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PubMed2004

Sequences of B-chain/domain 1-10/1-9 of insulin and insulin-like growth factor 1 determine their different folding behavior.

Although insulin and insulin-like growth factor-1 (IGF-1) belong to one family, insulin folds into one thermodynamically stable structure, while IGF-1-folds into two thermodynamically stable structures (native and swap forms). We have demonstrated previously that the bifurcating folding behavior of IGF-1 is mainly controlled by its B-domain. To further elucidate which parts of the sequences determine their different folding behavior, by exchanging the N-terminal sequences of mini-IGF-1 and recombinant porcine insulin precursor (PIP), we prepared four peptide models: [1-9]PIP, [1-10]mini-IGF-1, [1-4]PIP, and [1-5]mini-IGF-1 by means of protein engineering, and their disulfide rearrangement, V8 digestion, circular dichroic spectra, disulfide stability, and in vitro refolding were investigated. Among them only [1-9]PIP, like mini-IGF-1/IGF-1, was expressed in yeast as two isomers: isomer 1 (corresponding to swap IGF-1) and isomer 2 (corresponding to native IGF-1), which are supported by the experimental results of disulfide rearrangements, peptide mapping of V8 endoprotenase digests, circular dichroic analysis, in vitro refolding, and disulfide stability analysis. The other peptide models, [1-10]mini-IGF-1, [1-4]PIP, and [1-5]mini-IGF-1, fold into one stable structure as PIP does, which indicates that sequence 1-4 of mini-IGF-1 is important for the folding behavior of mini-IGF-1/IGF-1 but not sufficient to lead to a bifurcating folding. The results demonstrated that the folding information, by which mini-IGF-1/IGF-1-folds into two thermodynamically structures, is encoded/written in its sequence 1-9, while sequences 1-10 of B chain in insulin/PIP play an important role in the guide of its unique disulfide pairing during the folding process.

Amino Acid Sequence↗
PubMed2004

[Primary culture of human periodontal ligament fibroblasts by explants with enzymatic digestion].

OBJECTIVE: To increase the success rate of primary culture of human periodontal ligament fibroblasts (HPLF), and to establish an experimental model for studying HPLF in vitro. METHODS: The primary cells were isolated from human periodontal ligament by explants with enzymatic digestion method. Morphological analysis and immunocytochemical staining were used to characterize the cell lineage, and growth curve assay to evaluate the biological features of HPLF. RESULTS: The success rate of primary culture of HPLF was 77.8%. Cultured cells were spindle-shaped, and had a positive reaction to antibodies against vimentin, and a negative reaction to antibodies against keratin. Their morphological and biological characteristics were similar to those of typical HPLF. Growth of HPLF obtained by this method was satisfactory. CONCLUSION: The success rate of primary culture of HPLF is significantly increased by explants combined with enzymatic digestion. The method is simple and feasible.

Cell Culture Techniques↗
PubMed1996

Mobilization of PAH and PCB from contaminated soil using a digestive tract model.

Environmental contaminants are mainly incorporated by ingestion. In general only those contaminants mobilized by the digestive juices are available for absorption in the digestive tract, while pollutants still fixed to indigestible particles leave the body without any effect. To evaluate the different health risks arising from the ingestion of individual types of polluted soil or other materials, we developed an in vitro test system which simulates the transition of pollutants from contaminated materials into digestive juices by means of a standardized artificial gastro-intestinal model. The test system simulates the influence of the acidic environment of the stomach (gastric model) followed by the neutral or slightly alkaline environment of the small intestine (gastro-intestinal model). Investigations on small amounts of polluted soil, sewage sludge, asphalt, metal scrap and blast sand showed that the mobilization of polycyclic aromatic hydrocarbons (PAH) and polychlorinated biphenyls (PCB) by artificial gastric juice reaches 3% up to 22% of the pollutant concentration introduced into the test system. Elutions of the contaminated materials under gastric and subsequently under intestinal conditions with bile concentrations of 3 g/l resulted in PAH- and PCB-mobilizations in the range of 5% up to 40%. The degree of mobilization depends considerably on supplementary food material added to the test system. Lyophilized milk increased the fraction of mobilized PAH and PCB to 40%-85%. Application of the test system on 22 different contaminated soils showed that the mobilization of PAH under gastro-intestinal conditions with the addition of lyophilized milk ranged from 7% up to 95%, and the mobilization of PCB ranged from 32% up to 83%. This indicates that the test system can be a useful tool for evaluating the individual health risks arising from polluted soil or other materials.

