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K Ormstad

Publications and source records attributed to K Ormstad.

At least 37 records · Page 2Linked to original sources
PubMed1985

Formation, toxicity and inactivation of acrolein during biotransformation of cyclophosphamide as studied in freshly isolated cells from rat liver and kidney.

In the present study the formation and the effects of cyclophosphamide-derived acrolein were investigated using isolated cells from rat liver and kidney, with particular regard to the protective action of low molecular weight thiols against cellular toxicity. The results may be summarized as follows: Cyclophosphamide (CTX)-mediated toxicity to isolated cells is dependent on cytochrome P-450 activity; Loss of viability in cells incubated with cyclophosphamide is preceded by a depletion of cellular GSH; Stimulation of cellular GSH synthesis or the presence of low molecular weight thiols in the incubation medium protects against cyclophosphamide-induced toxicity; Acrolein is probably formed extracellularly as well as intracellularly and can be detoxified by thiol compounds, forming a thiochemiacetal or a thioether.

Acrolein↗
PubMed1985

Allyl alcohol toxicity in isolated renal epithelial cells: protective effects of low molecular weight thiols.

The toxicity of allyl alcohol was studied in freshly isolated renal epithelial cells prepared from male and female rats. Cells from female rats demonstrated a greater susceptibility to allyl alcohol toxicity as assessed by glutathione depletion and loss of cell viability. The sensitivity of female rat renal cells appears to relate to the higher activity of alcohol dehydrogenase found in the female rat kidney, which metabolizes allyl alcohol to the highly reactive aldehyde, acrolein. Pyrazole, an inhibitor of alcohol dehydrogenase, abolished the cytotoxic effects of allyl alcohol whereas inhibition of aldehyde dehydrogenase by disulfiram treatment was found to increase the sensitivity of renal cells to the effects of allyl alcohol. The toxicity of allyl alcohol was decreased by a number of treatments which resulted in increased levels of glutathione or other low molecular weight thiols. These results indicate that acrolein is the toxic metabolite responsible for the renal cell injury following exposure to allyl alcohol, and unless immediately inactivated acrolein interacts with critical nucleophilic sites of the cell and initiates cell injury. These studies demonstrate that freshly isolated kidney cells represent a convenient model system for studies of thiol-mediated protective mechanisms against toxic renal cell injury.

1-Propanol↗
PubMed1985

Mechanism of allyl alcohol toxicity and protective effects of low-molecular-weight thiols studied with isolated rat hepatocytes.

Freshly isolated hepatocytes from male rats were incubated with allyl alcohol at concentrations up to 2 mM. Allyl alcohol exerted a dose-dependent toxicity on the cells which was inversely related to cellular glutathione (GSH) content and accordingly influenced by stimulation as well as inhibition of GSH synthesis. The toxicity was prevented by inhibitors of alcohol dehydrogenase and augmented by the aldehyde dehydrogenase inhibitor disulfiram, suggesting that the toxic metabolite was the reactive aldehyde acrolein. The pattern of hepatocellular metabolism of allyl alcohol was monitored by high-pressure liquid chromatography (HPLC) analysis. The results suggest that acrolein, which is formed by the activity of alcohol dehydrogenase, preferentially reacts with cellular GSH to form an aldehyde-GSH adduct which subsequently is metabolized to the corresponding acid. In addition, a thiohemiacetal may be produced and subsequently degraded. In cells depleted of GSH, acrolein may react with essential macromolecules and thereby lead to structural and functional derangement and, eventually, irreversible injury.

1-Propanol↗
PubMed1985

The role of metabolic activation in drug toxicity.

Several xenobiotics undergo biotransformation reactions which yield reactive and potentially toxic compounds. Activation may occur via cytochrome P-450-mediated oxidation, prostaglandin synthetase-related hydroperoxidase-activity, or alcohol dehydrogenase/aldehyde dehydrogenase activity. The reactive metabolites thus formed may initiate lipid peroxidation or covalent binding to cell macromolecules, and secondarily lead to acute cytotoxicity or to tumorigenesis. Most cells possess mechanisms for protection against chemical toxicity, e.g. glutathione-related pathways and epoxide hydrolase activity. A possible strategy in handling toxic drug effects in the clinical situation may be chemotherapeutic manipulations aiming at a stimulation of protective mechanisms or at an inhibition of activating pathways.

