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To demonstrate the superoxide radical (.O(2)(-)) -scavenging activity of 2-mercaptoethylamine (MEA), we investigated the induction of the oxidative stress-inducible (soi) gene fused lacZ gene (soi-28:: lacZ) by the use of paraquat as a source of.O(2)(-). When MEA or cysteine was added to the cultures before paraquat treatment, soi gene induction by paraquat was significantly inhibited. However, a high quantity of ascorbic acid (5 mm) inhibited soi gene induction by paraquat far less than MEA or cysteine did. The induction of soi gene induction by MEA exhibited a dose-dependent manner in the range of over 0.2 mm. The antagonistic molecules on the radioprotective action of MEA, ascorbic acid and cysteine did not counteract MEA action on the inhibition of paraquat-mediated soi gene induction. To clarify that the MEA action on the inhibition of paraquat-mediated soi gene induction may be due, in part, to.O(2)(-)-scavenging activity, we investigated the ability of MEA to inhibit the nitroblue tetrazolium (NBT) reduction mediated by.O(2)(-)generated in the xanthine oxidase/hypoxanthine system in vitro. At concentrations above 1 mm, MEA effectively inhibited the NBT reduction in a concentration-dependent fashion. Our results demonstrated that MEA has an ability to scavenge.O(2)(-), and so protects against.O(2)(-)-mediated damage.
The effect of mercaptoethylamine (MEA) on degradation of DNA in thermophilic bacteria Bac. stear. exposed to gamma-, UV-rays or methylnitrosourea (MNU) was studied. Using centrifugation on alkaline and neutral sucrose gradients, it was shown that MEA inhibits the accumulation of breaks in the DNA of Bac. stear. It also lowers the level of DNA degradation in toluene-treated cells of Bac. stear. under the action of the intrinsic nuclease, reduces the activity of the endonuclease specific for apurinic DNA, as well as that of S1-nuclease and DNase-I in vitro. The inhibition in the accumulation of DNA breaks is assumed to be due to a decrease of the endonuclease activity in the cells of thermophilic bacteria.
The antioxidant 2-mercaptoethylamine (MEA) was added to the culture medium of WI-38 cells throughout their lifespan. MEA concentrations of 0.5 microM, 5 microM and 50 microM were used. The presence of 5 microM or 50 microM MEA decreased the fraction of rapidly dividing cells and slightly reduced cell density at confluence, whereas 0.5 microM MEA had no significant effect on these parameters. All MEA-treated cultures had somewhat reduced plating efficiency. Cultures treated with 0.5 microM, 5 microM and 50 microM MEA attained population doubling levels of 72.80, 78.35 and 70.92, respectively, compared to 73.55 for untreated controls. Cells grown in 5 microM MEA underwent 4.8 more population doublings, in six weeks more time in culture, compared to controls. This is a 12.2% increase in the portion of the lifespan examined and a 6.5% increase in total lifespan. These results are consistent with the free radical theory of aging.
For purposes of studying stereostructure-activity relationships at the molecular, cellular, and animal levels and probing the mechanism of 2-mercaptoethylamine (MEA) radioprotection we synthesized several conformationally constrained cyclobutyl analogs. The comparative radioprotective properties for MEA, cis- and trans-2-mercaptocyclobutylamine (2), cis- and trans-2-mercaptocyclobutylmethylamine (3), and trans-2-mercaptomethylcyclobutylamine (4) are discussed in terms of their ability to chemically reduce transient free radicals, the formation of single strand breaks in DNA, and protect Chinese hamster cells (in vitro) and mice against the lethal effects of ionizing radiation. The results are interpreted in light of current proposed mechanisms of action for MEA. No correlation exists between ability of these analogs to enhance mice survival times and their ability to protect against the induction of DNA single strand breaks and the inactivation of proliferative capacity of hamster cells growing in vitro. Analysis of two isomers (cis- and trans-3) on the repair of single strand breaks showed both isomers only marginally influenced the rate and did not influence of extent of single strand break rejoining. The results are consistent with a mode of action involving chemical repair of transient radicals and protection against DNA and critical enzymatic sites.
In the mouse, chemical interference with cellular proliferation alters the radiosensitivity of the bone marrow, and this results in protection from otherwise lethal x-irradiation. When intestinal damage is minimized by appropriate timing and dosage, many mitotic inhibitors increase radioresistance and enhance the protective effects of mercaptoethylamine.
In experiments with Ehrlich ascites tumor cells with the use of a specific thiol blocker, 6,6'-dithiodinicotinic acid, it was shown that thiols of a cell plasmic membrane are necessary for the radioprotective effect of mercaptoethylamine to be realized.
