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Biomedical subjects

L Ehrenberg

Publications and source records attributed to L Ehrenberg.

At least 55 records · Page 3Linked to original sources
PubMed1986

Monitoring of environmental cancer initiators through hemoglobin adducts by a modified Edman degradation method.

Tissue doses of cancer initiators/mutagens are suitably monitored through hemoglobin adducts formed in vivo, but the use of this method has been hampered by a lack of sufficiently simple and fast procedures. It was previously observed that when the N-terminal amino acid in hemoglobin, valine, is alkylated it is cleaved off by the Edman sequencing reagent, phenyl isothiocyanate, in the neutral-alkaline coupling medium, as opposed to the acidic medium required by normal amino acids. Based on this principle, conditions for a functioning procedure for gas chromatography/mass spectrometry (GC/MS) determination of N-terminal alkylvalines in hemoglobin were worked out. Derivatizing the protein in formamide solution with pentafluorophenyl isothiocyanate, using a 2H-alkylated protein as internal standard, and applying on-column injection during analysis, permit reproducible determination of hydroxyethylvaline and other adducts down into the dose range where cancer risks may be considered acceptably low.

Alkylation↗
PubMed1986

Mutagenic and comutagenic action of 5'-deoxy-5'-(methylthio)adenosine.

5'-Deoxy-5'-(methylthio)adenosine (MTA) alone and in combination with methionine was found to increase frequencies of background HGPRT mutation and SCE in V79 Chinese hamster cells. The same agents exert a comutagenic action on these effects as well as upon mutation induction in Escherichia coli stain AB1157 (but not in its non-adaptable derivative ada-6) following treatment with N-methyl-N-nitrosourea (MNU). MTA plus methionine also enhanced the lethal action of MNU on hamster cells. The effects observed may tentatively be ascribed to hypomethylation due to inhibition of DNA methylase by MTA.

Adenosine↗
PubMed1986

Enhancement by cysteamine of N-methyl-N-nitrosourea mutagenesis in E. coli.

Cysteamine (MEA) is comutagenic to methylnitrosourea (MNU) in E. coli AB 1157 but not in the nonadaptable mutant derivative ada-6 of that strain. The comutagenic action of MEA was eliminated by cysteine at low concentrations, which also lowered mutation frequencies in AB1157 but not in ada-6. In model experiments it was shown that cysteine counteracted the inhibition by MEA of beta-galactosidase induction in both bacterium strains. The comutagenic action of MEA is interpreted as being due to an inhibition of induction of methyltransferase during treatment with MNU.

Bacterial Proteins↗
PubMed1986

Tissue doses of ethylene oxide in cigarette smokers determined from adduct levels in hemoglobin.

Determination of adducts to hemoglobin (Hb) is a useful approach for monitoring tissue doses of ultimate carcinogens. This approach provides a basis for both risk estimation and for the identification of a priori unknown environmental carcinogens. This paper describes the application of a new method for the analyses of Hb adducts to cigarette smokers and non-smokers. The results demonstrate a raised level of hydroxyethylation of N-terminal valine of Hb of smokers that is quantitatively compatible with ethene in the smoke being the source. The magnitude of the tissue doses of ethylene oxide originating from inhaled ethene suggests that this factor is a major contributor to smoking-associated cancer risk.

Alkylation↗
PubMed1986

Misincorporation of alkylated amino acids into hemoglobin--a possible source of background alkylations.

Misincorporation of 2-hydroxyethylated amino acids into hemoglobin during de novo synthesis was studied by injecting mice with radiolabelled N-(2-hydroxyethyl)valine, S-(2-hydroxyethyl)cystine or N tau-(2-hydroxyethyl)histidine. The results showed that S-(2-hydroxyethyl)cysteine and N tau-(2-hydroxyethyl)histidine were misincorporated, whereas N-(2-hydroxyethyl)valine was not. Monitoring of in vivo doses of hydroxyethylating agents by determination of N-(2-hydroxyethyl)valine was free of the disturbing influence of such misincorporation.

Alkylation↗
PubMed1984

Covalent binding of genotoxic agents to proteins and nucleic acids.

To a large extent, initiators of current cancer incidence are unknown. This is due partly to lack of proper variables and low statistical power of epidemiological studies and to difficulties of risk estimation from experimental data. Considering these facts, as well as long latent times of genotoxic effects, monitoring systems aiming at risk prevention should: (1) respond soon after onset of exposure; (2) have sufficiently high power; (3) identify causative agents; and (4) permit risk quantitation. The determination of in-vivo adducts to DNA (the target in most genotoxic effects) and, especially, to blood proteins, fulfils these criteria, since the demonstration of protein adducts is a relevant measure of formation of the corresponding DNA adducts.

Alkylation↗
PubMed1983

Dosimetry of ethylene oxide in the rat by quantitation of alkylated histidine in hemoglobin.

Blood samples were obtained from male Fischer 344 rats exposed to controlled air concentrations of ethylene oxide; 0, 10, 33, and 100 ppm, 6 h/day, 5 days/week, for 2 years. N tau-(2-hydroxyethyl)histidine was isolated from hemoglobin hydrolysates and analyzed quantitatively by means of gas chromatography--mass fragmentography and by amino acid analysis. The degrees of alkylation found were 1.3 and 2.8 nmol hydroxyethylhistidine per gram hemoglobin in two groups of unexposed rats, and 14, 34, and 82 nmol per gram hemoglobin, respectively, at the three air levels of ethylene oxide. Rats of the same breed were given two concentrations of radiolabeled ethylene oxide by IP injection. The degrees of alkylation of amino acids in hemoglobin and of guanine-N-7 in DNA from livers and testes were determined. The degrees of alkylation of liver and testicular DNA were about 150% and 50%, respectively, of the values expected from the degree of alkylation of hemoglobin, basing the expectancy on a direct proportionality between the reactivity of the specific nucleophilic sites and the degree of alkylation obtained at these sites, assuming that the dose of ethylene oxide was the same in the different tissues studied. The in vivo dose of ethylene oxide determined from data on hemoglobin alkylation thus gives a reasonable approximation of the DNA dose. The data were in agreement with a fast elimination of ethylene oxide from the tissues, the biological half-life being estimated as about 10 min.

