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PubMed1976

Evaluation of a possible role for antimutagens, antiteratogens, and anticarcinogens in reducing environmental health hazards.

The use of protective agents (e.g., sulfhydryl compounds, certain vitamins, amino acids, cations, and antibiotics) offers a novel and promising means of dealing with the ever increasing burden of environmental hazards facing man. Through the daily uptake of minimal doses as a prophylactic measure by the most endangered groups of the population or by direct mixing of the appropriate protective agent with the inducer (e.g., pesticides or anticancer drugs) it should be possible to reduce or prevent some of the most serious toxic side effects including those of a mutagenic, teratogenic or carcinogenic nature. Among some of the most outstanding protection examples cited are the antimutagenic, antiteratogenic and anticarcinogenic effects of L-cystein, and of some of the vitamins. However, in view of our limited understanding of protection mechanisms in this fairly new field of research and due to the toxic side effects of some of the protection agents themselves, a large-scale application of this approach cannot be recommended as yet. More research is urgently needed to study protection mechanisms in suitable standardized model systems and to develop safer and more efficient protective agents.

Amino Acids↗
PubMed1996

Reduced, oxidized and protein-bound forms of homocysteine and other aminothiols in plasma comprise the redox thiol status--a possible element of the extracellular antioxidant defense system.

Reduced, oxidized and protein-bound forms of homocysteine (Hcy), cysteine and cysteinylglycine in plasma interact via redox and disulphide exchange reactions, and these aminothiol species comprise a dynamic system referred to as redox thiol status. Notably, in plasma reduced cysteine is the most abundant low molecular weight sulfhydryl compound. Elevation of plasma Hcy (hyperhomocysteinemia) causes changes in redox thiol status. Protein-bound Hcy increases up to a maximum capacity of about 140 micromol/L, and there is a concurrent displacement of protein-bound cysteine. When the Hcy binding approaches saturation, free oxidized and reduced Hcy show a substantial increase. The resulting increase in reduced/total ratio for Hcy causes a parallel change in this ratio for the other aminothiols. These dynamics were observed during both chronic hyperhomocysteinemia (due to cobalamin deficiency or homocystinuria) and acute hyperhomocysteinemia (induced by methionine or Hcy loading). In addition, changes in redox thiol status have been observed in patients with vascular disease (decreased reduced/total ratio for cysteine), renal failure (low reduced/total ratio for aminothiols) or HIV infection (high level of reduced Hcy), which suggest primary imbalance between prooxidant and antioxidant processes in these patients. In conclusion, redox thiol status is a dynamic system which is probably linked to the extracellular antioxidant defence system. This must be taken into account when designing future experimental or epidemiological studies on Hcy and cardiovascular disease.

Animals↗
PubMed1995

Intestinal toxicity of acrylonitrile: in vitro metabolism by intestinal cytochrome P450 2E1.

Acrylonitrile (VCN) is known to cause extensive gastrointestinal damage and tumors in rats. In this study the metabolism of VCN to cyanide (CN-) was characterized in the small intestinal mucosa. The majority of the metabolic reactivity was localized in the microsomal fraction and required reduced nicotinamide adenine dinucleotide phosphate for maximal activity. The intestinal metabolism of VCN to CN- was characterized with respect to VCN concentration, time, pH, and microsomal protein concentration. VCN metabolism to CN- was enhanced significantly by the addition of sulfhydryl compounds such as glutathione, cysteine, and D-penicillamine (10 mM) to 142, 161, and 189% of control, respectively. The intestinal bioactivation of VCN to CN- was enhanced by microsomes obtained from intestinal mucosa of phenobarbital (455% of control), beta-naphthoflavone (375% of control), 4-methylpyrazole (305% of control), or ethanol (165% of control)-treated rats. Addition of ethanol (80 mM) to incubation mixtures containing control or ethanol-induced microsomes resulted in significant inhibition of microsomal metabolism of VCN to CN- to 20 and 34% of control, respectively. Addition of dimethyl sulfoxide induced a similar inhibitory effect on VCN metabolism by control or ethanol-induced microsomes (8 and 26% of control, respectively). Furthermore, antibody to cytochrome P450 2E1, but not antibody to cyt P450 2B1, significantly inhibited VCN metabolism by ethanol-induced intestinal microsomes to about 25% of control. Mild inhibition (80-85% of control) of VCN metabolism was detected when antibody to cyt P450 2B1 or 2E1 was added to incubation mixtures containing Pb-induced intestinal microsomes. These findings indicate that extrahepatic tissues such as the intestinal mucosa are capable of metabolizing VCN to CN- and establish a major role of intestinal cyt P450, particularly cyt P450 2E1, in the intestinal metabolism of VCN to CN-.

