Expression Of Cytochrome P450 Isozymes Research Articles

The deleterious effects of cadmium on oxidative stress markers, drug-metabolizing, and antioxidant enzyme activities: Role of Silymarin and Garlic as Antioxidants.

Exposure to cadmium has been related to liver and kidney diseases such as polycystic and nephrotic syndrome. It is still unclear how cadmium contributes to these diseases. It is believed that the induction of oxidative stress resulting from the inhibition of antioxidant enzyme activities and changes in drug-metabolizing enzymes in the liver could explain the role of cadmium in the development of different diseases in the kidney and probably other organs. Changes in oxidative stress markers, antioxidant enzymes, and drug-metabolizing enzyme activities were assessed in the liver of male rats exposed to cadmium chloride. Additionally, the protective effects of silymarin and garlic extract against cadmium toxicosis were evaluated. Rats were randomly divided into eight groups as follows, groups 1, 2, 3, 4, and 5, received orally saline, CdCl2 (1mg/kg), garlic extract [800mg/kg], silymarin (25mg/kg) and silymarin plus garlic extract respectively for 28 consecutive days. Rats in groups 6, 7, and 8 were pretreated with the same doses of garlic, silymarin, and garlic plus silymarin, respectively for two hours before cadmium administration. The Western immunoblotting technique was used to investigate the protein expression of cytochrome P450 isozymes. Spectrophotometric methods were used to assess the activity of both antioxidant- and drug-metabolizing enzymes. Free radical levels [measured as thiobarbituric acid reactive substances (TBARS)], catalase, superoxide dismutase, and glutathione peroxidase activities increased whereas the levels of glutathione and the activities of glutathione S-transferase, glutathione reductase, and glutamyl transferase, cytochrome P450, aryl hydrocarbon dehydrogenase (AHH), dimethylnitrosamine-N-demethylase I (DMN-dI), 7-ethoxycoumarine-O-deethylase (ECOD), cytochrome b5 and NADPH-Cytochrome-c-reductase enzyme activities decreased after cadmium treatment. Furthermore, Western immunoblotting data revealed that glutathione peroxidase protein expression increased following cadmium exposure, but cytochrome P450 2E1 and 3A4 expressions were downregulated. However, pretreatment of rats with silymarin or garlic extract or both before cadmium administration was found to restore the protein expression of cytochrome P450 2E1 and 3A4, the level of free radicals, antioxidant enzymes, drug-metabolizing enzyme activities to their normal levels. Similarly, histological studies revealed that silymarin and/or garlic extract reduced the liver damage caused by cadmium. Silymarin and/or garlic extract reduced the adverse effects of cadmium on the activity of both drug-metabolizing and antioxidant enzymes activity. These antioxidants could be provided to those who work in cadmium-based sectors to help them cope with the adverse effects of cadmium on their kidneys. In addition, Inhibiting drug-metabolizing enzyme activity should be considered when administering therapeutic medications to persons exposed to cadmium because most therapeutic drugs and many endogenous substances are largely metabolized by these enzymes.

Prenatal ethanol exposure induces dynamic changes of expression and activity of hepatic cytochrome P450 isoforms in male rat offspring

This study aimed at determining the effect of prenatal ethanol exposure (PEE) on the expression and activity of cytochrome P450 (CYP) isozymes at different life stages of male rat offspring. Pregnant Wistar rats were administered with ethanol (4 g/kg/d) intragastrically from gestational day (GD) 9–20. Male offspring’s gene and activity of CYP isozymes were analyzed on GD 20 (only expression), postnatal day (PD) 84 and 196. Using aniline as probe, we compared the enzyme kinetics of hepatic CYP2E1 between two groups. Expression of CYP isozymes was examined in rat primary hepatocytes and human hepatic cell lines treated with ethanol or/and glucocorticoid. Gene level of Cyp1a2, 2b1, 2d1, 2e1, 3a1 and aryl hydrocarbon receptor were increased in PEE group on GD 20 and PD 84 and Cyp2e1 still exhibited an increasing trend on PD 196 compared with the control. PEE inhibited CYP2D1 and 2E1 activities in male offspring on PD 84. CYP activities in two groups became the same level on PD 196. PEE induced an opposite change in gene and protein level of hepatic CYP2E1 before and after birth. In consistent with lower protein level, aniline metabolism in PEE was weaker in liver microsome. Both single and combined use of ethanol or/and glucocorticoid increased CYPs expression in vitro. In conclusion, PEE programmed a higher gene and lower protein level of CYPs in male offspring, which dwindled with age. Impairment of protein levels and enzyme activities of CYPs may affect individual metabolism of endogenous and exogenous substances in early adulthood.