Alkylation↗
PubMed1983

International Commission for Protection Against Environmental Mutagens and Carcinogens. Dosimetry of genotoxic agents and dose-response relationships of their effects.

Dose-response relationships and determination of dose of mutagens and carcinogens are summarized and discussed on the basis of conceptual and kinetic aspects. Different dose definitions may be referred to steps in the chain of events from exposure (or emission) to observed effects. A system is applied to show the influence of various processes on the kinetics of the transfers between consecutive steps. The same system illustrates processes influenced by protraction and fractionation of dose, synergists, comutagens/cocarcinogens, heritable factors, etc. The response at a given dose is expected to depend on the product of consecutive transfer functions. An application of general rules of chemical kinetics shows that when a chemical is introduced at a sufficiently low level, all processes affecting the transfers and therefore the transfer functions themselves become first-order, provided the induction status of enzymes and the cell-division rate remain constant. Under the same conditions, dose-response relationships are expected to be linear, i.e. without "safe" thresholds. However, present knowledge of the kinetics of repair at low levels of DNA damage and of the kinetics of induction of repair functions is not enough complete to be decisive. These considerations and the fact that observed dose-response data in some cases indicate the existence of thresholds but in others appear able to reject the threshold hypothesis lead to the conclusion that, generally, dose-response curves are most probably linear down to dose zero. However, certain mutagens/carcinogens give rise to lesions repaired so effectively that quasi-thresholds appear in certain subpopulations or organs.

Animals↗
PubMed1983

Mutagenicity of methyl nitrite in Salmonella typhimurium.

Methyl nitrite was tested for mutagenicity in Salmonella typhimurium TA1535. In the first set of experiments, plated bacteria were exposed to methyl nitrite in desiccators both in the absence and presence of a metabolizing system (S9 from Aroclor-pretreated Sprague-Dawley rats). Initial concentrations from 125 to 500 ppm were tested. In all experiments an increased initial concentration gave an increased mutagenic response. The mutagenic effect in the presence of S9 was similar to that in the absence of S9. Owing to difficulties in dose determinations in this type of experiment it could not be decided, unequivocally, whether the mutagenic effect was caused by methyl nitrite or its hydrolysis products. Experiments were therefore carried out in suspension, and the concentrations of methyl nitrite and inorganic nitrite were determined. Treatments with inorganic nitrite were also carried out under similar conditions. From the results of these experiments we concluded that methyl nitrite is mutagenic. Possible mechanisms of action of methyl nitrite are discussed, and it is suggested that mutagenicity may be a general property of alkyl nitrites.

Animals↗
PubMed1981

Alkylating properties of dichlorvos (DDVP).

Dichlorvos (DDVP) is a methylating agent. In DNA from mice given 1.9 x 10(-6) mol/kg of DDVP, a degree of alkylation of guanine-N-7 amounting to 8 x 10(-13) mol methyl per g DNA, was found. From this, a rate of clearance of 29 hr-1 was estimated. This value is in reasonable agreement with the value (55 hr-1), calculated from published data on the concentration over time of DDVP in the brain after injection of the compound in mice. Applying a risk estimation on humans exposed to DDVP, the genetic risk connected with the methylating activity of DDVP is low or very low. Comparing the mutagenic effectiveness of DDVP with that of methyl methanesulfonate, indicates that DDVP is more effective than expected from reaction kinetic data. The possible contribution of the dichloroacetaldehyde formed in vivo from DDVP has to be evaluated before a complete risk estimate can be made for DDVP.

Alkylating Agents↗
PubMed1980

Alkylation of macromolecules for detecting mutagenic agents.

At present, experiments with laboratory organisms and epidemiological studies are the major source of information about the genetic toxicology of environmental agents. Laboratory systems are limited in value by difficulties in the interpretation of negative results, in quantitation, and in extrapolation from experimental effects of chemicals to specific levels of activity in man. Epidemiologic methods measure effects in man but are weakened by long latency times, confounding environmental factors, imprecise endpoints, and high background levels, which reduce sensitivity. Several methodological improvements in genetic toxicity testing are needed, including increased resolving power, greater relevance of observations to effects in man, techniques for evaluating interactions of compounds in chemically complex systems, and improvements in quantitative risk assessment. Because most genetically toxic agents ultimately react as electrophilic agents with nucleophilic centers in cellular macromolecules, the quantitative analysis of the resulting products may be a useful approach to the evaluation of the risks posed by exposure to specific chemicals. The main nucleophilic centers in biological macromolecules are thiol and thioether sulfurs, nitrogens in amino groups and rings, and oxygen atoms. Using the laws of reaction kinetics of alkylation and the observed kinetics of induced mutagenic effects, it is possible to relate the formation of alkylated products in macromolecules to genetic toxicity. The alkylation of amino acids (eg, histidine and cysteine) in hemoglobin can be measured with sufficient sensitivity and accuracy to use it as a monitor of exposure to alkylating agents. By determining the degree of alkylation of a specific center, it is possible to calculate the internal dose of an agent and, because erythrocyte life-spans are relatively uniform, the incremental daily exposure of an individual to an alkylating agent. Dosimetry can be equated with radiologic dose so that exposure can be expressed in rad-equivalents and the effects of specific agents compared quantitatively to biologically well-characterized doses of radiation.

Alkylation↗