Animals↗
PubMed1987

cAMP elevation modulates physiological activity of pyloric neurons in the lobster stomatogastric ganglion.

1. We analyzed the physiological effects of the adenylate cyclase activator forskolin, and other adenosine 3',5'-cyclic monophosphate (cAMP)-elevating agents, on neurons of the pyloric circuit from the stomatogastric ganglion of the lobster Panulirus interruptus. Agents were bath applied to pyloric neurons either in the synaptically intact pyloric circuit or following isolation from all known synaptic input. 2. Several cAMP-elevating agents, including forskolin, 3-isobutyl-1-methylxanthine, Ro20-1724, and 8-bromo-cAMP, generated similar motor patterns from the pyloric circuit. The motor patterns exhibited an increased cycle frequency and enhanced spike activity from all classes of pyloric neurons. Since these agents differ both in structure and site of action in the cAMP pathway, their physiological effects on the motor pattern probably result from increased cAMP levels in pyloric neurons. 3. When forskolin was applied to synaptically isolated neurons, it caused a strong activation or enhancement of activity of all pyloric cells. However, it induced different types of activity in different cells, including the induction of bursting pacemaker potentials in one cell type, activation of plateau potentials in another, and depolarization with activation or enhancement of tonic spike activity in the remaining cells. Thus there is no single physiological response to cAMP elevation in the pyloric circuit; its effects can be quite diverse, mediating several activity states, in different cells. 4. Radioimmunoassays were performed on whole stomatogastric ganglia to determine whether known neuromodulators can affect cAMP concentrations. Both forskolin and octopamine increased cAMP levels, whereas dopamine, serotonin, proctolin, and FMRFamide did not appreciably affect cAMP levels. The physiological effects of octopamine and forskolin are similar in most, but not all, pyloric cells. Octopamine is thus a candidate neuromodulator whose actions may be mediated, at least in part, by increased cAMP in some pyloric cells; however, forskolin does not completely mimic the physiological effects of octopamine on all pyloric neurons, suggesting that octopamine can also act by other biochemical mechanisms.

1-Methyl-3-isobutylxanthine↗
PubMedDate not supplied

Application of an immobilized digestive enzyme assay to measure chemical and enzymatic hydrolysis of the cyclic peptide antibiotic lysobactin.

The natural product lysobactin is a cyclic peptide with greater antibiotic activity than vancomycin against Gram-positive aerobic and anaerobic bacteria. Although the potency of orally administered lysobactin has not been reported, lysobactin hydrolysis in the digestive tract following oral administration would be difficult to predict because of the cyclic structure and presence of beta-hydroxy and D-amino acids. Therefore, lysobactin served as a model compound for study using an in vitro assay to predict if hydrolysis in the digestive tract might severely limit its bioavailability. The in vitro immobilized digestive enzyme assay consisted of a gastric digester containing immobilized pepsin, and an intestinal digester consisting of immobilized trypsin, chymotrypsin, and mucosal peptidases. In order to determine the sites of lysobactin hydrolysis by each enzyme, lysobactin was incubated separately with immobilized pepsin, trypsin, chymotrypsin, or mucosal peptidases. Lysobactin was also incubated with a mixture of intestinal enzymes. The hydrolysis products of lysobactin in each incubation mixture were rapidly identified using reversed-phase HPLC, continuous-flow FAB/LC-MS, and tandem MS. Lysobactin was essentially stable at low pH and was not hydrolyzed by immobilized pepsin. Above pH 7, nonenzymatic hydrolysis of the lactone moiety occurred followed by proteolysis by all intestinal enzymes investigated. Lysobactin was not directly hydrolyzed by immobilized pepsin, chymotrypsin, trypsin, or mucosal peptidases. Hydrolysis rates of lysobactin at pH 7.5 with active or inactivated chymotrypsin were measured and were compared with the rate of chymotrypsin hydrolysis of the open-chain form following hydrolysis of the lactone.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2004

Effects of low-molecular-weight and unfractionated heparin on trophoblast function.