Differential regulation of hepatic cytochrome P450 monooxygenases in streptozotocin-induced diabetic rats

The present investigation was carried out to study the expression of major cytochrome P450 (CYP) isozymes in streptozotocin-induced diabetes with concomitant insulin therapy. Male Sprague-Dawley rats were randomly assigned to untreated control, streptozotocin-induced diabetic, insulin-treated groups and monitored for 4 weeks. Uncontrolled hyperglycemia in the early phase of diabetes resulted in differential regulation of cytochrome P450 isozymes. CYP1B1, CYP1A2, heme oxygenase (HO)-2 proteins and CYP1A2-dependent 7-ethoxyresorufin O-deethylase (EROD) activity were upregulated in the hepatic microsomes of diabetic rats. Insulin therapy ameliorated EROD activity and the expression of CYP1A2, CYP1B1 and HO-2 proteins. In addition, CYP2B1 and 2E1 proteins were markedly induced in the diabetic group. Insulin therapy resulted in complete amelioration of CYP2E1 whereas CYP2B1 protein was partially ameliorated. By contrast, CYP2C11 protein was decreased over 99% in the diabetic group and was partially ameliorated by insulin therapy. These results demonstrate widespread alterations in the expression of CYP isozymes in diabetic rats that are ameliorated by insulin therapy.

Administration of Xenobiotics With Anti-estrogenic Effects Results in mRNA Induction of Adult Male-Specific Cytochrome P450 Isozymes in the Livers of Adult Female Rats

Cytochrome P450 (CYP) catalyzes the oxidation of many endogenous and xenobiotic compounds. The expression of CYP isozymes are modulated by endogenous hormones and xenobiotics. We found that, although CYP2C11 and CYP3A2 are adult male-specific isozymes, they are also expressed in prepubertal female Sprague Dawley (SD) rats. However, the mRNA levels for these isozymes in prepubertal female SD rats decreased over time and became undetectable at 7 weeks of age. On the other hand, ovariectomy, administration of ICI182780, a specific estrogen antagonist, or administration of lindane, which is a widely used pesticide with anti-estrogenic effects, induced these adult male-specific CYP mRNAs in adult female SD rats. These results suggest that estrogen is involved in suppression of both CYP2C11 and CYP3A2 in adult female rats. The expression of these CYP isozymes in female rats, therefore, is affected by sexual maturity and by disrupting adult female hormonal homeostasis. We also performed a field survey to examine whether the induction of CYP2C11 or CYP3A2 differs between adult female roof rats in rural and metropolitan districts. RT-PCR showed that the mRNAs for CYP2C11 and CYP3A2 were expressed in half of the adult female roof rats captured in Osaka (as a metropolitan area district) but not in those captured in Hokkaido (as a rural district). Thus, induction of the adult male-specific CYP isozymes in adult female roof rats captured in Osaka might be caused by consumption of xenobiotics with anti-estrogenic effects.

Effects of Pristane on Cytochrome P450 Isozyme Expression in Rat Tissues

Chemical carcinogenesis studies are powerful tools to obtain information on potential mechanisms of chemical factors for malignancies. In this study Western blot analyses, using monoclonal antibodies specific for three different cytochrome P450 (CYP) isozymes (CYP1A1, CYP1A2 and CYP2B), were employed to examine the effect(s) of 3-methylcholanthrene and/or pristane (2,6,10,14-tetramethylpentadecane) on the basal and inducible levels of expression of CYP proteins within Copenhagen rat tissues. Pristane exposure led to tissue specific differences in the CYP isozymes expressed and elicited increased CYP protein expression over 3-methylcholanthrene induced levels in microsomes isolated from liver, Peyer's Patches, and thymus. Within the context of the chemical carcinogenesis model employed in this study, these observations correlated with the induction of B-cell malignancies by low doses of 3-methylcholanthrene and of thymic lymphomas by a high 3-methylcholanthrene dose. The data suggest that pristane treatment affects CYP isozyme expression. This pristane-mediated effect clearly could be a contributing factor in the chemical carcinogenesis of the previously observed lymphoid malignancies, and a possible basis for the tumor enhancing effects of pristane.

