Metabolism of nilutamide in rat lung (original) (raw)
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Physiological research / Academia Scientiarum Bohemoslovaca
Although nitrated proteins have been repeatedly used as markers of lung injury, little is known about their formation and metabolism under hyperoxia. We therefore measured 3-nitrotyrosine (3NTYR) concentrations in lung tissue and serum of rats with carrageenan-induced pneumonia exposed to hyperoxia. Twenty-nine Wistar male rats were assigned to one of 4 groups. Two experimental groups were treated by intratracheal application of carrageenan (0.5 ml of 0.7 % solution) and then one was exposed to hyperoxia for 7 days (FIO2 0.8), the other to air. Rats of two control groups breathed either hyperoxic gas mixture or air for 7 days. At the end of exposure the ventilation was determined in anesthetized, intubated animals in which 3NTYR concentrations were measured in the lung tissue and nitrites and nitrates (NOx) were estimated in the serum. Carrageenan instillation increased 3NTYR concentrations in lung tissue (carrageenan-normoxic group 147+/-7 pmol/g protein, control 90+/-10 pmol/g pro...
Archives of Toxicology, 2000
N-Nitrosodimethylamine is a procarcinogen that is activated by cytochrome P450 dependent N-nitrosodimethylamine N-demethylase to labile α-carbon hydroxylated products further resulting in active methylating agents. In vivo intraperitoneal administration of pyridine to rabbits significantly increased N-nitrosodimethylamine N-demethylase activity by 6.9- and 5.2-fold in liver and lung microsomes, respectively. Although, p-nitrophenol hydroxylase and aniline 4-hydroxylase activities were markedly enhanced by pyridine treatment in liver about 4.4- and 5.8-fold, respectively, no change was observed in the activities of these enzymes in lung microsomes. Pyridine treatment also elevated P450 contents of liver and lung by 2.04- and 1.4-fold, respectively. SDS-PAGE of pyridine-induced liver microsomes revealed a protein band of enhanced intensity having M r of 51,000 migrating in the region of cytochrome P4502E1. The results obtained in this study demonstrated for the first time, a significant 5.2-fold induction of NDMA N-demethylase activity in the rabbit lung over the controls. Pyridine is readily absorbed by inhalation and is a constituent of tobacco and tobacco smoke. Thus induction of NDMA N-demethylase suggests that in the lung, as in the liver, pyridine may stimulate the metabolic activation of this nitrosamine significantly.
Cellular metabolism of proxyl nitroxides and hydroxylamines
Biochimica et Biophysica Acta (BBA) - General Subjects, 1991
Previous data from model systems indicated that the proxyl nitroxides should be especially resistant to bioredacfion and therefore could be an effective solutinn to this often pt'oblematic characteristic of nitroxides. Therefore, we investigated the rate of reduction by cells and by the usual model system, aseorhote, of four proxyl nitvexides and three reference nitroxides. We found that, while the rate of reduction by ascor~ate of the proxyl nitroxidas was slower than the rate Of a prototypic pyrrolidino nitroxide (PCA), the reverse was tnJe for reduction by cells. We also studied the rate of oxidation of the c0reesponding bydroxylaminas. The rate of nxia~non by cells of the proxyl hydi'oxylamiues was relatively f~at, especially for the most liF~ilie derivative. These ~e~lts indicate that:. (i) pro>:yl nitroxliles may not be unusually resistant to bioreduefion by functional biological systems: (ii) accurate knowledge ol relative rates of metabolism of nttroxidee and hydroxylamines in cells and tissues will require direct studies in these systems because the tales may not closely parallel those observed in model (chemical) systems: and (iii) proxy] nitmxides show potential value as agents to measure oxygen concentrations by the rates of oxidation of their corresponding byd|roxylaminus.