OBJECTIVE: Unfractionated and low-molecular-weight heparin and low-dose aspirin are used for the prevention of pregnancy loss in pregnant women with thrombophilia. We investigated the effect of these drugs on in vitro models of human extravillous trophoblast motility and differentiation. METHODS: Chorion from term placentas was digested and extravillous trophoblast isolated. Extravillous trophoblast formed giant multinuclear cells that were counted after 24, 36, and 48 hours of culture. This model was then used to investigate the effect of unfractionated, low-molecular-weight heparin and aspirin on in vitro extravillous trophoblast differentiation at both therapeutic and supratherapeutic doses. In addition, the effect of unfractionated and low-molecular-weight heparin on hepatocyte growth factor-stimulated SGHPL-4 cell (extravillous trophoblast cell line) motility was determined by time-lapse microscopy. RESULTS: At therapeutic doses unfractionated heparin promoted extravillous trophoblast differentiation. However, low-molecular-weight heparin inhibited giant multinuclear cells formation. At supratherapeutic doses, both low-molecular-weight and unfractionated heparin promoted extravillous trophoblast differentiation. Low-dose aspirin had minimal effects on the extravillous trophoblast differentiation. Both unfractionated and low-molecular-weight heparin inhibited hepatocyte growth factor-stimulated extravillous trophoblast motility at supratherapeutic doses. At a therapeutic dose of 0.25 IU/mL, only unfractionated heparin inhibited hepatocyte growth factor-stimulated motility, whereas low-molecular-weight heparin had no effect. CONCLUSION: Our data suggest that unfractionated and low-molecular-weight heparin have differing effects on trophoblast differentiation and motility at therapeutic doses. This finding may be one of many factors that contribute to the clinical scenario.

Anticoagulants↗
PubMed1986

An in vitro method for estimating biologically available vitamin B6 in processed foods.

1. An in vitro method which used enzymic digestion of the food matrix to release biologically available vitamin B6 is described. 2. Vitamin B6-fortified liquid model foods were thermally processed. After these foods had been freeze-dried, one part was subjected to enzymic hydrolysis at pH 2.0 with pepsin (EC 3.4.23.1) followed by a hydrolysis at pH 8.0 with pancreatin. The vitamins that were found in the supernatant fraction, after an acidified methanol treatment of the hydrolysate, were estimated by high-performance liquid chromatography (HPLC). The other part was given to rats who were kept on a vitamin B6-depleted diet. 3. The biologically available vitamin B6 content of the processed model foods, as determined by rat bioassay, showed good correlation with the vitamin B6 determined by HPLC. 4. It has proved possible to use this in vitro, two-stage enzymic digestion system followed by HPLC determination to determine biologically available vitamin B6 in vitamin B6-fortified processed model foods.

Animals↗
PubMed1997

Human newborn and adult myenteric plexus grows in different patterns.

Whilst embedded within the gut wall the inaccessibility of the enteric nervous system (ENS) is a major drawback for the establishment of an in vitro model for the human ENS. Using a method which combines collagenase digestion, mechanical agitation and manual dissection it was possible to dissect myenteric plexus from human colon of patients at all ages, from newborn to old-age. While complex networks of ganglia and their interconnecting strands could be isolated from newborn gut, the adult tissue allowed only single or small groups of ganglia to be dissected coherently. Pieces of plexus were cultivated on glass coverslips or on plastic sheets respectively. Explants from newborn or older patients displayed different growth patterns. The cytological behaviour of the newborn explants is characterized by an intensive neurite outgrowth. After 1 to 2 days in culture, glial cells start to leave the explant while proliferating and forming a dense cellular carpet. The axons appear partly arranged in bundles, expanding above the glial carpet. Single neurites can leave the carpet and attach directly on the substrate. Semithin sections and EM studies reveal the existence of numerous neurons within the ganglia. The characteristic dense arrangement of neurons, glial cells and neuropil of the myenteric ganglia in vivo was only partly conserved in newborns while in cultured adult ganglia the cells were sparsely scattered throughout the explant with large clefts between the single cells. The ganglia of the adults do not show any considerable neurite outgrowth, which correlates with the low amount of neurons within the ganglia. The migratory behaviour of the adult glial cells is rather moderate, also the proliferation rate compared to the newborn cultures. In general single cells leave the explant without forming an glial carpet as seen in the newborn cultures. The described method delivers an in vitro paradigm for the study of human myenteric plexus. It underlines the differences in growth pattern, neurite outgrowth and glial proliferation from newborn and older children, as well as from adult patients, thus establishing a base line for future studies.