Acrylonitrile↗
PubMed2000

Permeation and gating residues in serotonin transporter.

The third transmembrane domain (TM3) of serotonin transporter (SERT) contains two isoleucine residues previously proposed to be involved in binding and transport of serotonin. When Ile-172 was replaced with cysteine, SERT became sensitive to inactivation by externally added [2-(trimethylammonium)ethyl]methanethio-sulfonate (MTSET). The disulfide product of this inactivation was not sensitive to reduction by externally added sulfhydryl compounds, but apparently reacted with intracellular reducing agents to spontaneously regenerate active SERT. The apparent accessibility of this residue to both external and cytoplasmic reagents is consistent with its localization near a serotonin binding site that is alternately exposed to both internal and external media. In another SERT mutant, I179C, transport also was inactivated by MTSET but substrate binding was resistant. External substrate bound to the inactivated I179C and enhanced its reactivation by free thiols. In norepinephrine transporter (NET), cysteine replacement of Ile-155 (corresponding to SERT Ile-179) also rendered the transporter sensitive to MTSET inactivation. In NET I155C, cocaine enhanced this inactivation, and the substrate, dopamine, apparently protected against inactivation. The characteristics of this protection suggest that dopamine was transported, converting NET to a form in which Ile-155 was occluded. The results support the proposal that TM3 of SERT and NET constitute part of the substrate permeation pathway, and that Ile-172 in SERT resides close to the substrate binding site. They also suggest that Ile-179 in SERT (and Ile-155 in NET) is in a conformationally sensitive part of TM3, which may act as part of an external gate.

Allosteric Regulation↗
PubMed1980

Thiol S-methylation in uremia: erythrocyte enzyme activities and plasma inhibitors.

Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine. Thiol methyltranferase (TMT) catalyzes the S-methylation of a variety of aliphatic sulfhydryl compounds. Erythrocyte (RBC) TPMT activity is elevated in the blood of uremic patients on maintenance hemodialysis, 15.83 +/- 0.90 U/ml RBCs (mean +/- SEM, n = 41), whereas in blood from randomly seleted nonuremic subjects it was 12.76 +/- 0.16 U/ml (n = 298, p < 0.001). RBC TPMT activity is not affected by hemodialysis. The plasma of uremic patients reversibly inhibits RBC TPMT activity to a greater extent than normal plasma does and contains higher concentrations of endogenous methyl acceptors than normal plasma. Plasma TPMT inhibitors are not removed by hemodialysis. There are large individual variations in inhibition of RBC TPMT by plasma from patients with renal failure. Inhibition varied from 1% to 93% in 20 microliters of plasma from each of 20 randomly selected uremic patients. There was a positive correlation between the inhibition of TPMT and the content of endogenous methyl acceptors in uremic plasma (r = 0.914, n = 20, p < 0.001), but there was no significant correlation between degree of inhibition and urea nitrogen, serum creatinine, or hematocrit. The ability of plasma from individual uremic patients to inhibit TPMT also correlated with its ability to inhibit two other drug metabolizing methyltransferases in the RBC, catechol-O-methyltransferase and phenol-O-methyltransferase, RBC TMT activity is not altered in patients with uremia. The results of these and other studies of methyl conjugation in renal failure focus attention on the accumulation of methyl acceptor substrates in some of these patients and on the possible effects of these methyl acceptors on a variety of methylation reactions.

Adolescent↗
PubMed2002

Smoking is associated with alterations of blood thiol-group related antioxidants in patients on hemodialysis.

