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Biomedical subjects

P Eyer

Publications and source records attributed to P Eyer.

At least 91 records · Page 5Linked to original sources
PubMed1982

Inhibition of glutathione excretion, bile flow, and alterations of the glutathione status by 4-nitrosophenetol during perfusion of rat livers.

(1) Hemoglobin-free single-pass perfusion of isolated rat livers was carried out with various concentrations of 4-nitrosophenetol (NOPt). (2) NOPt, up to 2 mumol/min/g liver wet wt., was reduced by the liver with formation of N-hydroxy-4-phenetidine (NHOHPt), 4-phenetidine (NH2Pt), phenacetin and polar metabolites. (3) Three per cent of NOPt was irreversibly bound to liver proteins after a load of 20 mumol/g liver wet wt. After 30 min perfusion, 0.2 mumol of liver glutathione was lost by 1 mumol NOPt infused. (4) Bile flow and glutathione release by the bile decreased rapidly during NOPt perfusion. (5) Glutathione release of the livers into venous effluent was diminished by NOPt and was stimulated only slightly by t-butylhydroperoxide (BOOH). Because BOOH reduction and glutathione peroxidase were not altered and intracellular glutathione disulfide (GSSG) levels were elevated, inhibition of the GSSG excretory mechanism is assumed.

Animals↗
PubMed1981

Biotransformation of 4-dimethylaminophenol in man.

1) The biotransformation of 4-dimethylaminophenol (DMAP) was studied on six healthy male volunteers. After i.v. injection of 3.2 mg DMAP-HCl/kg the metabolites were analyzed in the 24 h urine with an isotope dilution technique. 2) For the isotope dilution technique the 14C-labeled metabolites were synthetized from 14C-DMAP. 14C-DMAP-glucuronide was produced in isolated hepatocytes and purified. 3) Two thirds of the DMAP applied were identified in the 24 h urine: 40% DMAP-glucuronide, 12% DMAP-sulfate, and 15% DMAP-thioethers. About 65% of the thioether fraction consisted of S,S,S-(2-dimethylamino-5-hydroxy-1,3,4-phenylene)tris-cysteine and 3% of the corresponding N-acetyl derivative. 4) As compared to dogs and rats humans produced more glucuronide at the expense of sulfate whereas thioether formation was equal in man and dog.

Aminophenols↗
PubMed1979

[Treatment of psoriasis vulgaris with external sulfur mustard gas with particular reference to its potential carcinogenic risk. III. Clinical and experimental studies on the extent of percutaneous and inhalational uptake of sulfur mustard gas].

Concerning the often discussed carcinogenic risk of psoriasis treatment with 0.005% S-mustard-vaseline (so-called Russian Ointment) -- especially by inhalation -- 19 patients were treated with a radioactive labeled S-mustard-ointment and examined. The patients' whole bodies were inuncted for 1--2 days with about 50 g of radioactive S-mustard vaseline (U14C, 3 muCi/g). Afterwards the radioactivity was determined in the patients' expired air, blood, urine, and in their surrounding air. In three patients punch biopsy material from normal and psoriatic skin was assayed for radioactivity after combustion. In the skin, radioactivity distinctly decreased from the epidermis (13.1 pCi/mg) to the subcutis (0.77 pCi/mg) without significant differences between normal skin and psoriatic lesions as confirmed by autoradiography. In all samples of air, body fluids and tissue, definitive amounts of radioactivity were found, which, however, were far below the US-American MAK-values. Between skin surface and shirt, the values varied from 1.5 to 13.7 nCi/20 l air, at a distance of 2 meters by 0.3 nCi/100 l air, in the breath by 0.5 nCi/20 l. The radioactivity decreased to 1/10 of the maximum values after 1--2 hours. In blood the activity was at the limit of detection and was parallelled by the activity of the urine. Generally, 1--7% of the radioactivity applied to the skin was eliminated with the urine within one week. Thus, the carcinogenic risk may be very low in the external S-mustard therapy of psoriasis and other skin diseases.

Air↗
PubMed1979

Reactions of nitrosobenzene with reduced glutathione.

Nitrosobenzene (NOB) formed acid labile conjugates with reduced glutathione (GSH) and hemoglobin within red cells. In vitro, NOB rapidly reacted with GSH with formation of phenylhydroxylamine (PH), oxidized glutathione (GSSG), and a water-soluble compound identified as glutathionesulfinanilide (GSO-AN). Free aniline (AN), aminophenols and azoxybenzene were not detected. The proportion of PH formed increased with increasing GSH concentration and at higher pH values. Spectroscopic analysis revealed the formation of a labile adduct following a second order reaction (K = 5 x 10(3) M-1 . sec-1 at pH 7.4 and 37 degrees). This reaction was reversible because nearly all NOB could be extracted with ether from the labile intermediate. On the other hand, the labile intermediate was transformed into GSO-AN (with increasing rate at lower pH values) or it was cleaved by GSH with formation of GSSG and PH. Intermediate formation of NOB and thiol radicals was ruled out by analysis of the equilibrium data. A tentative scheme is presented for the proposed reaction mechanism.

