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Biomedical subjects

H Peter

Publications and source records attributed to H Peter.

At least 55 records · Page 3Linked to original sources
PubMed1989

Metabolism of methyl chloride by human erythrocytes.

Erythrocyte cytoplasm of rats, mice and humans was incubated in head space vials with methyl chloride and the decline in concentration of the substance monitored as a parameter of metabolism. The production of S-methylglutathione was controlled by tlc. Rats, mice, bovines, pigs, sheep and rhesus monkeys showed no conversion of methyl chloride in erythrocyte cytoplasm. About 60% of the human blood samples showed a significant metabolic elimination of the substance (conjugators), whereas about 40% did not (non-conjugators). The production of S-methylglutathione indicated enzymatic metabolism of the substance by glutathione S-transferases. In literature, a "major" and "minor" form of human erythrocyte glutathione S-transferase has been described. The results indicate that the "minor" form is probably responsible for the unique metabolism of methyl chloride in human erythrocytes.

Animals↗
PubMed1989

A T-cell clone recognizing an MLC stimulating epitope located on the DRw11 beta 1 chain.

An alloreactive proliferative T-cell clone, 6065 WS, was obtained in an intrafamilial cell combination where the stimulator was a homozygous DRw11, DRw52, DQw3 son and the responder his haploidentical mother. Proliferation assays on eight local DRw11 families, 75 homozygous B-cell lines (Tenth Histocompatibility Workshop panel) and blocking assays with monoclonal antibodies showed that clone 6065 WS recognizes an epitope on the DRw11 beta 1 chain. Comparison of the reactivity of clone 6065 WS with cells expressing the three known DRw11 beta 1 amino acid sequences identified two unique amino acids at positions 71 and 86 which contribute to determining the specific recognition by the T-cell clone 6065 WS. Our data suggest that one or both of these amino acids can either be directly involved in the recognition by the T-cell receptor or responsible for critical conformation of the determinants on the DR molecule. Alternatively, they could affect recognition of a self peptide bound to the major histocompatibility complex class II molecule.

Amino Acid Sequence↗
PubMed1989

A non-human primate model for the study of oral iron chelators.

Recent studies have demonstrated that parenteral deferroxamine can prolong life in patients with iron overload. We have developed a non-human primate model of iron overload and have accurately determined negative iron balance in parenteral and oral studies of deferroxamine and a new chelator, desferrithiocin. Cebus monkeys were loaded with iron dextran (10 mg/kg twice weekly) until their serum contained a transferrin saturation greater than 75%, and (in two animals) liver biopsies showed iron loading. When complete iron balance studies were performed at this time, basal iron balance was -53 +/- 11 micrograms (N = 4), providing a low background for provocative studies. Iron balance was determined for intramuscular (N = 2) and oral (N = 3) deferroxamine, as well as intramuscular (N = 1) and oral (N = 4) desferrithiocin. The pattern of iron excretion after parenteral deferroxamine strongly resembled that of the iron-loaded, transfused human. Desferrithiocin was found to have significant activity as an oral chelator. This Cebus monkey model accurately determines negative iron balance and readily permits precise comparison of iron chelators given parenterally or orally. This model may offer an important step between rodent and human trials of promising new iron chelators.

Administration, Oral↗
PubMed1988

Analysis of macromolecular ethylene oxide adducts.

Ethylene oxide is a carcinogenic compound which is also an ethylene metabolite. Ethylene oxide forms macromolecular adducts with proteins and nucleic acids. Targets in proteins are the amino acids cysteine, histidine and valine (if N-terminal, as in hemoglobin). The major DNA adduct is 7-(2-hydroxyethyl)-guanine. Methods for detection of this adduct include radiolabelling and GC-MS. The sensitivity of current GC/MS methods can be improved by selective enrichment of adducts from DNA samples. Studies in this direction are presently being performed.

Alkylation↗
PubMed1988

Biochemical effects of methyl chloride in relation to its tumorigenicity.

The biochemical effects of methyl chloride were investigated in tissues of F-344 rats and B6C3F1 mice (both sexes). Activities of GST were 2-3 times higher in livers of male B6C3F1 mice, compared with those of female mice, and with rats of both sexes. In kidneys GST activities of (male) mice were about 7 times lower than those found in livers. The activity of FDH was higher in livers of mice (both sexes) than in those of rats. No obvious sex difference was found in livers of rats and mice with respect to FDH. In kidneys, however, (minor) differences in FDH activities occurred between male and female B6C3F1 mice (4.7 vs. 3.1 nmol/min per mg). Sex differences of FDH activity in kidneys were not observed in F-344 rats. The microsomal transformation (by cytochrome P-450) of methyl chloride and S-methyl-L-cysteine to formaldehyde in tissues of B6C3F1 mice occurred preferentially in the liver. More formaldehyde was produced in liver microsomes of male, compared to those of female mice. Kidney microsomes metabolized methyl chloride to formaldehyde much less than liver microsomes. After a single exposure of mice of both sexes to 1000 ppm methyl chloride no elevation in formaldehyde concentrations was observed in livers and kidneys ex vivo. The determination of DNA lesions, using the alkaline elution technique, revealed no DNA-protein crosslinks in kidneys of male B6C3F1 mice after exposure to methyl chloride (1000 ppm, 6 h day-1, 4 days) and gave only minor evidence of single-strand breaks. Lipid peroxidation (production of TBA reactive material), induced by single exposure to methyl chloride (1000 ppm, 6 h), was very pronounced in livers of male and female mice. Smaller increases in peroxidation were observed in the kidneys of exposed mice. The theory that renal tumors observed in male mice after chronic exposure of the test animals to high (1000 ppm) concentrations of methyl chloride, are evoked by intermediates and in situ produced formaldehyde is proven unlikely by our results.