Cancer research, 1983
The tumorigenic activities in A/J mouse lung of the tobaccospecific nitrosamines A/'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and their metab olites retaining the nitroso group were studied, and the metab olism of NNN and NNK in cultured mouse peripheral lung was investigated. A total dose of 0.12 mmol of each NNN metabolite was given in 22 i.p. injections to each A/J mouse. Thirty weeks after the last injections, the number of lung tumors per animal induced was NNN, 1.2; 3'-hydroxy-A/'-nitrosonornicotine, 0.9; 4'-hydroxy-A/'-nitrosonornicotine, 1.6; and A/'-nitrosonornicotine-1 -A/-oxide, 0.8. [2',5',5'-frideufero]-/V'-Nitrosonornicotine, an a-trideutero analogue of NNN, induced 1.5 lung tumors/animal.
Metabolism and bioactivation of toxicants in the lung. The in vitro cellular approach
Experimental and Toxicologic Pathology, 2005
Lung is a target organ for the toxicity of inhalated compounds. The respiratory tract is frequently exposed to elevated concentrations of these compounds and become the primary target site for toxicity. Occupational, accidental or prolonged exposure to a great variety of chemicals may result in acute or delayed injury to cells of the respiratory tract. Nevertheless, lung has a significant capability of biotransforming such compounds with the aim of reducing its potential toxicity. In some instances, the biotransformation of a given compound can result in the generation of more reactive, and frequently more toxic, metabolites. Indeed, lung tissue is known to activate pro-carcinogens (i.e. polycyclic aromatic hydrocarbons or N-nitrosamines) into more reactive intermediates that easily form DNA adducts. Lungs express several enzymes involved in the metabolising of xenobiotics. Among them, cytochrome P450 enzymes are major players in the oxidative metabolism as well metabolic bioactivation of many organic toxicants, including pro-carcinogens. Xenobiotic-metabolising P450 enzymes are expressed in bronchial and bronchiolar epithelium, Clara cells, type II pneumocytes, and alveolar macrophages Individual CYP isoforms have different patterns of localisation within pulmonary tissue. With the aid of sensitive techniques (i.e. reverse transcriptase-polymerase chain reaction, RT-PCR) it has become possible to detect CYP1A1, CYP1B1, CYP2A6, CYP2B6, CYP2E1 and CYP3A5 mRNAs in lung cells. Less conclusive results have been obtained concerning CYP2Cs, CYP2D6 and CYP3A4. CYP3A5 protein appears to be widely present in all lung samples and is localised in the ciliated and mucous cells of the bronchial wall, bronchial glands, bronchiolar ciliated epithelium and in type I and type II alveolar epithelium. Lung cells also express Phase II enzymes such as epoxide hydrolase, UGT1A (glucuronyl transferase) and GST-P1 (glutathione S-transferase), which largely act as detoxifying enzymes. A key question concerning organ-specific chemical toxicity is whether the actual target has the capacity to activate (or efficiently inactivate) chemicals. Results of several studies indicate that the different xenobiotic-metabolising CYPs, present in the human lung and lung-derived cell lines, likely contribute to in situ activation of pulmonary toxins, among them, pro-carcinogens. Some CYPs, in particular CYP1A, are polymorphic and inducible. Interindividual differences in the expression of these CYPs may explain the different risk of developing lung toxicity (possibly cancer), by agents that require metabolic activation. Few cell lines, principally A549, have been used with variable success as an experimental model for investigating the mechanisms of toxicity. Although RT-PCR analysis has evidenced the presence of the major human pulmonary CYP mRNAs, the measurable P450 specific activities are, however, far below those present in human lungs. Detection of the toxicity elicited by reactive metabolites requires the use of metabolically competent cells; consequently, better
Journal of Toxicology and Environmental Health Sciences, 2013
