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PubMed2002

Neuroendocrine tumors of the lung: recent developments in histopathology.

Lung tumors with neuroendocrine differentiation are made up of several neoplasms with particular epidemiologic, clinical, morphologic, and molecular characteristics. Typical and atypical carcinoid tumors represent low-grade and intermediate-grade carcinomas, respectively, whereas small-cell carcinoma and large-cell neuroendocrine carcinoma are considered high-grade carcinomas. Recent studies support the use of this four-tumor, three-tier classification scheme, but in practice, definitive diagnoses on small tissue samples remain a challenge for even the most experienced lung pathologists.

Carcinoid Tumor↗
PubMed2004

Distal angiogenesis: a new concept for lung vascular morphogenesis.

Although several molecular players have been described that play a role during the early phases of lung development, it is still unknown how the vasculature develops in relation to the airways. Two opposing models describe development of lung vasculature: one suggests that both vasculogenesis and angiogenesis are involved, whereas the second describes vasculogenesis as the primary mechanism. Therefore, we examined the development of the murine pulmonary vasculature through a morphological analysis from the onset of lung development [9.5 days postcoital (dpc)] until the pseudoglandular stage (13.5 dpc). We analyzed fetal lungs of Tie2-LacZ transgenic mice as well as serial sections of wild-type lungs stained with endothelial-specific antibodies (Flk-1, Fli-1, and PECAM-1). Embryos were processed with intact blood circulation to maintain the integrity of the vasculature; hence individual vessels could be identified with accuracy through serial section analysis. Furthermore, circulating primitive erythrocytes, formed exclusively by the blood islands in the yolk sac, are trapped in vessels during fixation, which proves the connection with the embryonic circulation. We report that from the first morphological sign of lung development, a clear vascular network exists that is in contact with the embryonic circulation. We propose distal angiogenesis as a new concept for early pulmonary vascular morphogenesis. In this model, capillary networks surround the terminal buds and expand by formation of new capillaries from preexisting vessels as the lung bud grows. The fact that at an early embryonic stage a complete vascular network exists may be important for the general understanding of embryonic development.

Animals↗
PubMed1999

Surfactant protein C in fetal and ventilated preterm rabbit lungs.

The developing lung contains surfactant protein (SP) C mRNA levels comparable to term values before mature type II cells and alveolar surfactant lipids are detectable. Estimates of the amount of mature SP-C in the alveolar lavages of preterm lungs are not available. We used an antibody to a recombinant human SP-C to measure the amount of SP-C in alveolar lavages of preterm fetal rabbits, ventilated preterm rabbits, and term rabbits. The amounts of SP-C were compared with the amounts of saturated phosphatidylcholine (Sat PC). Median Sat PC amounts increased about 680-fold, and median SP-C values increased by over 5,000-fold in alveolar washes from 27 days gestation to term. There was no increase in Sat PC or SP-C with ventilation at 27 and 28 days gestation, but ventilation increased both Sat PC and SP-C at 29 days gestation. The molar percent of SP-C relative to Sat PC also increased with gestational age and with ventilation at 29 days gestation. proSP-C was abundant in a membrane fraction from lung tissue at 27 and 28 days gestation when minimal mature SP-C was detected in alveolar washes. At 29 days and at term, proSP-C decreased in membrane fractions. The preterm lung that is surfactant lipid deficient is also severely deficient in mature SP-C.

Animals↗
PubMed1996

Retinoic acid alters the expression of pattern-related genes in the developing rat lung.

Exogenous retinoids alter pattern formation and differentiation in many developing systems, such as limb, vertebrae, and central nervous system. Many of these effects are mediated by changes in expression of patterning genes such as Hox genes and Sonic hedgehog. We have previously shown that exogenous retinoic acid, administered to the embryonic rat lung in culture alters the structural pattern of the developing lung, suppressing formation of distal lung and favoring growth of proximal tubules. To determine whether these retinoic acid-induced changes in lung development were linked to alterations in pattern-related genes, we characterized the expression of Hoxa-2, Hoxb-6, and Sonic hedgehog mRNAs in vivo and in vitro, with or without 10(-5)M retinoic acid, by in situ hybridization and quantitative polymerase chain reaction. Each of these genes demonstrated unique timing and distribution of expression that was similar in vivo and in control cultured embryonic lungs. Hoxb-6 and Sonic hedgehog mRNAs both decreased during lung development in vivo or in vitro. From the patterns of mRNA expression we propose that Hoxb-6 is involved in distal airway branching while Hoxa-2 is involved in differentiation of proximal mesenchymal derivatives and vasculogenesis in the lung. RA upregulated all three genes, changing their developmental pattern of distribution and preventing the developmental decrease in Sonic hedgehog expression. We propose that RA acts to maintain high levels of expression of these and likely other pattern-related genes in a fashion that is characteristic of the immature lung, promoting continued formation of proximal lung structures and preventing formation of typical distal lung structures of the mature lung.