Changes in the expression of cytochrome P450 isozymes and related carcinogen metabolizing enzyme activities in Schistosoma mansoni-infected mice.

Mixed-function oxidase enzymes metabolize most xenobiotic agents. Western blotting was used to investigate the effect of Schistosoma mansoni infection on the expression of various cytochrome P450 (CYP) isozymes and specific enzyme assays to study related metabolic functions in mouse liver microsomes. Male BK-TO mice were infected with 200 cercariae per mouse and their livers were assayed at 6, 15, 30 and 45 days post-infection (p.i.) and compared with appropriately matched controls. The expression of each of the CYP isozymes (1A1, 2B1/2, 2C6, and 4A) was either unaffected or transiently increased up to 30 days post-infection. By 45 days, a significant loss of signal was observed, particularly for CYP 1A1 and 2B1 /2 where no signal could be detected. Evidence supporting these findings was obtained from enzyme assays specific for particular CYP isozymes. The activity of ethoxyresorufin O-deethylase (CYP 1A1) was reduced by 97% and that of pentoxyresorufin O-depentylase (CYP 2B1 /2) by 96% at 45 days p.i. Similarly, the activity of ethoxycoumarin hydroxylase was progressively reduced over the period under study. It is believed that N-nitrosamines are activated principally by N-nitrosodimethylamine N-demethylase I which was significantly increased at both 30 and 45 days p.i. To further investigate metabolic competency following S. mansoni infection, the in vitro binding of benzo(a)pyrene metabolites to DNA was measured, using isolated liver microsomes to activate benzo(a)pyrene. Benzo(a)-pyrene-DNA adduct formation was markedly increased at 6,15 and 30 days with a maximum at 15 days, but decreased at 45 days p.i. It was concluded that S. mansoni infection changes the expression of different CYP isozymes and also the activity of phase I drug-metabolizing enzymes at different periods of infection and may thus change the liver's capacity to activate or detoxify many endogenous and exogenous compounds. Such alterations may also change the therapeutic actions of drugs that are primarily metabolized by the P450 system, when administered to patients with schistosomiasis.

Cytochrome P450 expression and related metabolism in human buccal mucosa.

Constituents in food and fluids, tobacco chemicals and many drugs are candidates for oral absorption and oxidative metabolism. On this basis, the expression of cytochrome P450 isozymes (CYPs) and the conversion of CYP substrates were analysed in reference to buccal mucosa. A RT-PCR based analysis of human buccal tissue from 13 individuals demonstrated consistent expression of mRNA for the CYPs 1A1, 1A2, 2C, 2E1, 3A4/7 and 3A5. CYP 2D6 was expressed in six out of the 13 specimens, whereas all samples were negative for 2A6 and 2B6. Serum-free monolayer cultures of the Siman virus 40 large T-antigen-immortalized SVpgC2a and the carcinoma SqCC/Y1 buccal keratinocyte lines expressed the same CYPs as tissue except 3A4/7 and 3A5 (SVpgC2a), and 2C, 2D6 and 3A4/7 (SqCC/Y1). Dealkylation of ethoxyresorufin and methoxyresorufin in both normal and transformed cells indicated functional 1A1 and 1A2, respectively. SVpgC2a showed similar activity as normal keratinocytes for both substrates, whereas SqCC/Y1 showed about 2-fold lower 7-ethoxyresorufin O-deethylation and 7-methoxyresorufin O-demethylation activities. SVpgC2a showed detectable and many-fold higher activity than the other cell types towards chlorzoxazone, a substrate for 2E1. Absent or minute catalytic activity of 2C9, 2D6 and 3A4 in the various cell types was indicated by lack of detectable diclofenac, dextromethorphan and testosterone metabolism (<0.2-0.5 pmol/min/mg). Metabolic activation of the tobacco-specific N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the mycotoxin aflatoxin B1 (AFB1) to covalently bound adducts was indicated by autoradiographic analysis of both monolayer and organotypic cultures of SVpgC2a. In contrast, SqCC/Y1 showed lower or absent metabolic activity for these substrates. Finally, measurements of various non-reactive AFB1 metabolites indicated rates of formation <0.1 pmol/min/mg in both normal and transformed cells. The results indicate presence of several CYPs of which some may contribute to significant xenobiotic metabolism in human buccal epithelium. Notably, metabolic activation of AFB1 was not previously implicated for oral mucosa. Further, the results show that CYP-dependent metabolism can be preserved or even activated in immortalized keratinocytes. Metabolic activity in SVpgC2a under both monolayer and organotypic culture conditions suggests that this cell line may be useful to pharmaco-toxicological and carcinogenesis studies.