Nitrites and morpholine are ubiquitous environmental contaminants found in drinking water and food. NMOR can be formed endogenously from nitrite and morpholine. Increased levels of reactive oxygen species/ reactive nitrite species (ROS/RNS) are involved in the mechanism of NMOR toxicity. Certain antimicrobial, antifungal and antioxidant potential were observed in heterocyclic benzimidazole derivatives and dimethyl sulfoxide (DMSO). This study was designed to evaluate the biological potential of 3-aminothiazolo[3-2a]benzimadzole-2-carbonitrile in the protection of lung and colon tissues against the increased levels of ROS/RNS that are induced by administration of nitrite and morpholine in drinking water for 15 weeks. Forty adult male rats were categorized into 4 groups, 10 rats each. The results showed a significant increase in NO, lipid peroxidation (LPO), total peroxides (TPO), superoxide anion (O 2-) and DNA fragmentation in lung and colon tissues of rats treated with nitrite and morpholine compared to the control group. Moreover, histological observation of the lung and colon tissues showed cell necrosis, increase in the leukocyte infiltration and blood vessel congestion. Immunostaining for inducible nitric oxide synthase (iNOS) showed positive reaction for lung and colon tissues. After the co-treatment of rats with DEMSO and 3-aminothiazolo[3-2a]benzimadzole-2carbonitrile, all the previous biochemical changes were reduced in addition to the relative improvement in the morphological changes of both lung and colon. In conclusion, the injury in lung and colon tissues induced by nitrite and morpholine may return to the increased production of ROS and to the alterations in the levels of antioxidants. Co-treatment of rats with 3-aminothiazolo[3-2a]benzimadzole-2carbonitrile and DMSO may protect them against nitrite and morpholine toxicity.
Enhanced acute lung damage in mice following administration of 1,3-bis(2-chloroethyl)-1-nitrosourea
PubMed, 1985
1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU), also known as carmustine, is a lipid soluble anticancer drug which produces pulmonary fibrosis in up to 30% of the patients who receive this drug. The major risk factor for this disorder is preexisting lung damage. Animal models of this interaction have not been reported previously. A diffuse alveolar lesion was produced in male BALB/c mice by the administration of butylated hydroxytoluene (BHT). Total lung hydroxyproline levels, an index of fibrosis, were not increased in mice 21 days after single doses of BHT or BCNU. Total lung DNA synthesis, an index of pulmonary damage, was slightly increased after 15 and 18 days in rats and mice treated with BCNU (15 and 35 mg/kg, respectively). This suggested that a single dose of BCNU had only a minimal toxic effect on lung tissue. Combined treatments in mice given BHT (350 or 400 mg/kg), followed on Day 1 by BCNU (35 mg/kg), resulted in the deposition of significantly more hydroxyproline than with either agent alone. This enhancement was not seen following lower doses of BHT and was diminished when the dose of BCNU was decreased. Delaying the administration of BCNU (35 mg/kg) until Day 3 or 5 eliminated increases in hydroxyproline content, but not histological evidence of enhanced lung damage. Additional histological analyses confirmed the presence of an increased fibrotic reaction, especially when high doses of BCNU were administered 1 day after BHT (400 mg/kg). Most of the lungs were totally consolidated with numerous hyperactive fibroblasts and a large number of giant type II cells with atypical nuclei. These effects may be related to the ability of BCNU to inhibit pulmonary glutathione reductase activity and the increased DNA synthesis normally seen after BHT. These data show that BCNU treatment can enhance BHT-induced lung damage resulting in a fibrotic lesion similar to that seen in some human patients. This effect is dependent on the extent of the initial lung lesion as well as the time when BCNU is administered and may represent an animal model of the primary risk factor for the development of pulmonary fibrosis in human patients receiving this drug.