Animals↗
PubMed1992

Ontogenetic development, differentiation, and phenotypic expression of macrophages in fetal rat lungs.

Development, differentiation, and distribution of macrophages in fetal rat lungs were investigated immunohistochemically using anti-rat macrophage monoclonal antibodies. In the lung buds, RM-1+ macrophages were first detected on fetal day 13, and some showed reactivity for TRPM-2. They populated in the peribronchial mesenchyme of the lung buds, proliferated in loco, and showed no peroxidase activity in any intracellular organelles. Their immunophenotypic and ultrastructural features were consistent with those of primitive/fetal macrophages. By fetal day 16, some of them expressed ED1, but ED1+ cells were a minor subpopulation throughout the fetal period. On fetal day 18, ED2+ macrophages developed; some also were positive for RM-1, but the others were negative. Both the RM-1+ and ED2+ macrophages were major macrophage subpopulations and expressed Ki-M2R and/or TRPM-3; ED2+ and/or Ki-M2R+ cells are regarded as pulmonary interstitial resident macrophages. In organ culture, a similar expression of differentiation antigens by macrophages was confirmed. None of these macrophages cytochemically showed any peroxidase activity in vivo or in vitro. In the fetal stage, both RM-1+ and ED2+ macrophage subpopulations showed proliferative potential, suggesting their ability to proliferate and survive in vivo.

Animals↗
PubMed1990

Changes in the DNA polymerase beta gene expression during development of lung, brain, and testis suggest an involvement of the enzyme in DNA recombination.

Changes in the expression pattern of DNA polymerase beta gene during rat lung, brain, and testis development have been investigated. A decrease in the level of beta-pol mRNA was observed during postnatal development of lung and brain. By contrast, an almost 20-fold increase in the level of beta-pol mRNA was observed during spermatogenesis. For most adult rat tissues the abundance of beta-pol mRNA was low compared with that of beta-actin mRNA. Northern blot analysis revealed four distinct transcripts hybridizing to beta-pol probes. At least two of them, 1.4 kb and 4.0 kb, were products of a beta-polymerase gene. The changes in the expression pattern during lung and brain development, and during spermatogenesis, suggest involvement of DNA polymerase beta in gap-filling DNA synthesis during recombination.

Animals↗
PubMed2006

[Effect of lethal hyperoxia on pulmonary development and lung injury in neonatal rats].

OBJECTIVE: To study the effect of oxygen at lethal levels (95%) on pulmonary development and lung injury in neonatal rats and establish rat models of bronchopulmonary dysplasia. METHODS: Three-day-old and adult SD rats were assigned to experimental or control groups and subjected to 95% O(2) exposure and room air for 7 days. Body weight and length of the rats were recorded, and histological study of the lung tissue and radical alveoli count (RAC) were carried out. RESULTS: The mortality rate of the neonatal and adult rats was 12.5% and 35.2% in hyperoxia group, respectively. The newborn rats in hyperoxic group had lower body weight (18.02-/+0.68 vs 13.24-/+0.59 g) and length (8.83-/+0.25 vs 6.76-/+0.51 cm) than those in the control group (P<0.05), with also lower RAC (9.50-/+1.05 vs 13.00-/+1.79, P<0.05); RAC of the adult rats with hyperoxic exposure (12.67-/+2.25) was higher that of exposed neonatal rats, but not significantly different from that of the adult or neonatal rats in the control group (P>0.05). Structure configuration of the rats on the first 10 days of life resembled that of adulthood. The lung of hyperoxic neonatal rats showed thinner walls of alveoli, simple alveolar structure, fewer and larger alveoli, expanded and shrunk alveoli, while the lung of the adult rats displayed thicker septa, smaller space of alveoli, and cells in the space of the alveoli. CONCLUSION: Exposure of neonatal rats to 95% O(2) may result in mild pulmonary inflammation in addition to growth impediment and impaired lung development, which shares morphologic similarities to human bronchopulmonary dysplasia.

Animals↗
PubMedDate not supplied

Distal pulmonary cell proliferation is associated with the expression of EIIIA+ fibronectin in the developing rat lung.

