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H Kappus

Publications and source records attributed to H Kappus.

At least 73 records · Page 4Linked to original sources
PubMed1977

Pharmacokinetics of vinyl chloride in the rat.

When rats are exposed to [14C]vinyl chloride in a closed system, the vinyl chloride present in the atmosphere equilibrates with the animals' organism within 15 min. The course of equilibration could be determined using rats which had been given 6-nitro-1,2,3-benzothiadiazole. This compound completely blocks metabolism of vinyl chloride. The enzymes responsible for metabolism of vinyl chloride are saturated at an atmospheric concentration of vinyl chloride of 250 ppm. Pharmacokinetic analysis shows that no significant cumulation of vinyl chloride or its major metabolites is to be expected on repeated administration of vinyl chlorides. This may be consistent with the theory that a reactive, shortly living, metabolite which occurs in low concentration only, may be responsible for the toxic effects of vinyl chloride.

Animals↗
PubMed1977

Interaction of rifampicin treatment with pharmacokinetics and metabolism of ethinyloestradiol in man.

[6,7-3H]Ethinyloestradiol (50 microng) was administered intravenously to volunteers and the free extractable ethinyloestradiol in the plasma was measured. The compound showed a biphasic plasma decline. The half-life of the second phase was 7.5+/-1.7 (SD) hours. Administration of rifampicin (600 mg for 6 days) shifted the half-life of ethinyloestradiol to 3.3+/-0.9 h while the apparent volume of distribution for the second phase of elimination was not changed. When [2,4,6,7-3H]ethinyloestradiol (100 microng) was administered orally, some of the tritium was released by oxidative metabolism from the steroid and transformed to tritiated water (HTO) which equilibrated with whole body water. This portion, normally 7.17+/-1.66% of the tritium dose, was increased by previous administration of rifampicin to 10.62+/-2.27%. The initial rate of oxication of [2,4,6,7-3H]ethinyloestradiol was increased more than twofold by rifampicin treatment. The results are consistent with previous findings that rifampicin induces the oestrogen-2-hydroxylase in the endoplasmic reticulum of human liver, and explain the reduced effectiveness of ethinyloestradiol in oral contraceptives, if the patients are treated with rifampicin.

Administration, Oral↗
PubMed1976

Irreversible protein binding of 14C-imipramine in rats in vivo.

Forty-eight hours after a single dose of 14C-imipramine to rats, 14C-radioactivity could be measured in the following organs: liver greater than kidney greater than serum greater than fat greater than spleen greater than duodenum greater than lung greater than muscle and brain. Liver microsomes contained the main part of radioactivity derived from 14C-imipramine. After exhaustive extraction, only the proteins of liver, kidney, spleen, lung and serum contained measurable amounts of radioactive labeling. The greatest amount of 14C-imipramine irreversibly bound to proteins was detected in liver microsomes. The question, as to whether the irreversible protein binding of imipramine, if it occurs during therapy, results in toxic side-effects, is discussed.

Animals↗
PubMed1976

Irreversible protein binding of norethisterone (norethindrone) epoxide.

14,15-3H-Norethisterone-4 beta, 5 beta-epoxide, a metabolite of norethisterone, was incubated with several proteins and nucleic acids. After 30 min incubation 0.19 nmol of the epoxide were irreversibly bound per mg albumin which contains free sulfhydryl groups; proteins without SH-groups, such as concanavalin A, gamma-globulin, DNA and RNA, did not irreversibly bind norethisterone epoxide. A superoxide (O2) generating enzyme system comprised of xanthine oxidase and hypoxanthine was capable of catalyzing the irreversible binding of the parent compound, norethisterone, to albumin, indicating that an oxidation product was formed which reacted with the protein. When norethisterone epoxide was incubated for 60 min with hepatic microsomes of rats in absence of NADPH, about 2.0 nmol of the epoxide were irreversibly incorporated per mg microsomal protein. This binding was increased to 5.2 nmol by addition of a NADPH regenerating system. Addition of glutathione and cytosol decreased only the NADPH-dependent protein binding; phenobarbital pretreatment of rats induced this NADPH-dependent binding of norethisterone epoxide to microsomal protein by a factor of 2. In presence of NADPH, binding of the epoxide to microsomal protein depended on substrate concentration used. The results indicate that norethisterone epoxide is able to chemically react with proteins. In addition, hepatic microsomal enzymes convert the epoxide to another metabolite which also can react with proteins.