Proceedings of the American Thoracic Society, 2006
The chemical properties of nitric oxide (NO) have been studied for over 200 years. However, it is only within the last 20 years that the biological implications of this chemistry have been considered. The classical model of NO action within the vasculature centers on production in the endothelium, diffusion to the smooth muscle, and subsequent activation of guanylate cyclase via binding to its heme iron. In the context of this model, it is difficult to conceptualize extrapulmonary effects of inhaled NO. However, NO possesses complex redox chemistry and is capable of forming a range of nitrogen oxide species and is therefore capable of interacting with a variety of biomolecules. Of particular interest is its reaction with reduced cysteine to form an S-nitrosothiol (SNO). SNOs are formed throughout NO biology and are a post-translational modification that has been shown to regulate many proteins under physiologic conditions. Hemoglobin, which was considered to be solely a consumer of ...
Journal of Applied Toxicology, 2004
Toxic effects of several nitro-aryl drugs are attributed to the nitro-reduction that may be suffered in vivo, a reaction that may be catalysed by different reductases. One of these enzymes is NADPH–cytochrome P450 reductase, which belongs to the cytochrome P450 oxidative system mainly localized in the endoplasmic reticulum of the hepatic cell. This system is responsible for the biotransformation of oxidative lipophilic compounds, so that oxidative and reductive metabolic pathways of lipophilic nitro-aryl drugs can take place simultaneously. Because of the affinity of nitro-aryl drugs (xenobiotics) for the endoplasmic reticulum, we propose this subcellular organelle as a good biological system for investigating the toxicity induced by the biotransformation of these or another compounds.In this work we used rat liver microsomes to assess the oxidative stress induced by nitro-aryl drug biotransformation. Incubation of microsomes of rat liver with nifurtimox and nitrofurantoin in the presence of NADPH induced lipoperoxidation, UDP-glucuronyltransferase activation and an increase in the basal microsomal oxygen consumption. Nitro-aryl-1,4-dihydropyridines did not elicit these prooxidant effects; furthermore, they inhibited lipoperoxidation and oxygen consumption induced by Fe3+/ascorbate. Nifurtimox and nitrofurantoin modified the maximum absorption of cytochrome P450 oxidase and inhibited p-nitroanisole O-demethylation, an oxidative reaction catalysed by the cytochrome P450 system, signifying that oxidation may proceed in a similar way to that described for nitro-aryl-1,4-dihydropyridines. Thus the balance between lipophilic nitro-aryl drug oxidation and reduction may be involved in the potential oxidative stress induced by biotransformation. Copyright © 2004 John Wiley & Sons, Ltd.
Reductive metabolism and hypoxia-selective toxicity of nitracrine
International Journal of Radiation Oncology*Biology*Physics, 1986
The I-nitroacridine nitracrine [NC,l-nitro-9-(dimethylaminopropyl-amino)acridine] is a potent hypoxia-selective cytotoxic agent in culfure, but lacks activity against hypoxic tumor cells in viva at therapeutically accessible doses. To clarify reasons for this failure in vim the metabolism of NC was investigated in stirred suspension cultures of Chinese hamster ovary cells, in EMT-6 spheroids, and in mice. One major low molecular weight metabolite (identical to that generated by NaBH,/Pd/C reduction) was observed in hypoxic (40 ppm 0,) single cell suspensions, while [G-3H-acridinyl]NC formed trichloroacetic acid-and acetonitrile-insoluble macromolecular adducts (MA) at a rate seven-fold higher than in aerobic (20% 02) cultures. Formation of these adducts correlated with cytotoxicity under air or nitrogen, and hence may provide a dosimeter for NC-induced damage. Autoradiographic investigation of the distribution of MA in spheroids equilibrated with 5% O2 showed that the label was restricted to the outer cell layers rather than being localized in the hypoxic central region. Thus metabolic activation is probably too rapid, even in well-oxygenated cells, to allow adequate distribution to hypoxic microenvironments in tumors. In mice, levels of MA were higher in liver, kidney, spleen and lung than in Lewis lung tumors, indicating that oxygen concentration does not exert a dominant influence on relative rates of metabolic activation in viva The development of nitroacridines with useful hypoxic selectivity in viva will require identification of analogs for which reductive metabolism is more completely inhibited at oxygen concentrations found in normal tissues.