Fibronectin is known to regulate the development of the lung. The EIIIA segment of fibronectin is one of the major alternatively spliced segments and modulates the cell proliferative potential of fibronectin in vitro. But the specific role of the EIIIA-containing fibronectin isoform (referred to as EIIIA+ fibronectin) in pulmonary cell proliferation has not been explored in vivo as yet. In this study, to see whether EIIIA+ fibronectin is associated with pulmonary cell proliferation in vivo, the authors immunohistochemically examined the spatiotemporal relationship of the EIIIA+ fibronectin isoform protein and proliferating cell nuclear antigen (PCNA), a biochemical marker for the cell proliferation, during the alveolar formation in the developing rat lung. EIIIA+ fibronectin protein was localized in the epithelial cells and in the mesenchymal tissues. The expression of EIIIA+ fibronectin protein gradually decreased from the pseudoglandular stage to the saccular stage and then slightly increased from the saccular stage to the alveolar stage. This change in the EIIIA+ fibronectin expression seemed to be in accord with the change in the number of PCNA-positive cells in the distal pulmonary cells throughout the lung development. These results suggest that the expression of EIIIA+ fibronectin is associated with the distal pulmonary cell proliferation during the alveolar formation.

Animals↗
PubMed1991

[Effect of cigarette smoking and/or N-bis(2-hydroxypropyl)nitrosamine (DHPN) on the development of lung and pleural tumors in rats induced by administration of asbestos].

Occupationally induced lung cancer and mesothelioma have long been attributed to asbestos and moreover, several epidemiological studies have indicated a co-carcinogenic effect of cigarette smoking on the incidence of lung cancer in asbestos workers. The aim of the present study was to investigate the co-carcinogenic effects of asbestos and other carcinogens with emphasis placed on determining the effects of cigarette smoking on the incidence of asbestos induced carcinomas. Doses of 15 mg of chrysotile asbestos were administered intratracheally to Wistar rats alone and in conjunction with N-bis(hydroxypropyl)nitrosamine (DHPN) and/or cigarette smoking. DHPN at dose of 1 g/kg/B.W. was injected three times intraperitoneally, and the subject animals were exposed to smoke from 10 cigarettes per day, six days a week, for their entire life span. As a result, lung carcinomas were induced in one out of the 31 rats receiving only asbestos. Lung tumors were induced at a much higher incidence in the groups receiving DHPN alone and in conjunction with asbestos: of the 37 rats treated with DHPN alone 19 (51.4%) developed lung tumors, whereas those receiving asbestos as well showed an incidence of 68.4% (23/38) of carcinomas. The development of lung carcinomas (including adenocarcinomas, epidermoid carcinomas, anaplastic carcinomas, and combined carcinomas) was seen in 8 (21.6%) out of the 37 rats receiving DHPN alone and in 23 (60.5%) out of the 38 rats receiving asbestos as well. The incidence of lung carcinoma was significantly increased in combined treatment with asbestos than DHPN alone. In the group receiving asbestos in combination with cigarette smoke, 4 (13.8%) out of the 29 rats developed lung carcinomas, but these carcinomas were more common than in the group receiving only asbestos. Moreover, in the group administered asbestos, DHPN and smoking combined, lung tumors developed in 18 (62.1%) out of the 29, 15 (51.7%) of which proved to be malignant. Mesothelioma (pleura) was induced in three groups in the following combinations: DHPN plus asbestos, 8/38 (21.1%); smoking plus asbestos, 2/29 (6.9%); and smoking, DHPN and asbestos, 4/29 (13.8%). These tumors were extensively located, that is, on the parietal pleura, visceral pleura, epicardium and diaphragm surface. However, mesothelioma was not induced by asbestos alone nor by DHPN alone. Carcinogenicity of asbestos for pleural tumors was significantly promoted by combined treatment with DHPN to an extent greater than DHPN alone. It should be noted that asbestos plus smoking resulted in a higher incidence of mesothelioma than asbestos alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1995

Influence of smoking on the development of lung metastases from breast cancer.