5-Methylcytosine↗
PubMed1988

NH4+ ion-selective microelectrode based on the antibiotics nonactin/monactin.

A liquid-membrane microelectrode (less than or equal to 1 micron tip diameter) using macrotetrolide antibiotics as ion-selective components is described. The electrode shows selectivities of NH4+ over K+, Na+ and H+ of 3.8, 100 and 150, respectively. The stability and reproducibility of the sensor signal and the response time are determined in solutions with a typical intracellular ion background. The microelectrode does not suffer from significant interference by inorganic and organic inhibitors and lipophilic cations, but high concentrations of lipophilic anions may interfere considerably.

Anti-Bacterial Agents↗
PubMed1987

Pharmacokinetics of the neurotoxin n-hexane in rat and man.

The pharmacokinetics of inhaled n-hexane in rat and man were compared. In the rat metabolism was saturable. Up to 300 ppm, the metabolic rate was directly proportional to the concentration in the atmosphere, reaching 47 mumol/(h X kg). Only 17% of n-hexane was exhaled unchanged. Above 300 ppm, the amount of n-hexane in the body rose with increasing atmospheric concentrations from 1.6 up to a limiting value of 9.6, which corresponded to the thermodynamic distribution coefficient of n-hexane between the organism and the atmosphere. Up to 3000 ppm, the rate of metabolism increased to 245 mumol/(h X kg); only a slow further increase was found up to 7000 ppm (285 mumol/(h X kg]. In man the steady-state concentrations of n-hexane were about 1 ppm. The metabolic clearance was 132 1/h, and n-hexane accumulated to a factor of 2.3 in the organism. The thermodynamic distribution coefficient was calculated to be 12. Twenty per cent of n-hexane in the body was exhaled unchanged. At low concentrations the rate of metabolism of n-hexane is limited in both species by transport to the enzyme system. Under these conditions the rate of metabolism of n-hexane should not be influenced by xenobiotics which induce the n-hexane metabolizing enzyme system.

Administration, Inhalation↗
PubMed1987

Pharmacokinetics of isoprene in mice and rats.

Pharmacokinetic analysis of isoprene inhaled by male Wistar rats and male B6C3F1 mice showed saturation kinetics in both species. Below atmospheric concentrations of 300 ppm in rats and in mice the rate of metabolism is directly proportional to the concentration. The low accumulation of isoprene in the body at low atmospheric concentrations suggests transport limitation of the metabolism. Only small amounts of isoprene taken up are exhaled as unchanged substance (15% in rats and 25% in mice). Its half life in rats is 6.8 min and in mice 4.4 min. At concentrations above 300 ppm the rate of metabolism does not increase further in proportion to the atmospheric concentration. It finally approaches maximal values of 130 mumol/(h X kg) body weight at atmospheric concentrations above 1500 ppm in rats, and 400 mumol/(h X kg) body weight at concentrations above 2000 ppm in mice. This indicates limited production of the two possible mono-epoxides of isoprene at high concentrations. Isoprene is endogenously produced and is systemically available. Its production rate is 1.9 mumol/(h X kg) in rats, and 0.4 mumol/(h X kg) in mice, respectively. Part of the endogenous isoprene is exhaled by the animals but it is metabolized to a greater extent: the rate of metabolism of endogenously produced and systemically available isoprene is 1.6 mumol/(h X kg) (rats) and 0.3 mumol/(h X kg) (mice).

Administration, Inhalation↗
PubMed1986

Different pharmacokinetics of dichlorofluoromethane (CFC 21) and chlorodifluoromethane (CFC 22).

Inhalation pharmacokinetics of dichlorofluoromethane (CFC 21) and chlorodifluoromethane (CFC 22) were studied in male Wistar rats by use of a closed inhalation chamber system. CFC 21 was readily eliminated via metabolism. However, CFC 22 underwent no detectable metabolism; pretreatment of the rats with DDT or phenobarbital did not stimulate metabolic transformation of the compound. Hence, formation of biologically relevant amounts of reactive intermediates from CFC 22 as a mechanism of toxicity seems unlikely.

Animals↗
PubMed1986

DNA adducts of halogenated hydrocarbons.

Although formation of DNA adducts has been postulated for several halomethanes, no chemical identification of such adducts has been performed so far. There is, however, evidence that methyl chloride does not act biologically as a DNA methylating agent. 1,2-Dichloroethane and 1,2-dibromoethane are activated through conjugation with glutathione. There is some evidence for formation on an N-7 adduct of guanine which carries an ethyl-S-cysteinyl moiety. Extensive work has been published on adducts of vinyl chloride, both in vitro and in vivo. The major DNA adduct is 7-(2-oxoethyl)guanine; a minor adduct appears to be N2,3-ethenoguanine. Other "etheno" adducts, i.e., 1,N6-ethenoadenine and 3,N4-ethenocytosine, are readily formed with DNA, vinyl chloride, and a metabolizing system in vitro and with RNA in vivo, but are usually not detected as DNA adducts in vivo. The data on DNA alkylation by vinyl chloride (and vinyl bromide) metabolites are compared with those of structurally related compounds (acrylonitrile, vinyl acetate, vinyl carbamate).

Alkylating Agents↗