Acetaminophen↗
PubMed1984

Pharmacokinetics and mechanism of action of detoxifying low-molecular-weight thiols.

A number of thiol compounds have been studied with reference to their selective protective action against urotoxic side-effects of oxazaphosphorine cytostatics. The uroprotective capacity is determined exclusively by the pharmacokinetic behavior of the compound. When given PO, all compounds tested were absorbable from the gut. Both thiols and disulfides are rapidly eliminated from the blood, but during their short half-life a number of unknown chemical reactions probably take place to maintain a physiological redox equilibrium. Elimination from the blood plasma occurs via two fundamentally different mechanisms: by distribution throughout the tissues and intracellular uptake or, alternatively, by rapid renal excretion. Most of the compounds tested belong to the first group: N-acetylcysteine, carboxycysteine, disulfiram and its metabolite DDTC, glutathione, WR 2721, etc. Few compounds are quantitatively excreted through the urine: mesna, dimesna, and DA 12. Only these compounds were suitable for selective regional detoxification and for the prevention of oxazaphosphorine-induced urotoxic lesions.

Animals↗
PubMed1984

Postmortem findings of pulmonary lesions of older datum in intravenous drug addicts. A forensic-pathologic study.

At post-mortem examination the lungs of 30 intravenous narcotic addicts were compared to two groups of 30 age- and sex-matched controls with no history of narcotic abuse. A distinctly uneven distribution of pulmonary pathology among the two groups was found, with various non-acute, non-granulomatous lesions dominating in the addict group. Microscopically, the typical pattern consisted of focally thickened, fibrotic and hypercellular alveolar septa, accumulation of haemosiderin-laden macrophages in alveolar walls as well as in the lumina of alveoli and respiratory passages, and vascular lesions with full-thickness fibrosis of arterial walls. An attempt at quantitative scoring of the changes indicated that the extent of pulmonary pathology increases with the addict's age or duration of narcotic abuse and with the degree of social deterioration. The same changes could also be demonstrated in some control cases with a history of salicylate or alcohol abuse, or with known heart/lung disease. The addict group also exhibited myocardial alterations in 28 of 30 cases. Typical findings were myofibrillar degeneration and fatty infiltration. In 15 of 30 addicts morphological and toxicological examination did not yield a definitive cause of death. However, the present demonstration of cardiopulmonary pathology suggests that narcotic addicts may be prone to acute circulatory and/or respiratory derangement even if no overdose of drugs is taken.

Adult↗
PubMed1984

Difference between in vivo and postmortem distances between anterior chest and heart surface. A combined autopsy and in vivo computerized tomography study.

The distance between anterior chest surface and intrapericardial surfaces of the heart and great blood vessels was measured on 37 cases (seven with acute fatal hemopericardium) at autopsy and on 24 live persons by computerized tomography. At autopsy, the apex of the heart was always closest to the skin surface except in cases with acute fatal hemopericardium, where the heart was displaced backwards by 10-40 mm. At computerized tomography, chest-heart distances were approximately 16 mm shorter than at autopsy. Changing the position of the patient from supine to prone decreased the distances by about 10 mm. The data presented demonstrate that the topography of the heart and great vessels is changing with the position of the body in vivo and that chest-heart distance tend to increase postmortem; therefore, the depth of a stab wound in the anterior surface of the heart as measured at autopsy should be regarded as a maximal estimate of the length of the stabbing weapon actually having penetrated the tissues.

Adolescent↗
PubMed1984

N-acetylcysteine and sodium 2-mercaptoethane sulfonate as sources of urinary thiol groups in the rat.