Adolescent↗
PubMed2004

Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation.

PURPOSE: To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly water-soluble drug. METHODS: Three lipid-based danazol formulations [a long-chain triglyceride solution (LCT-solution) and self-microemulsifying drug delivery systems (SMEDDS) based on long-chain (C18) lipids (LC-SMEDDS) and medium-chain (C8-C10) lipids (MC-SMEDDS)] were administered to fasted beagle dogs and compared with a micronized danazol formulation administered postprandially and in the fasted state. In vitro dispersion and particle size data for the two SMEDDS were compared, and the distribution/solubilization patterns of danazol across the various phases produced during in vitro digestion quantified. RESULTS: The LCT-solution and LC-SMEDDS formulations significantly enhanced the oral bioavailability of danazol when compared to fasted administration of the powder formulation. In contrast, and despite displaying excellent dispersion properties, the MC-SMEDDS resulted in little enhancement in danazol bioavailability. In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations. CONCLUSIONS: Digestion of microemulsion preconcentrate formulations based on medium-chain lipids may limit in vivo utility when compared with similar formulations based on long chain lipids.

Administration, Oral↗
PubMed2003

Antacid medication inhibits digestion of dietary proteins and causes food allergy: a fish allergy model in BALB/c mice.

BACKGROUND: Digestible proteins were supposed to be irrelevant for oral sensitization and induction of food allergy. Approximately 10% of the adult population uses antacids for the treatment of dyspeptic disorders, drugs that hinder peptic digestion. In these patients, proteins that are normally degradable might act as food allergens. OBJECTIVE: We aimed to study the influence of antacid intake on the allergenicity of dietary proteins, taking sturgeon caviar and parvalbumin, the major fish allergen, as examples. METHODS: Caviar proteins and recombinant parvalbumin from carp, rCyp c 1, were applied for intragastric feedings with or without the antacids sucralfate, ranitidine or omeprazole, using a Balb/c mouse model. RESULTS: Both caviar proteins and parvalbumin were rapidly degraded in an in vitro digestion assay at pH 2.0, but not at pH 5.0, imitating the effect of antacids. The groups fed with caviar in combination with ranitidine hydrochloride intramuscularly or sucralfate orally had significant levels of caviar-specific IgE antibodies (P <.01), T-cell reactivity, and elevated counts of gastrointestinal eosinophils and mast cells. Food allergy in these groups was further evidenced by oral provocation tests and positive immediate-type skin reactivity. In contrast, feedings with caviar alone led to antigen-specific T-cell tolerance. None of the groups showed immune reactivity against the daily mouse diet. As a proof of the principle, feeding mice with parvalbumin in combination with ranitidine or omeprazole intramuscularly induced allergen-specific IgE antibodies (P <.05). CONCLUSIONS: When antacid medication impairs the gastric digestion, IgE synthesis toward novel dietary proteins is promoted, leading to food allergy.

Administration, Oral↗
PubMed2005

Biochemical characterization of autologous fibrin sealants produced by CryoSeal and Vivostat in comparison to the homologous fibrin sealant product Tissucol/Tisseel.

Different principles for production of "autologous fibrin sealant" have been established, and commercial devices employing these methods are nowadays available and used in clinical routine. Users might anticipate for these autologous fibrin sealants features comparable to commercial homologous fibrin sealants, used in surgical routine for many years. However, only little is known about biochemical properties, formation, cross-linking and stability of fibrin sealant clots produced for autologous use with the aid of commercially available devices. We have investigated protein composition, formation and stability of clots obtained from autologuous fibrin sealants produced with commercially available devices (CryoSeal and Vivostat) and compared these parameters to those of the industrially produced homologous fibrin sealant Tissucol/Tisseel. The CryoSeal product is a mixture of many plasma proteins; the Vivostat product and Tissucol/Tisseel appear as comparatively pure plasma derivatives. The products differ in their protein composition and concentrations, including their concentration in fibrin. Significant fibrin alpha and gamma-chain cross-linking by FXIIIa occurs only in Tissucol/Tisseel clots. In test tubes CryoSeal and Vivostat (tranexamic acid-free formulation) fibrin clots liquefy within 1-2 days, but Vivostat (tranexamic acid containing formulation) clots were stable for 4 days and showed partial liquefaction after 5 days. Tissucol/Tisseel clots, containing the protease inhibitor aprotinin, appeared unchanged over the observation period of 5 days. In an in vitro model mimicking in vivo conditions (diffusion of protease inhibitors and proteolytic digestion) clot liquefaction occurs at day 1 for all autologous fibrin sealants clots, with an observable delay for the tranexamic acid containing Vivostat, and day 5 for Tissucol/Tisseel clots. Characterization of the CryoSeal and Vivostat fibrin sealants and Tissucol/Tisseel and their performance show a clear difference in biochemical properties.

