PubMed Health⌕ Search

Biomedical subjects

D Segerbäck

Publications and source records attributed to D Segerbäck.

32 records · Page 2Linked to original sources
PubMed1990

Reaction products in hemoglobin and DNA after in vitro treatment with ethylene oxide and N-(2-hydroxyethyl)-N-nitrosourea.

Reaction products with DNA and blood proteins have been used for monitoring human exposure to electrophilic compounds and metabolites. The formation of products with nucleophilic sites in DNA after treatment with such reagents has been well characterized (especially for alkylating agents). It is therefore of great importance to collect corresponding data for nucleophilic groups in proteins. The formation of reaction products in hemoglobin (Hb) and DNA was studied after in vitro treatment with ethylene oxide (EtO) and N-(2-hydroxyethyl)-N-nitrosourea (HOEtNU). In DNA N-7-(2-hydroxyethyl)guanine was the main product of EtO, whereas O6-(2-hydroxyethyl)guanine was much lower (0.5% of the alkylation of guanine-N-7). For HOEtNU O6-(2-hydroxyethyl)guanine was found to be 63% of N-7-(2-hydroxyethyl)guanine. These relative reactivities are in agreement with what has been reported for related alkylating agents. The main reaction products in Hb were 2-hydroxyethylations of cysteine, N-terminal valine, the two imidazole nitrogens in histidine and carboxylic groups. The reactivities of human, mouse and rat Hb towards EtO were compared. The main difference between species was the 12 and 170 times higher reactivity of cysteine in mouse and rat Hb, respectively, than in human Hb. As expected from relative reactivities of alkylating agents with model nucleophiles, products with cysteine dominated for EtO (except in human Hb) whereas for HOEtNU products with carboxylic groups were far larger than any other. Relative amounts of cysteine and carboxylic group alkylation in mouse Hb were compared with corresponding data for other alkylating agents. The comparison showed that these amounts were close to what could be expected from known reactivities of these compounds with model nucleophiles, but that sterical and other modifying factors have to be taken into account. Each compound gives therefore a species-specific pattern that might be used for tracing human exposure of unknown origin.

Alkylation↗
PubMed1988

Estimation of the cancer risk of genotoxic chemicals by the rad-equivalence approach.

The genotoxic effectiveness of ethylene oxide is compared with that of gamma-radiation, as measured by induced transformation of C3H 10T1/2 mouse embryo fibroblasts. The resultant value of the quality factor, Q approximately 80 rad/mM X h, is compatible with earlier data on mutation and other endpoints in various test systems. This quality factor can thus be used to estimate the risk of exposures to ethylene oxide or its precursor, ethene, on the basis of human doses monitored by haemoglobin adducts.

Cell Transformation, Neoplastic↗
PubMed1984

Relationships between ethylation of hemoglobin, ethylation of DNA and administered amount of ethyl methanesulfonate in the mouse.

Ethylation of guanine-N-7 in the DNA of liver and kidney and of nucleophilic groups in hemoglobin has been studied as a measure of the in vivo dose in the mouse after i.p. administration of radiolabeled ethyl methanesulfonate (EMS). The degree of ethylation in both hemoglobin and DNA of the studied tissues was found to increase proportionally to the injected amount in the range 0.32-100 mumoles EMS/kg b.w. Above this range a somewhat higher than proportional degree of ethylation was found, indicating saturation of a system for detoxification of the compound, resulting in a decreased rate of elimination and consequently an increased dose in the tissues of this directly alkylating agent. The ratio between covalent binding to DNA and to hemoglobin, however, was approximately constant over the wide range of doses studied. For biological effects with a linear dose-response relationship, this demonstrates the validity of hemoglobin alkylation as an indicator of the risk.

Alkylation↗
PubMed1983

Alkylation of DNA and hemoglobin in the mouse following exposure to ethene and ethene oxide.