Increasing the urinary output of free thiol groups protects against cyclophosphamide-induced bladder toxicity. In the present study, intact rats, isolated perfused kidneys, and freshly isolated cells from various rat organs are used to compare the efficacy of N-acetylcysteine and sodium 2-mercaptoethane sulfonate (mesna) as sources of urinary thiols. In intact rats given a single i.v. dose of mesna, urinary thiol output is approximately 10-fold higher than in rats given an equimolar dose of N-acetylcysteine. this is partly due to the fact that N-acetylcysteine is rapidly absorbed by various types of cells, whereas mesna is transported selectively to the kidney, and partly to different renal handling of the two compounds. The results suggest that mesna is a more favorable drug than N-acetylcysteine for increasing urinary thiol excretion.

Acetylcysteine↗
PubMed1983

Characteristics of the uptake of cysteine-containing leukotrienes by isolated hepatocytes.

Leukotrienes were transported into rat hepatocytes by a temperature- and energy-dependent mechanism. The uptake was saturable with high- and low-affinity sites (Km values approx. 1 and 17 microM). Competition and kinetic experiments indicated that leukotrienes C4, D4 and E4 were transported by a common mechanism. The maximal velocity of transport was about 50% higher for leukotrienes D4 and E4 than for leukotriene C4. Leukotriene B4, glutathione disulfide, and the glutathione-S-conjugate of acetaminophen did not interfere with the transport of leukotriene C into hepatocytes. This suggests that the process is specific for cysteine-containing leukotrienes. It is likely that the transport mechanism described here participates in biliary excretion of leukotrienes. This route was previously found to be a major one for elimination of leukotriene C3 in mice and guinea-pigs.

Acetaminophen↗
PubMed1983

Turnover and functions of glutathione studied with isolated hepatic and renal cells.

Suspensions of freshly isolated rat hepatocytes and renal tubular cells contain high levels of reduced glutathione (GSH), which exhibits half-lives of 3-5 and 0.7-1 h, respectively. In both cells types the availability of intracellular cysteine is rate limiting for GSH biosynthesis. In hepatocytes, methionine is actively converted to cysteine via the cystathionine pathway, and hepatic glutathione biosynthesis is stimulated by the presence of methionine in the medium. In contrast, extracellular cystine can support renal glutathione synthesis; several disulfides, including cystine, are rapidly taken up by renal cells (but not by hepatocytes) and are reduced to the corresponding thiols via a GSH-linked reaction sequence catalyzed by thiol transferase and glutathione reductase (NAD(P)H). During incubation, hepatocytes release both GSH and glutathione disulfide (GSSG) into the medium; the rate of GSSG efflux is markedly enhanced during hydroperoxide metabolism by glutathione peroxidase. This may lead to GSH depletion and cell injury; the latter seems to be initiated by a perturbation of cellular calcium homeostasis occurring in the glutathione-depleted state. In contrast to hepatocytes, renal cells metabolize extracellular glutathione and glutathione S-conjugates formed during drug biotransformation to the component amino acids and N-acetyl-cysteine S-conjugates, respectively. In addition, renal cells contain a thiol oxidase acting on extracellular GSH and several other thiols. In conclusion, our findings with isolated cells mimic the physiological situation characterized by hepatic synthesis and renal degradation of plasma glutathione and glutathione S-conjugates, and elucidate some of the underlying biochemical mechanisms.

Animals↗
PubMed1983

Pharmacokinetics and metabolism of sodium 2-mercaptoethanesulfonate in the rat.