Blood Coagulation↗
PubMed1981

Weak electrolyte permeation in alimentary epithelia.

The potential significance of ionized species in weak electrolyte absorption or secretion has been reexamined using a mathematical model that represents the epithelium as a system of parallel ion-permeable and ion-impermeable channels. An important determinant of weak electrolyte movement in this system is the ratio of ionized and nonionized permeabilities (Pi/Pni). This variable, which has been termed the discrimination coefficient, interacts with the degree of ionization in determining the contributions of ionized and nonionized species to the transepithelial movement of a weak electrolyte. Calculations based on the model suggest that ionized species may contribute significantly to the absorption or secretion of many common weak electrolytes. It is concluded that the frequently made assumption that ionized species do not contribute significantly to transepithelial movements of weak electrolytes in the alimentary tract is not generally valid. Further work is required to delineate the quantitative determinants of discrimination in alimentary epithelia, and two methods for evaluation of epithelial discrimination coefficients are described.

Absorption↗
PubMed1991

Blood-brain barrier alterations in bacterial meningitis: development of an in vitro model and observations on the effects of lipopolysaccharide.

To further examine the effects of purified Haemophilus influenzae type b lipopolysaccharide (LPS) on blood-brain barrier permeability, we have developed an in vitro model of the BBB. Microvascular endothelial cells were isolated from rat cerebral cortices by enzymatic digestion, dextran centrifugation, and separation on percoll gradients. The cells were determined to be endothelial in origin by positive fluorescent staining for Factor VIII-related antigen and the ability to take up acetylated low density lipoproteins, and their cerebral origin by the formation of junctional complexes in vitro. Cells were seeded onto semipermeable polycarbonate filters and permeability assessed by measuring traversal of radioactive albumin across the monolayer. Treatment of the cells with LPS at concentrations of 1.0 microgram/ml and 0.1 microgram/ml for 4 h led to statistically significant increases in albumin permeability of 4.6% (P = 0.001) and 5.6% (P less than 0.001), respectively, without evidence of cell death as assessed by release of lactate dehydrogenase into the media. These results indicate that LPS significantly increases albumin permeability across a monolayer of cerebral microvascular endothelial cells in the absence of host inflammatory cells. Future studies on the effects of LPS on intracellular regulation will determine the mechanisms responsible for these alterations.

Albumins↗
PubMed2004

Peanut protein allergens: gastric digestion is carried out exclusively by pepsin.

BACKGROUND: A major characteristic of many food allergens, including Ara h 1, a major peanut allergen, is their resistance to gastric digestion. One estimate of the allergenic potential of a possible protein allergen is its stability under simulated gastric conditions. OBJECTIVE: Because the rate and extent of digestion of allergenic proteins will affect the severity of any subsequent allergic response, it is important to correlate protein allergen digestion in simulated gastric fluid with that in actual gastric fluid. METHODS: A major peanut allergen, Ara h 1, was digested in vitro by using both pepsin and porcine gastric fluid. Several comparisons between the 2 sets of proteolytic conditions were assessed including pH optima and the effect of temperature, denaturants, and specific enzyme inhibitors. RESULTS: In vitro digestion of Ara h 1 with pepsin and porcine gastric fluid resulted in virtually identical hydrolysis patterns as observed on SDS-PAGE. The protease activity of both pepsin and gastric fluid were inhibited at high pH and in the presence of pepstatin. However, both remained active in 4 mol/L urea and at 60 degrees C. CONCLUSIONS: Protein digestion in the porcine stomach is carried out by pepsin. In vivo gastric digestion is modeled accurately by peptic hydrolysis. Digestion conditions in vivo are comparable to experimental conditions in vitro provided that the acidic nature of the stomach contents is optimal for characterization of the allergen under standard pepsin digestion conditions. Additional experimentation using crude food extracts, both in the presence and absence of a complete meal, is needed to elucidate the complete physiologic nature of food allergen digestion.

