Biosynthesis of leukotoxin, 9, 10-epoxy-12 octadecenoate, by leukocytes in lung lavages of rat after exposure to hyperoxia

Ozawa, Takayuki; Hayakawa, Mika; Takamura, Tadanobu; Sugiyama, Satoru; Suzuki, Kiyoshi; Iwata, Masaru; Taki, Fumio; Tomita, Tadao

doi:10.1016/0006-291x(86)90360-8

Cited by 87 publications

(32 citation statements)

References 3 publications

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“…In addition, hyperoxia also has been shown to increase oxygen radical production in rat lung homogenates (47), while oxygen metabolite scavengers inhibit hyperoxic lung injury (48) and protect alveolar macrophages from hyperoxic injury in vitro (49). Lipid peroxides also have been shown to be directly toxic to alveolar cells (50). The above findings support the view that hyperoxic lung injury occurs as a result of the natural antioxidant defenses being overwhelmed by the increased oxidant stress resulting from breathing high oxygen concentrations.…”

Section: Rna Extaction and Northern Blot Analysissupporting

confidence: 75%

Attenuation of oxidant-induced lung injury by 21-aminosteroids (lazaroids): correlation with the mRNA expression for E-selectin, P-selectin, ICAM-1, and VCAM-1.

Griffin¹,

Krzesicki²,

Fidler³

et al. 1994

Environ Health Perspect

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We compared the effects of treatment with methylprednisolone or the 21-aminosteroids, U-74389 and U-74006F (Tirilizad mesylate), on hyperoxic lung injury and the associated expression of mRNA for several adhesion molecules in rats. Inhalation of >95% oxygen for up to 72 hr in Sprague-Dawley rats produced a marked increase in lung weight and an accumulation of fluid in the thorax when compared with air-breathing controls. Hyperoxia also induced a marked neutrophil-rich influx of inflammatory cells into the bronchial lumen as measured by bronchoalveolar lavage. Neutrophil numbers in bronchoalveolar lavage fluid peaked after 60 hr of exposure to > 95% oxygen; this was associated with a marked upregulation of mRNA for the adhesion molecules P-selectin and E-selectin but not VCAM-1. mRNA for ICAM-1 was constitutively expressed at high levels in both air-breathing controls and in the lungs of rats exposed to high concentrations of oxygen. Pretreatment with the 21-aminosteroids reduced hyperoxic lung damage and improved survival times in animals exposed to >95% oxygen. However, treatment with methylprednisolone significantly decreased survival times. Treatment with U-74389 did not significantly (p > 0.05) inhibit the BAL neutrophilia and did not significantly (p > 0.05) reduce hyperoxia-induced increases in mRNA expression for P-selectin and E-selectin. The inhibition of hyperoxic lung damage coupled with improved survival seen in treated animals suggests that 21-aminosteroids may provide valuable treatments for pulmonary disorders in which oxidant damage has been implicated. -Environ Health Perspect 102 (Suppl 10):193-200 (1994)

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Section: Rna Extaction and Northern Blot Analysissupporting

confidence: 75%

Attenuation of oxidant-induced lung injury by 21-aminosteroids (lazaroids): correlation with the mRNA expression for E-selectin, P-selectin, ICAM-1, and VCAM-1.

Griffin¹,

Krzesicki²,

Fidler³

et al. 1994

Environ Health Perspect

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“…CYP2C44 metabolized linoleic acid principally to HODEs as major metabolites (61%) and EOAs as minor metabolites (39%). Although the action of HODEs and EOAs has received little study, 9,10-EOA is a hepatic toxin (Ozawa et al, 1986), and 9,10-EOA and 12,13-EOA have been associated with death due to severe burns (Kosaka et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

CYP2C44, a New Murine CYP2C That Metabolizes Arachidonic Acid to Unique Stereospecific Products

DeLozier¹,

Tsao²,

Coulter³

et al. 2004

J Pharmacol Exp Ther

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The human CYP2Cs have been studied extensively with respect to the metabolism of clinically important drugs and endogenous chemicals such as arachidonic acid (AA). Five members of the mouse CYP2C family have previously been described that metabolize arachidonic acid into regio-and stereospecific epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids, which have many important physiological roles. Herein, we describe the cloning and characterization of a new mouse cytochrome P450 (P450), CYP2C44, which has the lowest homology with other known mouse CYP2Cs. Western blotting and real-time polymerase chain reaction detected CYP2C44 mRNA and protein in liver Ͼ Ͼ kidney Ͼ adrenals. Kidney contained approximately 10% of the CYP2C44 mRNA content of liver. CYP2C44 metabolized AA to unique stereospecific products, 11R,12S-EET and 8R, 9S-EET, which are similar to those produced by rat CYP2C23. CY2C23 is highly expressed in rat kidney and has been suggested to be important in producing compensatory renal artery vasodilation in response to salt-loading in this species. Immunohistochemistry showed the presence of CYP2C44 in hepatocytes, biliary cells of the liver, and the proximal tubules of the kidney. Unlike mouse CYP2C29, CYP2C38, and CYP2C39, CYP2C44 did not metabolize the common CYP2C substrate tolbutamide. CYP2C44 was not induced by phenobarbital or pregnenolone-16␣-carbonitrile, two prototypical inducers of hepatic P450s. The presence of CYP2C44 in mouse liver, kidney, and adrenals and the unique stereospecificity of its arachidonic acid metabolites are consistent with the possibility that it may have unique physiological roles within these tissues, such as modulation of electrolyte transport or vascular tone.

