Abstract:
:Inhaled glucocorticoid (GC) therapy is a vital part of the management of chronic asthma. GCs are metabolized by members of the cytochrome P450 3A family in both liver and lung, but the enzymes are differentially expressed. Selective inhibition of one or more P450 3A enzymes could substantially modify target and systemic concentrations of GCs. In this study, we have evaluated the mechanism-based inactivation of P450 3A4, 3A5, and 3A7 enzymes by GCs. Among the five major inhaled GCs approved for clinical use in the United States, fluticasone propionate (FLT) was the most potent mechanism-based inactivator of P450 3A5, the predominant P450 enzyme in the lung. FLT inactivated P450 3A5 in a time- and concentration-dependent manner with K(I), k(inact), and partition ratio of 16 muM, 0.027 min(-1), and 3, respectively. In contrast, FLT minimally inactivated P450 3A4 and did not inactivate 3A7, even with a concentration of 100 muM. The inactivation of P450 3A5 by FLT was irreversible because dialysis did not restore enzyme activity. In addition, the exogenous nucleophilic scavenger GSH did not attenuate inactivation. The prosthetic heme of P450 3A5 was not modified by FLT. The loss of P450 3A5 activity in lung cells could substantially decrease the metabolism of FLT, which would increase the effective FLT concentration at its target site, the respiratory epithelium. Also, inactivation of lung P450 3A5 could increase the absorption of inhaled FLT, which could lead to high systemic concentrations and adverse effects, such as life-threatening adrenal crises or cataracts that have been documented in children receiving high doses of inhaled GCs.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Murai T,Reilly CA,Ward RM,Yost GSdoi
10.1021/tx100124ksubject
Has Abstractpub_date
2010-08-16 00:00:00pages
1356-64issue
8eissn
0893-228Xissn
1520-5010journal_volume
23pub_type
杂志文章abstract::Concerns have been raised that diacetyl (DA) might be a respiratory sensitizer based on its LUMO energy similar to that of the respiratory allergen toluene-2,4-diisocyanate (TDI) and results of a local lymph node assay (LLNA) that reported an EC3 of 1.9%. To better understand the concerns, we performed a systematic li...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
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更新日期:2013-05-20 00:00:00
abstract::1,3-Butadiene (BD) is a high-volume industrial chemical and a common environmental pollutant. Although BD is classified as a "probable human carcinogen", only limited evidence is available for its tumorigenic effects in occupationally exposed populations. Animal studies show a surprisingly high sensitivity of mice to ...
journal_title:Chemical research in toxicology
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abstract::The procarcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine formed during the cooking of foods. Metabolism of PhIP by CYP1A2 differs substantially between humans and rodents, with more N2-hydroxylation (activation) and less 4'-hydroxylation (detoxication) in humans....
journal_title:Chemical research in toxicology
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journal_title:Chemical research in toxicology
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journal_title:Chemical research in toxicology
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journal_title:Chemical research in toxicology
pub_type: 杂志文章
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abstract::The oxidation state of intracellular chromium has been determined directly in mammalian lung cells exposed to mutagenic and carcinogenic chromium compounds. Microprobe X-ray absorption spectroscopy (XAS) experiments on single V79 Chinese hamster lung cells showed that Cr(VI) and Cr(V) complexes were reduced completely...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
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abstract::The biological response of bronchial epithelial cells to particles is associated with a sequestration of cell metal by the particle surface and a subsequent disruption in host iron homeostasis. The macrophage is the cell type resident in the respiratory tract that is most likely to make initial contact with inhaled pa...
journal_title:Chemical research in toxicology
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abstract::Lindane and paraquat induce biochemical changes in the liver. In order to specify their molecular impact at the cellular level, a 300 MHz 1H NMR investigation of hepatoma cell lines Hep 3B and Hep G2 responses was performed. Cells were exposed over 24 h to 50 mg/L lindane (0.178 mM) or to 100 mg/L (0.389 mM) paraquat ...
journal_title:Chemical research in toxicology
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journal_title:Chemical research in toxicology
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更新日期:2005-02-01 00:00:00
abstract::Pyridoxamine (PM) is an effective inhibitor of the formation of the carcinogen acrylamide (AA) from its precursors in low-moisture model systems. Although AA is widely assumed to act by scavenging carbonyl compounds, no alternative pathways have to date been explored. In this work, we found AA to directly react with P...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx100293y
更新日期:2011-03-21 00:00:00
abstract::The toxic alpha,beta-unsaturated aldehyde acrolein readily attacks proteins, generating adducts at cysteine, histidine, and lysine residues. In this study, rabbit antiserum was raised against acrolein-modified keyhole limpet hemocyanin in the expectation that it would allow immunodetection of adducted proteins in biol...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0341106
更新日期:2003-10-01 00:00:00
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journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00043a010
更新日期:1995-01-01 00:00:00
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journal_title:Chemical research in toxicology
pub_type: 杂志文章
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abstract::Lesion-induced thermodynamic destabilization is believed to facilitate β-hairpin intrusion by the human XPC/hHR23B nucleotide excision repair (NER) recognition factor, accompanied by partner-base flipping, as suggested by the crystal structure of the yeast orthologue (Min, J. H., and Pavletich, N. P. (2007) Nature 449...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
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更新日期:2010-12-20 00:00:00
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journal_title:Chemical research in toxicology
pub_type: 杂志文章
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更新日期:2009-07-01 00:00:00
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journal_title:Chemical research in toxicology
pub_type: 杂志文章
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更新日期:2010-06-21 00:00:00
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更新日期:1997-04-01 00:00:00
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journal_title:Chemical research in toxicology
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abstract::Exposure to fine particulate matter (PM2.5), of which secondary organic aerosol (SOA) is a major constituent, is linked to adverse health outcomes, including cardiovascular disease, lung cancer, and preterm birth. Atmospheric oxidation of isoprene, the most abundant nonmethane hydrocarbon emitted into Earth's atmosphe...
journal_title:Chemical research in toxicology
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journal_title:Chemical research in toxicology
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journal_title:Chemical research in toxicology
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journal_title:Chemical research in toxicology
pub_type: 杂志文章
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journal_title:Chemical research in toxicology
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abstract::Vinyl chloride and acrolein are important industrial chemicals. Both form DNA adducts, vinyl chloride after enzymatic oxidation to chlorooxirane and acrolein by direct reaction. Reaction at the N(2) position of guanine is a major pathway. The resulting 2-oxoethyl and 3-oxopropyl adducts cyclize spontaneously to hydrox...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
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更新日期:2000-05-01 00:00:00