Cardiovascular disease is the major complication and cause of mortality in the dialysis population, accounting for about 40% of deaths. Oxidative stress has been strongly implicated in the pathogenesis of these events. As patients in end-stage renal disease (ESRD) are in a state of elevated free radical activity, the aim of the present study was to investigate the negative impact of smoking in 45 male hemodialysis (HD) patients. These patients, who were 40-85 years of age (mean age 60.9 +/- 13.3 years), had been on hemodialysis for at least 12 months before participating in this study. Fasting blood sampling for serum lipid, albumin, urate, lipid peroxides total blood glutathione (tGSH), non-GSH free sulfhydryl compounds (non-GSH fSH), plasma glutathione peroxidase (pGSHPx), erythrocytes glutathione peroxidase (rGSHPx), plasma glutathione S-transferase (pGST) and erythrocytes glutathione S-transferase (rGST) were determined. Our study showed that the plasma malonyldialdehyde (MDA) concentration was significantly higher in HD patients who smoked than in those who were non- smokers (1.99 +/- 0.53 vs. 1.55 +/- 0.46 nmol/ml, p = 0.008). No association was found between levels of MDA in smokers and BMI, serum cholesterol and triglycerides and smoking index. We also found that the circulating plasma levels of tGSH and non-GSH fSH was lower in the HD patients who smoked (tGSH 164.9 +/- 41.5 vs. 203.4 +/- 45.3 microg/ml; fSH 271.1 +/- 55.8 vs. 308.8 +/- 46.7 microg/ml; p < 0.05 and p < 0.001, respectively). There were no significant differences in the plasma levels of uric acid, pGSHPx, rGSHPx, pGST, rGST, albumin, and age between the 2 groups. Partial correlation analysis of the plasma levels of the measured antioxidants and the smoking index revealed a negative correlation between the plasma levels of tGSH and smoking index (r = -0.62, p < 0.003). Similarly, the plasma levels of tGSH was found negatively correlated with the levels of plasma MDA (r = -0.32, p < 0.05) of the HD patients. In conclusion, our data suggest that cigarette smoking has a negative impact on plasma-circulating products of lipid peroxidation in HD patients. The lower blood levels of the tGSH and non-GSH fSH in HD patients who smoked suggests that these patients may be more susceptible to oxidative damage caused by smoking.

Adult↗
PubMed1965

THE ACTION OF THIOL REAGENTS ON THE ADENOSINE-TRIPHOSPHATASE ACTIVITIES OF HEAVY MEROMYOSIN AND L-MYOSIN.

1. The Ca(2+)-activated adenosine triphosphatase of heavy meromyosin is maximally stimulated by lower relative molar concentrations of phenylmercuric acetate than are required with myosin. 2. Stimulation of the Ca(2+)-activated adenosine triphosphatase of both heavy meromyosin and myosin by thiol reagents is markedly affected by ionic strength, the effects being greater with the former than with the latter. In particular, N-ethylmaleimide strongly inhibits the Ca(2+)-activated adenosine triphosphatase of heavy meromyosin at ionic strength below about 0.2. 3. The precise behaviour of the thiol reagents at low ionic strength is slightly modified by the age of the heavy meromyosin and myosin preparations. 4. Stimulation of the Mg(2+)-activated adenosine triphosphatase of heavy meromyosin by thiol reagents is relatively insensitive to ionic strength. 5. The adenosine triphosphatases of heavy meromyosin and myosin activated by potassium chloride in the absence of bivalent activators are inhibited by thiol reagents over the range of ionic strength at which stimulation occurs in the presence of calcium chloride as activator. 6. The modifying effects of potassium chloride and sodium chloride are qualitatively different when heavy-meromyosin adenosine triphosphatase is stimulated with phenylmercuric acetate. No such difference is observed when the enzyme is stimulated with N-ethylmaleimide.

Adenosine↗
PubMed1965

EFFECT OF THIOL-BINDING REAGENTS ON THE METABOLISM OF THIOSULFATE AND TETRATHIONATE BY THIOBACILLUS NEAPOLITANUS.

Trudinger, P. A. (Division of Plant Industry, Canberra, Australia). Effect of thiol-binding reagents on the metabolism of thiosulfate and tetrathionate by Thiobacillus neapolitanus. J. Bacteriol. 89:617-625. 1965.-Iodoacetamide, N-ethyl maleimide (NEM), p-chloromercuribenzoate (CMB), Mercurochrome, and HgCl(2) inhibited the oxidation of thiosulfate to sulfate by Thiobacillus neapolitanus; tetrathionate accumulated under these conditions. High concentrations of the thiol-binding reagents lowered the rate of oxidation of thiosulfate to tetrathionate; inhibition by CMB was reversed by high concentrations of thiosulfate. Relatively low concentrations of the thiol-binding reagents completely inhibited the oxidation and anaerobic metabolism of tetrathionate. Similar reagents had no effect on a soluble thiosulfate-oxidizing enzyme. Inhibition by thiol-binding reagents was overcome by washing the bacteria with Na(2)S or thioethanol after their exposure to the inhibitors. Under some conditions, the addition of thiosulfate or tetrathionate to bacterial suspensions before the addition of the thiol-binding reagents prevented the inhibition of thiosulfate and tetrathionate metabolism by these reagents. Thiosulfate catalyzed a rapid chemical breakdown of NEM and reacted with iodoacetamide. A complex between thiosulfate and mercuribenzoate was demonstrated. Three types of thiol group appear to be associated with the metabolism of thiosulfate and tetrathionate; one of these types may be located at the bacterial cell membrane. The results are consistent with the hypothesis that thiols (or disulfide groups) are binding sites for the substrates.

Australia↗