BACKGROUND: This study examined the association between cigarette smoking status and the development of lung metastases in a group of 835 women diagnosed with primary malignant unilateral breast cancer. METHOD: Female patients with breast cancer diagnosed between 1982 and 1991 at Roswell Park Cancer Institute (RPCI) in Buffalo, New York, who provided information on their cigarette smoking history at the time of their diagnosis were included. The subsequent disease status of patients was monitored by the RPCI Tumor Registry. The Cox regression model was used to estimate the relationship between smoking status and the development of lung metastases, adjusting for the patient's age, stage of disease at diagnosis, and body weight. RESULTS: Of those patients who developed lung metastases, 8.7% were nonsmokers, 14.1% were former smokers, and 14.3% were current smokers. Tests showed that nonsmokers had significantly fewer lung metastases than either of the two smoking groups (P < 0.01). The estimated relative rates of lung metastases developing adjusting for age, stage, and body weight in women who smoked less than 10,000, between 10,001 and 20,000, and more than 20,000 packs over their lifetimes compared with nonsmokers were 1.06 (95% CI, 0.51-2.20), 3.10 (95% CI, 1.5-6.3), and 3.73 (95% CI, 1.6-8.9) respectively. The Cox regression model showed that every 1000 packs of cigarettes consumed over a lifetime increased a woman's risk of developing lung metastases by about 3% to 7% (P < 0.001). CONCLUSION: This study found a significant association between cigarette smoking history and risk of lung metastases developing in women diagnosed with primary invasive unilateral breast cancer. The risk of lung metastases developing increased as the number of cigarettes smoked in a lifetime increased.

Adolescent↗
PubMed1998

Thyroid transcription factor-1, hepatocyte nuclear factor-3beta and surfactant protein A and B in the developing chick lung.

Expression of surfactant proteins SP-A, SP-B and the transcription factors TTF-1 and HNF-3beta was identified by immunohistochemistry in the developing chicken. SP-B, a small hydrophobic peptide critical for lung function and surfactant homeostasis in mammals, was detected in the epithelial cells of parabronchi in embryonic chicken lung from the 15th day of incubation, prior to the onset of the breathing movements and was expressed at high levels in the posthatching chicken lung. SP-A, an abundant surfactant protein involved in innate defence of the mammalian lung, was detected in the chick embryo in subsets of epithelial cells in the mesobronchus, starting from d 15 and was detected in the posthatching chicken lung. The transcription factors hepatocyte nuclear factor 3beta (HNF-3beta) and thyroid transcription factor-1 (TTF-1), both regulators epithelial cell differentiation and gene expression in mammalian species, were detected at the onset of lung bud formation (d 4 of incubation) and throughout lung development. Abundant nuclear expression was detected in nuclei of respiratory epithelial cells of developing bronchial tubules for both transcription factors. In contrast to the surfactant proteins, expression of both TTF-1 and HNF-3beta decreased markedly in posthatching chicken lung. The expression of SP-A and SP-B in chick lung demonstrates the conservation of surfactant proteins in vertebrates. The temporospatial pattern of TTF-1 and HNF-3beta overlaps with that of SP-A and SP-B, supporting their potential roles in chick lung development and demonstrating the conservation of regulatory mechanisms contributing to gene expression in respiratory epithelial cells in vertebrates.

Animals↗
PubMed1999

Effects of dexamethasone, growth factors, and tracheal ligation on the development of nitrofen-exposed hypoplastic murine fetal lungs in organ culture.

BACKGROUND/PURPOSE: The addition of growth factors EGF (epidermal growth factor) plus TGFbeta1 (transforming growth factor beta1; E + T) or dexamethasone (DEX) to normal murine fetal lungs in culture enhances lung development. In addition, ligation of the airway in lungs in organ culture, enhances lung development. Nitrofen (2,4-dichlorophenyl-p-nitrophenylether) administration to pregnant mice results in pulmonary hypoplasia in the offspring with many similarities to human hypoplastic lung conditions. This study investigates the effects of growth factors, dexamethasone, and airway ligation on the development of hypoplastic fetal murine lungs in whole-organ culture. We hypothesized that E+T, DEX, or airway ligation will enhance the development and maturation of hypoplastic murine fetal lungs in vitro. METHODS: Time-dated pregnant CD-1 mice were given nitrofen, 25 mg, intragastrically at gestational day (Gd) 8. The dams were killed on Gd 14, and the fetuses were removed. The hypoplastic fetal lungs were excised, and the tracheae were transected. The lungs were cultured in serum-free BGJb media in the presence or absence of E+T (10 ng/mL + 2 ng/mL, respectively) or DEX (10 nmol/L). Some lungs were cultured for 7 days with the tracheae ligated. RESULTS: Gross morphology under a dissecting stereomicroscope showed that the lungs were larger after E+T, DEX, or tracheal ligation. Histologically, the untreated lungs had progressed from the pseudoglandular stage to a canalicular-like stage with poorly differentiated airways. The E+T-treated lungs had better developed airway branching and small acini; however, thick mesenchyme persisted. The ligated lungs had well-developed airway branching and acinar structures. After DEX treatment the lungs were most developed with very well defined airway branching and expanded acinar structures; however, there was no secondary septation. Ultrastructurally, the hypoplastic lungs at Gd 14 and after 7 days in culture had no glycogen in their epithelial cells, no defined acinar formation, and had damaged mitochondria. The E+T-treated or tracheally ligated lungs had abundant type II cells, secreted lamellar bodies (LBs), and showed infrequent tubular myelin. Mitochondrial damage was noted in these lungs as in the untreated lungs. DEX-treated hypoplastic lungs showed large acini. The acinar walls were thick; however, they had type II cells with abundant LBs and intact mitochondria. The airways were noted to have differentiated cell types. Surfactant secretions in acinar spaces showed tubular myelin structures. CONCLUSIONS: E+T, tracheal ligation, or DEX accelerates lung development and maturation of hypoplastic fetal murine lungs compared with untreated controls. DEX had a greater effect with special reference to repair of mitochondrial damage. DEX not only accelerated lung development, but it may have reversed some of the effects nitrofen.