The ability of amine-producing tissues (liver tissue, small intestine, mast cells) of rats to synthesize 5-hydroxytryptophan in response to irradiation and their involvement in creation of endogenous radioresistance was studied. Administration of a thiol radioprotector beta-mercaptoethylamine resulted in alteration of kinetic properties of tryptophane hydroxylase expressed as a decrease in the optimal concentration of the substrate; this decrease was more distinct in liver and small intestine as compared with mast cells.
After intraperitoneal administration of beta-mercaptoethylamine (MEA) into mice of F1 strain (CBA XC57B1) at a radioprotective dose, activity of PGE2 and PGF2 alpha-synthetases was decreased in liver microsomes, testicular and brain supernatants (16,000xg) within 15 min, which corresponded to period of the highest radioprotector activity. Amount of newly synthesized prostaglandins was increased in liver tissue within the subsequent periods. Within 3 hrs after the radioprotector administration these amounts constituted for PGE2 246% and for PGF2 alpha 262% as compared with controls; at the same time, activity of PG-synthetases in testes was normalized. In the brain tissue within 1 hr the newly synthesized prostaglandins amounted to 121% for PGE2 and 125% for PGF2 alpha, within 3 hrs they decreased to control values. Decrease in activity of PGE2 and PGF2 alpha-synthetases was shown to depend on MEA concentration in vitro. Possible mechanisms of the radioprotector effect at various steps of the prostaglandins biosynthesis are discussed.
Pool of ATP in thymus, spleen and liver tissues of non-irradiated rats underwent distinct tissue-specific alterations just after intraperitoneal administration of hydrotartrate of beta-mercaptoethylamine (cisteamine, MEA) at e radioprotective dose 300 mg/kg. The data obtained suggest that there are marked impairments in turnover of adenylic nucleotides at the period corresponding to manifestation of the MEA radioprotective efficiency.
Spermidine synthase from rat ventral prostate was inhibited by 2-mercaptoethylamine (MEA). Inhibition of spermidine synthase by MEA was competitive with respect to one of the substrates putrescine, but not competitive with respect to the other substrate decarboxylated S-adenosylmethionine. MEA markedly depressed spermidine and spermine contents in human erythroid leukemia K562 cells, suggesting that these changes resulted from the inhibitory effect of MEA on spermidine synthase in situ.
Our earlier finding that the radioprotective action of 2-mercaptoethylamine (MEA) is counteracted by ascorbate suggests a biochemical mechanism of action, which is supported by observations that MEA is not radioprotective in Rec- E. coli strains. In this study we show that MEA inhibits the induction of the recA gene by UV- or gamma-irradiation or by nalidixic acid in Escherichia coli strain GE94, which contains a recA-lacZ fusion. This effect, which may be counteracted by cysteine, indicates that in general MEA inhibits the induction of SOS functions.
2-Mercaptoethylamine (cysteamine) is an aminothiol compound used as a drug for the treatment of cystinosis, an autosomal recessive lysosomal storage disorder. Because of cysteamine's important role in clinical settings, its analysis by sensitive techniques has become pivotal. Unfortunately, the available methods are either complex or labor intensive. Therefore, we have developed a new rapid, sensitive, and simple method for determining cysteamine in biological samples (brain, kidney, liver, and plasma), using N-(1-pyrenyl) maleimide (NPM) as the derivatizing agent and reversed-phase high performance liquid chromatography (HPLC) with a fluorescence detection method (lambda(ex)=330 nm, lambda(em)=376 nm). The mobile phase was acetonitrile and water (70:30) with acetic acid and o-phosphoric acid (1 mL/L). The calibration curve for cysteamine in serine borate buffer (SBB) was found to be linear over a range of 0-1200 nM (r(2)=0.9993), and in plasma and liver matrix, the r(2) values were 0.9968 and 0.9965, respectively. The coefficients of the variation for the within-run and between-run precisions ranged from 0.68 to 9.90% and 0.63 to 4.17%, respectively. The percentage of relative recovery ranged from 94.1 to 98.6%.
The injection of ascrobate together with cysteamine (beta-mercaptoethylamin or MEA) was shown to cause a partial reversion of the radioprotective action of MEA in mice, and simultaneously of the suppressive action of MEA on RNA synthesis in bone marrow cells. In mouse spleen lymphocytes stimulated by concanavalin A in vitro, MEA and ascorbate exhibited a strong antagonism, neutralizing each other's inhibitory action on RNA synthesis. The latter effect failed to appear after chelation of trace metals, and it is indicated that the ability of ascorbate to counteract the effects of MEA on radiosensitivity and metabolism requires the formation of oxidized products, probably monodehydroascorbate, in agreement with previous observations on bacteria.
In the experiments with Ehrlich ascites tumor cells it was shown that specific oxidation of cellular glutathione after irradiation produced no effect on the degree of radiation injury in the air, but resulted in a decrease of radioprotective effect of beta-mercaptoethylamine. From these results it follows that for a complete realization of radioprotective effect normal level of cellular glutathione is necessary.
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