Mechanism of decrease in levels of hepatic P450 isozymes induced by intracerebral endotoxin: independence from sympathetic nervous and adrenocortical systems.

We previously reported that lipoplysaccharide (LPS) injected intracerebroventricularly (i.c.v.) at an ineffective dose (0.1 microgram/rat) decreased the drug metabolizing activities and related cytochrome P450 (CYP) isozymes in rat liver microsomes when injected intraperitoneally (i.p.). The dose study (doses < 0.1 microgram intracerebrally and > 0.1 microgram i.p.), which was carried out to examine how much more effective is i.c.v.-LPS than i.p.-LPS, showed that the pattern of alteration of expression of CYP isozymes induced by i.c.v.-LPS was different from that caused by i.p.-LPS at an effective dose (10 micrograms/rat). These results indicate that the decrease in hepatic CYP isozymes caused by i.c.v.-LPS could not be explained by the LPS leaked from the brain, suggesting that the decrease in hepatic CYP isozymes by i.c.v.-LPS may be caused by a central action of LPS. In this study, the possible involvement of sympathetic nervous and adrenocortical systems in the down-regulation of CYP isozymes by i.c.v.-LPS was investigated using surgical or chemical sympathetecomized or adrenalectomized rats. The norepinephrine (NE) content in the liver in rats with surgical hepatic sympathetectomy was reduced by 88% compared with that of sham-operated rats that received i.c.v.-saline and 85% compared with that of sham-operated rats that received i.c.v.-LPS, indicating that hepatic denervation was successful. The NE content in the liver in rats chemically sympathetectomized by two i.p. injections of 6-hydroxydopamine (40 mg/kg each time) 1 and 2 days before i.c.v. injection was reduced by 82% in i.c.v.-saline-treated and by 74% in i.c.v.-LPS-treated groups compared with that in rats pretreated with i.p.-saline. These results indicate that sympathetic NE terminals were effectively removed. Intracerebroventricular LPS decreased the total P450 content and the activities of CYP dependent drug metabolizing enzymes, ethoxyresorufin O-deethylase (EROD), pentoxyresorufin O-depentylase (PROD), imipramine N-demethylase (IMND) and erythromycin N-demethylase (ERND) after 24 h in both sympathetectomized rats and non-denervated rats. Adrenalectomy (ADX) reduced the level of corticosterone in serum by 81% compared to sham-operated rats, indicating that adrenalectomy was successful. ADX did not inhibit the decrease in the total P450 content and the metabolism of drugs induced by i.c.v.-LPS, but more profoundly emphasized the inhibitory effect of i.c.v.-LPS than the sham-operation. These results suggest that the sympathetic nervous systems both directly and indirectly innervating the liver do not participate in the primary mechanism of the decrease in the activities of CYP isozymes in rat liver microsomes induced by i.c.v.-LPS. Also, the adrenal glands, especially the adrenocortical system, play a suppressive role in the decrease in CYP isozymes caused by i.c.v.-LPS.

Effect of pyridine on the expression of cytochrome P450 isozymes in primary rat hepatocyte culture.