The synthetic low-molecular-weight thiol, 2-mercaptoethanesulfonate (mesna), exerts efficient protection against oxazaphosphorine-induced urothelial toxicity by binding the renally excreted and concentrated toxic metabolite(s). In this study, the pharmacokinetics and metabolism of mesna and its disulfide form (dimesna) have been investigated in the intact rat and in several in vitro systems, including isolated perfused organs, freshly isolated cells, and subcellular fractions; the mechanism of reduction of dimesna to form the pharmacologically active thiol mesna has been further studied with purified enzyme preparations. The results may be summarized as follows: (a) After p.o. administration, mesna and dimesna are both absorbed from the intestine, and dimesna undergoes reduction to mesna during intestinal absorption; (b) when present in plasma, mesna is rapidly oxidized to dimesna by a metal-dependent reaction; (c) mesna and dimesna pass unchanged through the hepatic vasculature, are not taken up into liver cells, and are not excreted in bile; (d) in the kidney, dimesna is filtered through the glomeruli and subsequently reabsorbed, whereupon reduction to the pharmacologically active thiol form occurs in the renal tubular epithelium, and the thiol is then reexcreted into the tubular lumen; (e) reduction of dimesna to mesna occurs in intestinal and renal epithelial cells by a mechanism involving the cytosolic enzymes thiol transferase and glutathione reductase. Thus, the formation of the pharmacologically active thiol form from dimesna is associated with the consumption of equimolar concentrations of reduced glutathione.

Animals↗
PubMed1982

Renal transport and disposition of Na-2-mercaptoethane sulfonate disulfide (dimesna) in the rat.

The transport and reduction of dimesna (Na-2-mercaptoethane sulfonate disulfide) was studied in vitro using isolated, perfused rat kidney, and isolated renal epithelial cells. Cellular uptake of dimesna was found to be dependent on an active transport mechanism working across the luminal brush border, with an app. Km of approximately 22 microM and Vmax approximately 1.4 nmol . 10(6) cells-1 . min-1. Among other low molecular thiols or disulfides reduced glutathione was the only one to exert competitive inhibition. gamma-GT-activity or cellular GSH status had no influence on renal uptake of dimesna, but the intracellular reduction rate was dependent on access to reduced glutathione as a cofactor.

Animals↗
PubMed1982

Evidence for different localization of glutathione oxidase and gamma-glutamyltransferase activities during extracellular glutathione metabolism in isolated perfused rat kidney.

The metabolism of extracellular glutathione was studied in the isolated, perfused rat kidney. The results indicate different localization of glutathione oxidase and gamma -glutamyltransferase (5-glutamyl)-peptide: aminoacid 5-glutamyltransferase, EC 2.3.2.2) activities, since glutathione oxidase activity was observed only with glutathione present in the perfusate, whereas gamma -glutamyltransferase-mediated metabolism of glutathione was restricted to glutathione present to the localization of renal gamma -glutamyltransferase in the brush border membranes of the tubular epithelium, but suggest an opposite localization of renal glutathione oxidase activity, i.e., in the basal plasma membrane fraction of the tubular cells, facing the capillary bloodstream. Furthermore, the existence of the tubular glutathione extraction mechanism operating in addition to glomerular filtration is confirmed.

Animals↗
PubMed1981

Turnover of cellular glutathione in isolated rat-kidney cells. Role of cystine and methionine.

Turnover of cellular glutathione in isolated rat kidney cells was studied using cystine or methionine as sulfur donor. In the absence of any sulfur donor a continuous decrease of intracellular reduced glutathione (GSH) during incubation of the cells was observed. This decrease was abolished in the presence of cystine, and, as indicated by incorporation of 35S, there was also a rapid synthesis of GSH. In the presence of gamma-glutamyltransferase inhibitor, the synthesis of intracellular GSH was accompanied by an accumulation of extracellular cysteine-glutathione mixed disulfide whereas only minor amounts of GSH and glutathione disulfide could be detected. The intracellular levels of both the cysteine-glutathione and glutathione disulfides were at all times points very low. Even though the uptake of cystine was rapid and not rate-limiting for GSH synthesis, almost no cystine could be detected intracellularly. An increasing intracellular cysteine concentration was however observed, indicating a rapid reduction of cystine. In contrast to cystine, methionine did not protect from the loss of intracellular GSH and only a low rate of incorporation of 35S into GSH was observed. Methionine was rapidly taken up into the cells but was apparently converted to cysteine only to a very limited extent. This is most likely due to a low activity of the enzyme cystathionase since neither homocysteine nor cystathionine was very effective in supporting GSH synthesis.

Animals↗