Animals↗
PubMed2002

Impairment of rat postnatal lung alveolar development by glucocorticoids: involvement of the p21CIP1 and p27KIP1 cyclin-dependent kinase inhibitors.

It has been shown that glucocorticoids accelerate lung development by limiting alveolar formation resulting from a premature maturation of the alveolar septa. Based on these data, the aim of the present work was to analyze the influence of dexamethasone on cell cycle control mechanisms during postnatal lung development. Cell proliferation is regulated by a network of signaling pathways that converge to the key regulator of cell cycle machinery: the cyclin-dependent kinase (CDK) system. The activity of the various cyclin/CDK complexes can be modulated by the levels of the cyclins and their CDKs, and by expression of specific CDK inhibitors (CKIs). In the present study, newborn rats were given a 4-d treatment with dexamethasone (0.1-0.01 microg/g body weight dexamethasone sodium phosphate daily on d 1-4), or saline. Morphologically, the treatment caused a significant thinning of the septa and an acceleration of lung maturation on d 4. Study of cyclin/CDK system at d 1-36 documented a transient down-regulation of cyclin/CDK complex activities at d 4 in the dexamethasone-treated animals. Analysis of the mechanisms involved suggested a role for the CKIs p21CIP1 and p27KIP1. Indeed, we observed an increase in p21CIP1 and p27KIP1 protein levels on d 4 in the dexamethasone-treated animals. By contrast, no variations in either cyclin and CDK expression, or cyclin/CDK complex formation could be documented. We conclude that glucocorticoids may accelerate lung maturation by influencing cell cycle control mechanisms, mainly through impairment of G1 cyclin/CDK complex activation.

Animals↗
PubMed1990

Type IV collagen in developing human lung: a comparison between normal and hypoplastic fetal lungs.

Human lung tissue obtained from 24 aborted fetuses of varying gestational ages (beyond 24 weeks) was examined for immunolocalisation of type IV collagen, using monoclonal antibody. Twelve cases of lung hypoplasia associated with oligohydramnios were compared with 12 normally developed lungs over the same gestational age range acting as control. Type IV collagen was located in alveolar septa and subepithelial basement membranes in all the lungs examined but showed less prominently in hypoplastic lungs than in control lungs of a similar gestational age. The findings suggest a potential role of type IV collagen in maturation of the developing human lung.

Amniotic Fluid↗
PubMed2007

Lung function and exhaled nitric oxide levels in infants developing chronic lung disease.

Chronic lung disease (CLD) is a common outcome of neonatal intensive care. To determine whether the results of serial exhaled nitric oxide (eNO) measurements during the perinatal period differed between infants who did and did not develop CLD. In addition, we wished to assess whether eNO results were more predictive of CLD development than lung function test results or readily available clinical data (gestational age and birthweight). The patients were 24 infants with a median gestational age of 27 (range 25-31) weeks. Measurements of eNO levels, functional residual capacity (FRC), and compliance of the respiratory system (CRS) were attempted on postnatal days 1, 3, 5, 7, 14, and 28 days. The 12 infants who developed CLD were of significantly lower birthweight and gestational age than the rest of the cohort; in addition, they had lower median FRC (P < 0.02) and CRS (P < 0.02) results, but not higher eNO levels, in the first week after birth. Construction of receiver operator characteristic (ROC) curves demonstrated that the CRS and FRC results on Day 3 were the best predictors of CLD development; the areas under the ROC curves were 0.94 and 0.91, respectively. Early lung function test results, but not eNO levels, are useful in predicting CLD development, but are not significantly better than birthweight.