In vivo administration of pyridine has been shown to increase the activity and content of several forms of cytochrome P450 by transcriptional and posttranscriptional mechanisms. The effect of pyridine on CYP1A and CYP2E1 isozymes was studied in a rat hepatocyte culture model. Hepatocytes were isolated from non-induced rats and seeded onto matrigel-coated dishes and incubated in William's medium E containing 10% fetal calf serum, hormones, and essential metals. Cultures were treated with 0, 10 or 25 mM pyridine for 1-3 days and microsomes were isolated to determine catalytic activity and for immunoblot analysis, and total RNA was isolated for mRNA determinations. CYP2E1 content, CYP2E 1 mRNA, and CYP2E1 catalyzed oxidation of p-nitrophenol declined during culture to values of 3, 30 and 19% that of initial, non-cultured controls by day 3 of culture. Pyridine prevented this decline of CYP2E1 protein and activity such that 60-80% original activity remained after 3 days of culture in the presence of 25 mM pyridine. However, pyridine did not prevent the fall in CYP2E1 mRNA levels, nor did pyridine increase the content or activity of CYP2E1 above initial values of microsomes from freshly isolated hepatocytes. Pyridine increased the content of CYP1A2 and the oxidation of ethoxyresorufin 2-4 fold compared to cultures incubated without pyridine over the 3 day culture period. CYP1A1 levels, which rapidly declined, were induced and maintained in the presence of pyridine. Pyridine increased CYP1A content and activity 2-3 fold over initial values of freshly isolated hepatocytes. These increases were associated with corresponding increases in CYP1A mRNA levels. CYP1A2, but not CYP1A1, mRNA levels increased in the cultures incubated in the absence of pyridine. These results indicate that pyridine has different effects on CYP1A and CYP2E1 in this hepatocyte culture model. Pyridine appears to modulate CYP2E1 levels by posttranscriptional mechanisms as CYP2E1 activity and content were maintained in the presence of pyridine under conditions in which CYP2E1 mRNA levels declined. These mechanisms may involve increased translational efficiency of existing CYP2E1 mRNA or stabilization of CYP2E1 protein against degradation. Pyridine increased CYP1A1 and CYP1A2 content, activity and mRNA levels, either inducing CYP1A transcription or stabilizing CYP1A mRNA. Hepatocyte cultures may be a useful model to study the interaction of pyridine with P450 isozymes and their associated drug-mediated toxicity.

Quantitative Histology and Cytochrome P-450 Immunocytochemistry of the Lung Parenchyma Following 6 Months of Exposure of Strain A/J Mice to Cigarette Sidestream Smoke

AbstractMale strain A/J mice were exposed for 6 h/day, 5 days/wk to aged and diluted cigarette sidestream smoke (ADSS) at a chamber concentration of 4 mg/m3 of total suspended particulate matter (TSP). After 6 mo, the lungs were examined for altered expression of cytochrome P-450 isozymes and for differences in total alveolar tissue volume or surface area, as well as changes in the numbers of epithelial type II cells and alveolar macrophages. Morphologic measurements showed no statistically significant differences for the air, alveolar tissue, or capillary volumes of the lungs or changes in the total number of epithelial type II cells or alveolar macrophages. In contrast, cytochrome P-4501A1 was elevated in the lungs of ADSS-exposed animals and localized in capillary endothelial cells. CYP2B1 was present in airway epithelial cells as well as in epithelial cells throughout the lung parenchyma, but its distribution was not changed by ADSS exposure. Isozyme CYP2E1 was also found in airway epithelial cells, b...

