridinium is a potent, irreversible and selective blocker of sodium-dependent, high-affinity transport of choline into rat forebrain synaptosomes; it was found to be 30 times less potent against low-affinity transport of choline. The IC50 value for high-affinity transport was 0.94 microM, compared to 29 microM for low-affinity uptake. The inhibitory action of choline mustard aziridinium ion on high-affinity transport of choline was graded with respect to time; a 12-fold increase in potency was obtained by increasing the inhibitor preincubation times from 1 to 30 min. Low concentrations of choline mustard aziridinium ion could produce significant blockade of choline carriers providing the exposure time was prolonged. The characteristics of the blockade of synaptosomal high-affinity choline transport by choline mustard aziridinium ion also changed depending upon preincubation time. The kinetics of inhibition of high-affinity choline transport by choline mustard aziridinium ion showed apparent competitive inhibition initially, followed by noncompetitive characteristics at longer preincubations with inhibitor. The rate of irreversible inhibition of carriers by this nitrogen mustard analogue would appear to be rapid; the rate constant was determined to be 5 X 10(-2) s-1 for micromolar concentrations of inhibitor. This action may preclude the transport of the mustard analogue into the nerve terminal, although initially some reversible binding with the carrier may result in the translocation of some choline mustard aziridinium ion into the presynaptic ending. The progressive alkylation of high-affinity carriers by the analogue could indicate the presence of excess carrier sites in the presynaptic membrane, or subpopulations of carriers in an inactive state in equilibrium with active carriers. A model is described for the inhibitory action of choline mustard aziridinium ion on synaptosomal high-affinity choline carriers.

Animals↗

PubMed1987

Glutathione and related enzymes in rat brain tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea and nitrogen mustard.

Reduced glutathione (GSH) and activities of several glutathione-related enzymes were measured in two 9L rat brain tumor cell lines with differing sensitivities to both 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and nitrogen mustard. GSH, measured by a specific high-performance liquid chromatographic method, was found to be approximately twice as high in 9L cells sensitive to BCNU but resistant to nitrogen mustard. The nitrogen mustard resistant cell line was also found to have 2.5-fold more bulk glutathione transferase activity and approximately 3-fold more gamma-glutamyl transpeptidase activity. Glutathione reductase activity, protein thiol, and total protein content were similar in the two cell lines. Pretreatment of 9L cells with 50 microM buthionine sulfoximine for 24 h to deplete GSH only slightly potentiated BCNU cytotoxicity in a clonogenic assay whereas that of nitrogen mustard was markedly potentiated in both cell lines. Similarly, buthionine sulfoximine pretreatment had little effect on the induction of sister chromatid exchanges by BCNU, but significantly increased the number of sister chromatid exchanges induced by nitrogen mustard in both cell lines. Depleting GSH also had no significant effect on the cytotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea to 9L cells. Pretreatment of 9L cells with 1 mM GSH significantly protected against nitrogen mustard cytotoxicity. Moreover, nitrogen mustard incubated with GSH and glutathione transferase was 4-fold less cytotoxic than nitrogen mustard incubated with GSH alone. Incubation of BCNU with GSH alone or with glutathione transferase had no effect on BCNU cytotoxicity. These results indicate that elevated GSH and glutathione transferase activity is one mechanism of cellular resistance to nitrogen mustard in the 9L cell line, but it does not correlate with resistance to BCNU or other clinically important nitrosoureas.

Animals↗

PubMed1987

Dysrhythmias following the Mustard and Senning operation for transposition of the great arteries.

The prevalence and nature of late dysrhythmias following operative repair of transposition of the great arteries were evaluated in 32 children using pre- and postoperative standard electrocardiograms and postoperative Holter monitoring. The Mustard procedure was performed in 17 patients, the Senning procedure in 15 patients. The mean age at operation was 40 +/- 35 months in the Mustard and 9 +/- 6 months in the Senning group. The mean interval between operation and Holter monitoring 7 +/- 2 years in the Mustard and 1.6 +/- 1 years in the Senning group. All patients had sinus rhythm preoperatively. Following operation, the incidence of sinus rhythm increased from 59% in the Mustard and 87% in the Senning group in the first postoperative week to 76% in the Mustard and 100% in the Senning group at the end of follow-up (mean 4.6 +/- 3.5 years). Holter monitoring revealed dysrhythmias or conduction abnormalities in 12 patients (9 Mustard, 3 Senning). A permanent pacemaker had to be inserted in 2 Mustard patients because of complete atrioventricular block and sinus bradycardia with sinus arrest, respectively. Results indicate a prevalence of late postoperative dysrhythmias of 20% in the Senning and of 59% in the Mustard group (p less than 0.05). However, the significantly longer mean follow-up period of the Mustard group precludes a direct comparison between the 2 types of repair.

Arrhythmias, Cardiac↗