Birth Weight↗
PubMed1982

De novo fatty acid synthesis in developing rat lung.

The rate of de novo fatty acid synthesis in developing rat lung was measured by the rate of incorporation of 3H from 3H2O into fatty acids in lung slices and by the activity of acetyl-CoA carboxylase in fetal, neonatal and adult lung. Both tritium incorporation and acetyl-CoA carboxylase activity increased sharply during late gestation, peaked on the last fetal day, and declined by 50% 1 day after birth. In the adult, values were only one-half the peak fetal rates. In vitro regulation of acetyl-CoA carboxylase activity in fetal lung was similar to that described in adult non-pulmonary tissues: activation by citrate and inhibition by palmitoyl-CoA. Similarly, incubation conditions that favored enzyme phosphorylation inhibited acetyl-CoA carboxylase activity in lung while dephosphorylating conditions stimulated activity. Incorporation of [U-14 C]glucose into lung lipids during development was influenced heavily by incorporation into fatty acids, which generally paralleled the rate of tritium incorporation into fatty acids. The relative utilization of acetyl units from exogenous glucose for overall fatty acid synthesis was greater in adult lung than in fetal or neonatal lung, suggesting that other substrates may be important for fatty acid synthesis in developing lung. In fetal lung explants, de novo fatty acid synthesis was inhibited by exogenous palmitate. Taken together, these data suggest that de novo synthesis may be an important source of saturated fatty acids in fetal lung but of lesser importance in the neonatal period. Furthermore, the regulation of acetyl-CoA carboxylase activity and fatty acid synthesis in lung may be similar to non-pulmonary tissues.

Acetyl-CoA Carboxylase↗
PubMed2003

Expression of Netrin-1 and its two receptors DCC and UNC5H2 in the developing mouse lung.

The ligand Netrin-1 and its receptors DCC and UNC5H2 are critical for the regulation of neuronal migration in nervous system development. Here we demonstrate expression of these molecules in lung development. The mRNA expression profiles of Netrin-1, DCC and UNC5H2 are developmentally regulated during embryonic mouse lung formation. Netrin-1 shows a bimodal expression pattern with elevated mRNA levels early followed by a second peak in late gestation. Peak expression of DCC occurs early in development whereas expression of UNC5H2 peaks late in development. We also demonstrate localization of Netrin-1, DCC and UNC5H2 during the stages of lung development. We present evidence that these proteins are modulated spatially in the mesenchyme and epithelium during lung organogenesis.

Animals↗
PubMed1992

Generation of free radicals during the reductive metabolism of nilutamide by lung microsomes: possible role in the development of lung lesions in patients treated with this anti-androgen.

The pulmonary metabolism of nilutamide, a nitroaromatic anti-androgen drug leading to pulmonary lesions in a few recipients, has been investigated in rats. Incubation of nilutamide (1 mM) with rat lung microsomes and NADPH under anaerobic conditions led to the formation of the nitro anion free radical, as indicated by ESR spectroscopy. The steady state concentration of this radical was not decreased by CO or SKF 525-A (two inhibitors of cytochrome P450), but was decreased by NADP+ (10 mM) or p-chloromercuribenzoate (0.47 mM) (two inhibitors of NADPH-cytochrome P450 reductase activity). Anaerobic incubations of [3H]nilutamide (0.1 mM) with rat lung microsomes and a NADPH-generating system resulted in the in vivo covalent binding of [3H]nilutamide metabolites to microsomal proteins; covalent binding required NADPH; it was decreased in the presence of NADP+ (10 mM), or in the presence of the nucleophile glutathione (10 mM), but was unchanged in the presence of carbon monoxide. Under aerobic conditions, in contrast, the nitro anion free radical was reoxidized by oxygen, and its ESR signal was not detected. Covalent binding was essentially suppressed. Instead, there was consumption of NADPH and oxygen, and production of superoxide anion and hydogen peroxide. We conclude that nilutamide is reduced by rat lung microsomes NADPH-cytochrome P450 reductase into a nitro anion free radical. In anaerobiosis, the radical is reduced further to covalent binding species. In the presence of oxygen, in contrast, this nitro anion free radical undergoes redox cycling, with the generation of reactive oxygen species.

Androgen Antagonists↗