Selective expression of cytochrome P450 isozymes by 4- n-alkyl-methylenedioxybenzenes in rat lung cells

Rat lung preparations were analyzed for cytochrome P450 expression as a function of pretreatment with 1 mmol/kg/day of various substituted n-alkyl-methylenedioxybenzenes (MDBs). Lung P450s were quantitated by Western blotting and visualized by immunocytochemical techniques using polyclonal antibodies directed against P450IA1/IA2 and P450IIB1/IIB2. Results demonstrated that n-hexyland n-octyl-MDB (but not n-butyl-MDB) increased P450IA1 in lung microsomes (50 pmol/mg microsomal protein) compared to untreated controls and n-butyl-MDB-treated animals (6 pmol/mg). However, treatment with all of these MDBs concomitantly decreased P450IIB1 in rat lung microsomes, from 40 pmol/mg in untreated control lungs to below the detection limit of this method (<2 pmol/mg). In vitro metabolism assays with rat lung microsomes, utilizing 7,12-dimethylbenz[ a]anthracene as substrate, confirmed the increase in P450IA1 by selected MDBs and the concomitant decrease of catalytically active P450IIB1. Immunocytochemistry of rat lungs with these same IgGs indicated selective cellular responses. n-Hexyl-MDB (but not n-butyl-MDB) increased P450IA1-like immunoreactivity, but the increase was specifically localized to Clara cells. Immunocytochemical results further showed that P450IIB1-like immunoreactivity disappeared entirely from alveolar type II cells, yet appeared unchanged in Clara cells relative to untreated controls. Increases in P450IA1 due to treatment with n-hexyl-MDB were associated with increases in P450IA1 mRNA as indicated by Northern blot experiments. In contrast, the decreased levels of P450IIB1, consequent to treatment with n-alkyl-MDBs, were not associated with altered levels of pulmonary P450IIB1 mRNA as determined by Northern blotting and solution hybridization assays. These results imply that n-alkyl-MDBs regulate pulmonary cytochromes P450 by both transcriptional and post-transcriptional mechanisms.

Expression of cytochrome P-450 isozymes in the liver of hypophysectomized rats. Evidence for different regulation mechanisms concerning P450IIB and P450IIIA subfamilies.

1. Monooxygenase activities have been examined in rat liver to determine the effects of castration and hypophysectomy on cytochrome P-450 species. In adult males, hypophysectomy caused a decrease of total P-450 concentration, aniline hydroxylase, benzopyrene hydroxylase, benzphetamine demethylase, testosterone hydroxylase and imipramine hydroxylase and demethylase activities. The treatment of hypophysectomized animals with human growth hormone or testosterone did not restore the full activity. 2. When probed with antibodies, microsomes from hypophysectomized males and females exhibited an intense reaction with a polyclonal anti-(phenobarbital-induced P-450) which was not observed with a monoclonal antibody of anti-(phenobarbital-induced P-450). 3. These microsomal preparations also reacted with an antibody raised against a developmentally regulated P-450. No sex difference could be detected with this antibody. Furthermore, administration of human growth hormone to hypophysectomized males prevented this immunoreaction. 4. Total RNA has been prepared from the same liver; when probed with cDNAs, no changes occurred in the content in P-450 b/e, PB 24 (a constitutive member of the phenobarbital subfamily) and phenobarbital-inducible mRNA for UDP-glucuronosyltransferase. 5. In contrast, P-450 mRNA induced by pregnenolone 16 alpha-carbonitrile was modulated by hormonal manipulations: lower in females and castrated males than in intact males, increased in both sexes after hypophysectomy. Treatment of hypophysectomized males with human growth hormone abolished this rise in pregnenolone-16 alpha-carbonitrile-induced P-450 mRNA accumulation. Data collected in this study support the assumption that hypophysectomy acts differently on the regulation of various P-450 isozymes and that this regulation clearly does not involve the phenobarbital subfamily of P-450s.