Animals↗
PubMed1976

Metabolism of 14 C-vinyl chloride in vitro and in vivo.

Rat liver microsomes metabolise 14 C-vinyl chloride to intermediates which irreversibly bind to the microsomal protein and to soluble proteins and RNA, when these compounds are added to the incubation. A superoxide (O2) generating system comprised of phenazine methosulfate and NADH also converts 14 C-vinyl chloride to metabolites which irreversibly bind to albumin. These data are consistent with the assumption of chloroethylene oxide being the primary reactive metabolite of vinyl chloride. If rats are exposed to 14 C-vinyl chloride, about half of the radioactive metabolites in the liver microsomal fraction is bound irreversibly to microsomal protein, when assessed immediately after exposure. Large amounts of polar, extractable, metabolites are present in the cytosol fraction. The amount of radioactivity in tissues of the rats, irreversibly bound immediately after exposure, comprises 10 - 40% of the total radioactivity in tissues. This percentage rises up to 70% after 48 hrs. Som radioactivity derived from 14 C-vinyl chloride is also incorporated into DNA and RNA of liver. Whereas the peak of incorporation of 14 C into DNA is already reached immediately after exposure to 14 C-vinyl chloride, specific labelling of RNA increases after exposure until its maximum after 24 hours.

Albumins↗
PubMed1976

[Effect of 2-hydroxyestradiol-17beta on NADPH-dependent electron transfer in rat liver microsomes in vitro (author's transl)].

If rat liver microsomes are incubated with NADPH and 2-hydroxyestradiol-17beta in vitro, the following is observed: 1. Inhibition of lipid peroxidation, 2.inhibition of cytochrome P-450 reduction, and 3.inhibition of cytochrome b5 reduction. Beyond this the catechole inhibits lipid peroxidation of liposomes in vitro. These phenomena can be explained by interaction of different states of oxidation of the estrogen with the NADPH-cytochrome reductase and with 0-2 radicals, which leads to terminal "uncoupling" of microsomal electron transport.

Animals↗
PubMed1975

Effect of rifampicin treatment on the metabolism of oestradiol and 17alpha-ethinyloestradiol by human liver microsomes.

Liver biopsies were obtained from four patients treated with rifampicin 600 mg for 6-10 days. Hepatic microsomes were incubated with an NADPH-regenerating system and the substrates [2,4,6,7-3H] oestradiol, [6,7-3H] oestradiol, [2,4,6,7-3H] ethinyloestradiol and [6,7-3H] ethinyloestradiol. The hydroxylation rates of these steroids at the labelled positions of rings A and B were determined by measuring the transformation of tritium into HTO by the microsomal enzymes. Comparison with previously published data showed that treatment with rifampicin caused a fourfold increase in the rate of hydroxylation of oestradiol and ethinyloestradiol at positions C-2/C-4 of ring A and C-6/C-7 of ring B. The acceleration of oestrogen hydroxylation by rifampicin was paralleled by an increase in microsomal cytochrome P-450, and also by microsomal reduction of rifampicin-quinone, a reactive metabolite of rifampicin. The increased aromatic hydroxylation of oestradiol and ethinyloestradiol leads to enhancement of their irreversible binding to microsomal protein. The data provide an explanation for the diminished efficacy of oestrogens in contraceptive formulations given to patients under treatment with rifampicin.

Adult↗