Allergens↗
PubMedDate not supplied

[Action of granulocyte-colony stimulating factor and cisplatin on two models of human digestive, esophageal and colonic, cancers].

A combined therapy using a colony-stimulating factor and a chemotherapeutic agent has been designed, in vitro and in vivo, on digestive tumor cells to assess the effects of these agents administered alone or in combination, on the cells' or the tumor's growth rate. A recombinant human granulocyte colony-stimulating factor (rh G-CSF) and Cisplatin (CDDP) has been administered at various concentrations in vitro on oesophageal (ECYO) or on colonic (COLO 205) cell lines and in vivo on oesophagal tumor transplanted in Nude mice. In vitro, the oesophagal model is sensitive to G-CSF. The administration of G-CSF induces a stimulation of the cell proliferation. The DNA synthesis is stimulated or inhibited by low or high concentrations of G-CSF without any dose-response relationship. CDDP inhibits the DNA synthesis in ECYO cells. The association of the two agents leads to an activation of the DNA synthesis but only for some concentrations. On the contrary, the colonic model treated or not by CDDP is not sensitive to G-CSF. In vivo, G-CSF does not allow any inhibition or activation of oesophagal tumor's growth rate. CDDP alone is also inefficient. When G-CSF is administered before CDDP, there is no effect on the tumors. On the contrary, when G-CSF is administered with or after the chemotherapeutic agent, there is a significant inhibition of the tumor's growth rate.

Animals↗
PubMed1997

[Cell culture of human lamina cribrosa in vitro].

OBJECTIVE: To investigate the physiology and pathology of the biosynthesis of extracellular matrix (ECM) by lamina cribrosa cells (LCC) and to establish a model of cultured LCC. METHODS: The LCC of 10 human dead fetal eyes were cultured with enzyme digestion procedures in vitro. The cultured cells were identified by immunohistochemistry assays and electron microscopy. RESULTS: The cultured cells were flat, polygonal in shape, and their cytoplasm contained abundant perinuclear granules. The nuclei were relatively transparent and nucleoli were clear, there were basement membrane-like material and ECM surrounding the cell membrane. The immunofluorescent staining was positive for collagen type I, III, IV, fibronectin and laminin, negative for glial fibrillar acid protein and factor-VIII. The characteristics mentioned above were coincident with the morphology of LCC. This cell line has been cultured to its fourth generation. CONCLUSION: We have successfully cultured a cell line of LCC, and it may be utilized in the study of pathogenesis of glaucoma.

Cells, Cultured↗
PubMedDate not supplied

Gastrointestinal metabolism of N-acetylcysteine in the rat, including an assay for sulfite in biological systems.

The intestinal metabolism of N-acetylcysteine was studied in the rat. Isolated intestinal epithelial cells were shown to rapidly deacetylate [14C]-N-acetylcysteine to [14C]-cysteine, with slight oxidation of the latter to disulfide species. The cells did not accumulate reduced or oxidized cysteine, and N-acetylcysteine itself was not detected either free or in oxidized species intracellularly. Further metabolism of this NAC-derived cysteine to inorganic sulfite or glutathione was not detected. Following the administration of [14C]-N-acetylcysteine (50 mg/kg; 25 microCi) in vivo into the ilium, small quantities of both reduced and oxidized [14C]-N-acetylcysteine were demonstrated in hepatic portal vein plasma. [14C]-cysteine and inorganic sulfite were demonstrated as the major metabolites of N-acetylcysteine. These were present in the portal vein plasma at levels five and three times greater than the parent drug, respectively, 30 min after dosing. Additionally, [14C]-glutathione was shown to be a minor metabolite of N-acetylcysteine accumulating in portal vein plasma. These results may provide an explanation for the apparent low bioavailability of N-acetylcysteine when administered orally in humans and are discussed in terms of the origins of the protective effect of the drug in cases of paracetamol intoxication in humans.

Acetylcysteine↗