Cellular Structure, Function and Organization in the Lower Respiratory Tract

Research ArticleOpen AccessCellular structure, function and organization in the lower respiratory tract. R Breeze, and M Turk R Breeze Search for more papers by this author and M Turk Search for more papers by this author Published:1 April 1984https://doi.org/10.1289/ehp.84553Cited by:15AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit FiguresReferencesRelatedDetailsCited by Haque S, Whittaker M, McIntosh M, Pouton C and Kaminskas L (2016) Disposition and safety of inhaled biodegradable nanomedicines: Opportunities and challenges, Nanomedicine: Nanotechnology, Biology and Medicine, 10.1016/j.nano.2016.03.002, 12:6, (1703-1724), Online publication date: 1-Aug-2016. Sirajuddin A, Raparia K, Lewis V, Franks T, Dhand S, Galvin J and White C (2016) Primary Pulmonary Lymphoid Lesions: Radiologic and Pathologic Findings, RadioGraphics, 10.1148/rg.2016140339, 36:1, (53-70), Online publication date: 1-Jan-2016. Nelli R, Maes R, Kiupel M and Hussey G (2016) Use of a feline respiratory epithelial cell culture system grown at the air–liquid interface to characterize the innate immune response following feline herpesvirus 1 infection, Virus Research, 10.1016/j.virusres.2016.01.006, 214, (39-48), Online publication date: 1-Mar-2016. Dodson R (2005) Analysis and Relevance of Asbestos Burden in Tissue Asbestos, 10.1201/9781420038149.ch3, (39-90), Online publication date: 29-Sep-2005. Ainsworth D and Hackett R (2004) Disorders of the Respiratory System Equine Internal Medicine, 10.1016/B0-72-169777-1/50009-3, (289-353), . Polosukhin V (2009) Ultrastructure of the Bronchial Epithelium in Chronic Inflammation, Ultrastructural Pathology, 10.1080/01913120120916, 25:2, (119-128), Online publication date: 1-Jan-2001. Kahwa C, Atwal O and Purton M (1997) Transmission electron microscopy of the epithelium of distal airways and pulmonary parenchyma of the goat lung, Research in Veterinary Science, 10.1016/S0034-5288(97)90157-0, 63:1, (49-56), Online publication date: 1-Jul-1997. James Catallo W, Hoover D and Vargas D (1994) Effects of an environmental toxicant on ultrastructure in Paramecium caudatum and the protective effect of dissolved calcium, Aquatic Toxicology, 10.1016/0166-445X(94)90073-6, 29:3-4, (291-303), Online publication date: 1-Aug-1994. RYAN U and LI A (1993) METABOLISM OF ENDOGENOUS AND XENOBIOTIC SUBSTANCES BY PULMONARY VASCULAR ENDOTHELIAL CELLS Metabolic Activation and Toxicity of Chemical Agents to Lung Tissue and Cells, 10.1016/B978-0-08-041177-4.50011-0, (107-122), . Yanev E, Markovska T, Momchilova A, Pankov R, Sedloev T and Koumanov K (1992) Alterations in rat alveolar surfactant system induced by treatment with carbicron (O-[(2-butenoic acid)-N,N-dimethylamide-3-yl]-O,O-dimethylphosphate), Comparative Biochemistry and Physiology Part C: Comparative Pharmacology, 10.1016/0742-8413(92)90180-F, 103:3, (553-555), Online publication date: 1-Nov-1992. (1991) Systemic Delivery of Peptide-Based Pharmaceuticals Novel Drug Delivery Systems, Second Edition,, 10.1201/b14196-12, (631-745), Online publication date: 31-Oct-1991. Marcus C, Wilson N, Keith I, Jefcoate C and Omiecinski C (1990) Selective expression of cytochrome P450 isozymes by 4-n-alkyl-methylenedioxybenzenes in rat lung cells, Archives of Biochemistry and Biophysics, 10.1016/0003-9861(90)90544-9, 277:1, (17-25), Online publication date: 1-Feb-1990. Filkelstein J (1990) Physiologic and toxicologic responses of alveolar type II cells, Toxicology, 10.1016/0300-483X(90)90161-9, 60:1-2, (41-52), Online publication date: 1-Jan-1990. Brandes M and Finkelstein J (1989) Stimulated Rabbit Alveolar Macrophages Secrete a Growth Factor for Type II Pneumocytes, American Journal of Respiratory Cell and Molecular Biology, 10.1165/ajrcmb/1.2.101, 1:2, (101-109), Online publication date: 1-Aug-1989. Breeze R (1985) Structure, Function, and Metabolism in the Lung, Veterinary Clinics of North America: Food Animal Practice, 10.1016/S0749-0720(15)31325-6, 1:2, (219-235), Online publication date: 1-Jul-1985. Vol. 55April 1984Metrics About Article Metrics Publication History Originally published1 April 1984Published in print1 April 1984 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.