Exposure of mice to 14C-labelled ethene or ethene oxide gave rise to hydroxyethylations of nucleophilic sites in hemoglobin and DNA. The relative amounts of alkylation products of different amino acids in hemoglobin were the same for the two compounds. Furthermore, the ratio between the degree of alkylation of DNA in various organs and of hemoglobin was approximately the same, supporting a previous conclusion that ethene oxide is the reactive intermediate formed in vivo from ethene. A comparison of the degrees of alkylation obtained per unit exposure dose (ppm X h) of ethene oxide and of ethene, respectively, showed that at low levels of ethene about 8% of the inhaled amount is metabolized to ethene oxide. It was estimated that the maximal rate of metabolism (Vmax) of ethene corresponds to exposure to an air level of 4 ppm of ethene oxide.

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↗
PubMed1981

Estimation of genetic risks of alkylating agents. VI. Exposure of mice and bacteria to methyl bromide.

Methyl bromide was studied in a forward mutation system of E. coli to evaluate the relationship between dose and mutagenic response. The compound had a high toxicity and a low mutagenic efficiency, as expected from the high s value. The mutagenic effectiveness was estimated to be 1 mutation per 10(8) surviving bacteria per mM . h, in reasonable agreement with expectation from reaction kinetic data. To study the possibilities of using hemoglobin alkylation for an estimation of DNA alkylation in vivo, mice were treated with 14C-labeled methyl bromide. The degree of alkylation of DNA, determined in liver and spleen, was considerably lower than expected (200 and 20 times, respectively) from the degree of alkylation of hemoglobin and from the relative reactivities of DNA and hemoglobin towards methyl bromide in vitro. when hemoglobin alkylation is used for quantitative risk estimations, a correction factor has to be applied by taking into account the difference between the dose in red blood cells and the dose in the compartments of DNA.

Alkylation↗
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↗
PubMed1977

Evaluation of genetic risks of alkylating agents. III. Alkylation of haemoglobin after metabolic conversion of ethene to ethene oxide in vivo.

Male CBA mice, exposed to air contaminated with [14C] labelled ethene, were able to metabolize this olefine to ethene oxide. The amount of epoxide formed was quantitatively determined from the degree of alkylation of cysteine and histidine in haemoglobin. These hydroxyethylated amino acids were determined by ion-exchange chromatography of the labelled products. In a separate experiment the formation of S-(2-hydroxyethyl) cysteine was verified by gas chromatography--mass spectrometry. In addition this cysteine derivative was determined in urine by thin-layer chromatography. For unknown reasons, uninduced mice varied strongly in the extent to which they converted ethene to epoxide.

Aerosols↗
PubMed1976

Evaluation of genetic risks of alkylating agents. II. Haemoglobin as a dose monitor.

The degree of alkylation of haemoglobin was determined at different times after treatment of mice with one directly active alkylating agent, ethylene oxide, and one agent that requires metabolic activation, dimethylnitrosamine. Because of the random alkylation of red blood cells of various ages and the stability of alkylated haemoglobin, the amount of alkylated amino acids in haemoglobin decreases linearly with time, reaching the value zero after about 40 days, the life-span of erythrocytes in the mouse. This provides a basis for the use of haemoglobin as a monitor for integral doses of genotoxic environmental chemicals.

Alkylating Agents↗
PubMedDate not supplied

Monitoring and risk assessment by means of alkyl groups in hemoglobin in persons occupationally exposed to ethylene oxide.

In persons occupationally exposed to ethylene oxide, i.e. under the conditions described by Dunkelberg and Hartmetz (1977), the degree of alkylation in histidine of hemoglobin was determined. Quantitative determination of N-3-(2-hydroxyethyl)histidine by mass fragmentography and by ion-exchange amino-acid analysis gave consistent results. Data are in agreement with the fast elimination from tissues (lambda = 4.6 hr-1, i.e. biological half-life about 9 min) found in the mouse. At the respiration rate of light work, and exposure dose of 1 ppm/hr results in a tissue dose that is estimated to involve a risk amounting to 1.101 mrad-equivalents of stochastic effects with a genetic mechanism.

Adult↗