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“…Unlike EETs and HETEs, the biological significance of the EOAs and HODEs remains largely unknown. 9,10-EOA and 12,13-EOA have been shown to be associated with death in patients with severe burns (Kosaka et al, 1994), and 9,10-EOA has been shown to be a hepatic toxin (Ozawa et al, 1986), a lung toxin that inhibits mitochondrial respiration (Sakai et al, 1995), and a potent cardiotoxin (Sugiyama et al, 1987).…”

Section: Characterization Of New Mouse Cyp2c Enzymes 1155mentioning

confidence: 99%

Cloning, Expression, and Characterization of Three New Mouse Cytochrome P450 Enzymes and Partial Characterization of Their Fatty Acid Oxidation Activities

Wang

Zhao²,

Bradbury³

et al. 2004

Mol Pharmacol

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The mammalian CYP2C subfamily is one of the largest and most complicated in the cytochrome P450 superfamily. In this report, we describe the organization of the mouse Cyp2c locus, which contains 15 genes and four pseudogenes, all of which are located in a 5.5-megabase region on chromosome 19. We cloned three novel mouse CYP2C cDNAs (designated CYP2C50, CYP2C54, and CYP2C55) from mouse heart, liver, and colon, respectively. All three cDNAs contain open reading frames that encode 490 amino acid polypeptides that are 57 to 95% identical to other CYP2Cs. The recombinant CYP2C proteins were expressed in Escherichia coli after N-terminal modification, partially purified, and shown to be active in the metabolism of both arachidonic acid (AA) and linoleic acid, albeit with different catalytic efficiencies and profiles. CYP2C50 and CYP2C54 metabolize AA to epoxyeicosatrienoic acids (EETs) primarily, and linoleic acid to epoxyoctadecenoic acids (EOAs) primarily, whereas CYP2C55 metabolizes AA to EETs and hydroxyeicosatetraenoic acids and linoleic acid to EOAs and hydroxyoctadecadienoic acids. Northern blotting and reverse transcription-polymerase chain reaction analysis reveal that CYP2C50 transcripts are abundant in liver and heart; CYP2C54 transcripts are present in liver, kidney, and stomach; and CYP2C55 transcripts are abundant in liver, colon, and kidney. Immunoblotting studies demonstrate that CYP2C50 protein is expressed in liver and heart, CYP2C54 protein is detected primarily in liver, and CYP2C55 protein is present primarily in colon. Immunohistochemistry reveals that CYP2C55 is most abundant in surface columnar epithelium in the cecum. We conclude that these new CYP2C enzymes are probably involved in AA and linoleic acid metabolism in mouse hepatic and extrahepatic tissues.Cytochrome P450s (P450s) have been the subject of intense investigation by toxicologists and pharmacologists because they catalyze the metabolism of a wide range of exogenous compounds, including drugs, industrial chemicals, environmental pollutants, and carcinogens (Guengerich, 1992;Nelson et al., 1996;Nebert and Russell, 2002). Many of the enzymes are also active in the NADPHdependent oxidation of endogenous compounds such as arachidonic acid (AA) and linoleic acid (Capdevila et al., 2000;Zeldin, 2001;Nebert and Russell, 2002). The P450-derived AA metabolites include cis-epoxyeicosatrienoic acids (5, 8, 11, 14,, midchain hydroxyeicosatetraenoic acids , and -terminal alcohols of AA

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Biosynthesis of leukotoxin, 9, 10-epoxy-12 octadecenoate, by leukocytes in lung lavages of rat after exposure to hyperoxia

Cited by 87 publications

References 3 publications

Attenuation of oxidant-induced lung injury by 21-aminosteroids (lazaroids): correlation with the mRNA expression for E-selectin, P-selectin, ICAM-1, and VCAM-1.

Attenuation of oxidant-induced lung injury by 21-aminosteroids (lazaroids): correlation with the mRNA expression for E-selectin, P-selectin, ICAM-1, and VCAM-1.

CYP2C44, a New Murine CYP2C That Metabolizes Arachidonic Acid to Unique Stereospecific Products

Cloning, Expression, and Characterization of Three New Mouse Cytochrome P450 Enzymes and Partial Characterization of Their Fatty Acid Oxidation Activities

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