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Mitsuyama, Takashi; Hidaka, Katsuhiko; Furuno, Takashi; Hara, Nobuyuki

doi:10.1023/a:1006894301389

Cited by 20 publications

(2 citation statements)

References 14 publications

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“…In keeping with the hypothesis on the endosymbiotic origin of mitochondria (51, 52), erythromycin also inhibits mitochondrial translation (26 -29). It is also suggested that the anti-inflammatory action of this antibiotic may reside in its ability to induce NO production in endothelial cells and also its ability to modulate interleukin-8 gene expression (53). In this paper, we demonstrate that overexpression of P4501A1 either by its cognate inducer or by transfection with expression cDNA constructs effectively rendered protection against erythromycin-mediated inhibition of mitochondrial protein synthesis.…”

Section: Reversal Of Erythromycin-induced Mitochondrial Translation Bmentioning

confidence: 63%

Physiological Role of the N-terminal Processed P4501A1 Targeted to Mitochondria in Erythromycin Metabolism and Reversal of Erythromycin-mediated Inhibition of Mitochondrial Protein Synthesis

Anandatheerthavarada

Vijayasarathy

Bhagwat

et al. 1999

Journal of Biological Chemistry

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Recently, we showed that the major species of ␤-naphthoflavone-inducible rat liver mitochondrial P450MT2 consists of N-terminal truncated microsomal P4501A1 (؉33/1A1) and that the truncated enzyme exhibits different substrate specificity as compared with intact P4501A1. The results of the present study show that P450MT2 targeted to COS cell mitochondria by transient transfection of P4501A1 cDNA is localized inside the mitochondrial inner membrane in a membrane-extrinsic orientation. Co-expression with wild type P4501A1 and adrenodoxin (Adx) cDNAs resulted in 5-7-fold higher erythromycin N-demethylation (ERND) in the mitochondrial fraction but minimal changes in the microsomal fraction of transfected cells. Erythromycin, a potent inhibitor of bacterial and mitochondrial protein synthesis, caused 8 -12-fold higher accumulation of CYP1A1 mRNA, preferential accumulation of P450MT2, and 5-6-fold higher ERND activity in the mitochondrial compartment of rat C6 glioma cells. Consistent with the increased mitochondrial ERND activity, co-expression with P4501A1 and Adx in COS cells rendered complete protection against erythromycin-mediated mitochondrial translation inhibition. Mutations that specifically affect the mitochondrial targeting of P4501A1 also abolished protection against mitochondrial translation inhibition. These results for the first time suggest a physiological function for the xenobiotic inducible cytochrome P4501A1 against drug-mediated mitochondrial toxicity.Mitochondria in mammalian organisms are important subcellular targets for a variety of xenobiotics including drugs, carcinogens, and environmental contaminants (1-6). Structurally diverse chemicals and pharmacologically important drugs, which alter mitochondrial membrane properties and affect mitochondrial enzyme complexes or gene expression, are thought to be contributing factors in a variety of human disorders (3,(5)(6)(7)(8). Efforts in our laboratory have been focused on the characterization of mitochondrial class I and class II drug metabolizing enzymes to determine their roles in modulating the toxic effects of various xenobiotic chemicals on the mitochondrial genetic system. Our studies showed the presence of five different xenobiotic-inducible P450 1 monooxygenases in rat liver mitochondria, which cross-react with antibodies to similarly induced microsomal P450 isoforms (9 -14). Enzyme reconstitution and immunochemical studies also showed the presence of several P450 isoforms, resembling the liver mitochondrial forms, in induced rat brain and human brain mitochondria (15-17). Additionally, reports from various groups have shown the occurrence of different isoforms of glutathione S-transferases in the mitochondrial membrane compartment of rat liver, brain, and lung (18 -21), suggesting the existence of both class I and class II enzymes in mitochondria.Recent studies in our laboratory showed that the two BNFinducible hepatic mitochondrial P450s, designated as P450MT2A and MT2B, are derived by differential proteolytic processing of the similarly...

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Section: Reversal Of Erythromycin-induced Mitochondrial Translation Bmentioning

confidence: 63%

Physiological Role of the N-terminal Processed P4501A1 Targeted to Mitochondria in Erythromycin Metabolism and Reversal of Erythromycin-mediated Inhibition of Mitochondrial Protein Synthesis

Anandatheerthavarada

Vijayasarathy

Bhagwat

et al. 1999

Journal of Biological Chemistry

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“…However, the role of PKA and PKC in the signaling pathway for the activation of ecNOS has not been completely clarified. We have recently reported that dbcAMP ameliorated endothelial cell damage induced by neutrophils [11]. In the present study, we investi gated whether the protective effect of dbcAMP is associated with an increased NO release into the medium.…”

Section: Discussionmentioning

confidence: 71%

The Role of Nitric Oxide in Human Pulmonary Artery Endothelial Cell Injury Mediated by Neutrophils

Hidaka

Mitsuyama

Furuno

et al. 1997

Int Arch Allergy Immunol

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Human endothelial cells are injured by the action of leukocytes. We investigated the role of nitric oxide (NO) in the induction of injury to human pulmonary artery endothelial cells. NO has been a putative source of cytotoxic reactive oxygen species in some settings. Incubation of endothelial cells with neutrophils increased the release of lactate dehydrogenase activity and preloaded fura-2 from endothelial cells, indicating that neutrophils induce endothelial cell injury. This effect was augmented by treatment with carboxy-PTIO, which traps NO in the medium, or with L-NAME, an inhibitor of NO synthase. When endothelial cells were incubated with neutrophils stimulated by phorbol myristate acetate, an activator of protein kinase C, endothelial cell damage was further enhanced and the amount of NO in the medium was decreased. Dibutyryl cyclic AMP, a cell-permeable analogue of cyclic AMP, protected against neutrophil-induced endothelial cell injury and increased NO release into the medium. The effects of dibutyryl cyclic AMP were abrogated by treatment with H-89, a potent inhibitor of cyclic AMP-dependent protein kinase. The protective effect on neutrophil-induced endothelial cell injury by dibutyryl cyclic AMP was abolished by addition of carboxy-PTIO or L-NAME. Thus, our studies suggest that NO, presumably released from endothelial cells, protects against endothelial injury by activated neutrophils and the protective effect by cyclic AMP during coculture with activated neutrophils is mediated through the action of NO. However, when monocytes activated by lipopolysaccharide and IFN-γ were used instead of neutrophils, endothelial cells were likewise injured, but a much higher level of NO was detected and injury was diminished by addition of carboxy-PTIO to the medium. These observations suggest that the high levels of NO released by activated monocytes contribute to endothelial injury, whereas low levels of NO protect endothelial cells against injury by neutrophils.

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Antibiotics, inflammation and its resolution: An overview

Parnham¹

Antibiotics as Anti-Inflammatory and Immunomodulatory Agents

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Cited by 20 publications

References 14 publications

Physiological Role of the N-terminal Processed P4501A1 Targeted to Mitochondria in Erythromycin Metabolism and Reversal of Erythromycin-mediated Inhibition of Mitochondrial Protein Synthesis

Physiological Role of the N-terminal Processed P4501A1 Targeted to Mitochondria in Erythromycin Metabolism and Reversal of Erythromycin-mediated Inhibition of Mitochondrial Protein Synthesis

The Role of Nitric Oxide in Human Pulmonary Artery Endothelial Cell Injury Mediated by Neutrophils

Antibiotics, inflammation and its resolution: An overview

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