Benzene Derivatives↗
PubMed1977

Pharmacokinetics of cyanide in poisoning of dogs, and the effect of 4-dimethylaminophenol or thiosulfate.

Cyanide in blood, plasma, and urine of dogs after administration of K14CN was determined with the isotope dilution technique. The addition of large amounts of inactive KCN as soon as possible to a sample to be analyzed inhibited the decrease of the original cyanide concentration. After administration of several lethal doses of cyanide into the stomach or by slow intravenous infusion a concentration of about 40 micron cyanide in plasma was found at the moment of respiratory arrest. Since 60% of the cyanide in plasma was bound to proteins the concentration of free cyanide which stopped respiration was about 16 micron. Quick formation of ferrihemoglobin by i.v. injection of 4-dimethylaminophenol after plasma cyanide had risen to or above 40 micron decreased the cyanide concentration in plasma and restored respiration, while cyanide was accumulated in red cells by formation of ferrihemoglobin cyanide. Equilibrium constants calculated for the reaction between ferrihemoglobin and cyanide in vivo indicated that the reaction approached equilibrium in a few minutes. Up to 60% of the radioactive cyanide absorbed was found as non-cyanide radioactivity in the urine.

Animals↗
PubMed1976

Biotransformation of 4-dimethylaminophenol: reaction with glutathione, and some properties of the reaction products.

4-Dimethylaminophenol (DMAP) forms ferrihemoglobin by catalytic transfer of electrons from ferrohemoglobin to oxygen. In solutions of purified human hemoglobin, quick binding of oxidized DMAP to the globin moiety of hemoglobin terminates this reaction. Reduced glutathione in high concentrations, as in the red cell, substantially diminished binding of oxidized DMAP to hemoglobin by formation of S,S,S-(2-dimethylamino-5-hydroxy-1,3,4-phenylene)-tris-glutathione (tris-(GS)-DMAP), which does not form ferrihemoglobin. In the presence of reduced glutathione, DMAP disappeared more rapidly from hemoglobin solutions than in its absence. The formation of tris(GS)-DMAP in red cells was found to be of importance for the termination of catalytic ferrihemoglobin formation by DMAP in vivo. With low concentrations of GSH, DMAP in hemoglobin solutions formed another conjugate, (GS)-DMAP, S,S(2-dimethylamino-5-hydroxy-1,3-phenylene)-bis-glutathione. Similar to DMAP, bis(GS)-DMAP catalyzed the formation of ferrihemoglobin. As the oxidized bis(GS)-DMAP was bound to hemoglobin more slowly and to a lesser extent, it produced more ferrihemoglobin than DMAP. In contrast to the reactions of DMAP with hemoglobin, hydrogen peroxide and superoxide radicals are involved in the ferrihemoglobin formation by bis(GS)-DMAP. The radicals accelerate the oxidation of bis(GS)-DMAP and thereby the ferrihemoglobin formation.

Aniline Compounds↗
PubMedDate not supplied

Reactivity of glutathione adducts of 4-(dimethylamino)phenol. Involvement of reactive oxygen species during the interaction with oxyhemoglobin.

Ferrihemoglobin formation by 4-(dimethylamino)phenol (DMAP), a potent cyanide antidote, is influenced by GSH under formation of various glutathione S-conjugates. Two of these were shown to be still reactive and able to produce ferrihemoglobin. The mechanism of ferrihemoglobin formation is fundamentally different from that found with the parent compound. First of all, induction periods of ferrihemoglobin formation were observed when 4-(dimethylamino)-2-(glutathion-S-yl)-phenol (2-GS-DMAP) and 4-(dimethylamino)-2,6-bis(glutathion-S-yl)phenol (2,6-bis-GS-DMAP) reacted with oxyhemoglobin at 100% and 20% oxygen, but not at 2% oxygen. This behavior points to thioether activation by autoxidation. Autoxidation proceeded in an autocatalytic manner, and the process was markedly modified by reducing agents, e.g., ferrihemoglobin and GSH, and by nucleophiles like GSH. Superoxide dismutase extended the lag phase of autoxidation and ferrihemoglobin formation. Catalase diminished markedly ferrihemoglobin formation, particularly at low oxygen pressure. The extent of this effect was much higher than expected if H2O2 had formed ferrihemoglobin directly. Conceivably, H2O2 might react with the thioethers or their oxidation products to give hitherto unidentified compounds of high catalytic activity in ferrihemoglobin formation. The results indicate that ferrihemoglobin formation by reactive glutathione conjugates of DMAP is essentially not a co-oxidation process as found with the parent DMAP and other aminophenols, but is mainly caused by an autocatalytic autoxidation process with formation of various reactive intermediates including superoxide radical anions and hydrogen peroxide. It appears that glutathione conjugation of autoxidizable aromatics does not necessarily lead to inactive phase II metabolites but opens new avenues of toxication reactions that may be a broader toxicological significance.

Aminophenols↗