Bleomycin genotoxicity alteration by glutathione and cytochrome P-450 cellular content in respiratory proficient and deficient strains of Saccharomyces cerevisiae

Poli, Paola; Buschini, Annamaria; Candi, Alessia; Rossi, Carlo

doi:10.1093/mutage/14.2.233

Cited by 18 publications

(3 citation statements)

References 28 publications

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“…Significant bleomycin-induced induction of gene and protein for thioredoxin was also demonstrated in bronchial epithelial cells in vivo and in vitro (29). A protective role for thiol has been demonstrated in recent investigations of bleomycin-induced lung injury, and glutathione inhibited bleomycin-induced DNA breaks in vitro (30). Further, protection against fibrosis was observed in thioredoxin transgenic mice challenged with bleomycin (31).…”

Section: Discussionmentioning

confidence: 87%

The transcription factor NRF2 protects against pulmonary fibrosis

et al. 2004

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The molecular mechanisms of pulmonary fibrosis are poorly understood, although reactive oxygen species are thought to have an important role. NRF2 is a transcription factor that protects cells and tissues from oxidative stress by activating protective antioxidant and detoxifying enzymes. We hypothesized that NRF2 protects lungs from injury and fibrosis induced by bleomycin, an anti-neoplastic agent that causes pulmonary fibrosis in susceptible patients. To test this hypothesis, mice with targeted deletion of Nrf2 (Nrf2-/-) and wild-type (Nrf2+/+) mice were treated with bleomycin or vehicle, and pulmonary injury and fibrotic responses were compared. Bleomycin-induced increases in lung weight, epithelial cell death, and inflammation were significantly greater in Nrf2-/- mice than in Nrf2+/+ mice. Indices of lung fibrosis (hydroxyproline content, collagen accumulation, fibrotic score, cell proliferation) were significantly greater in bleomycin-treated Nrf2-/- mice, compared with Nrf2+/+ mice. NRF2 expression and activity were elevated in Nrf2+/+ mice by bleomycin. Bleomycin caused greater up-regulation of several NRF2-inducible antioxidant enzyme genes and protein products in Nrf2+/+ mice compared with Nrf2-/- mice. Further, bleomycin-induced transcripts and protein levels of lung injury and fibrosis markers were significantly attenuated in Nrf2+/+ mice compared with Nrf2-/- mice. Results demonstrated that NRF2 has a critical role in protection against pulmonary fibrosis, presumably through enhancement of cellular antioxidant capacity. This study has important implications for the development of intervention strategies against fibrosis.

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Section: Discussionmentioning

confidence: 87%

The transcription factor NRF2 protects against pulmonary fibrosis

et al. 2004

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“…Bleomycin produces DNA strand breakages that are lung specific and can be stimulated with exposure to oxygen in mice (9). The DNA strand breakage by bleomycin can be inhibited in vitro by the addition of a variety of antioxidants, such as superoxide dismutase (10), glutathione (11), and dimethylurea (12).…”

mentioning

confidence: 99%

Attenuation of Bleomycin-Induced Pulmonary Fibrosis by a Catalytic Antioxidant Metalloporphyrin

Oury

Thakker²,

Ménache³

et al. 2001

Am J Respir Cell Mol Biol

128

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Oxidative stress plays an important role in the development of fibrotic responses in the lung. However, it is not clear whether inhibiting oxidative stress with antioxidants can attenuate fibrotic processes in the lung. The objective of these studies was to test whether the catalytic antioxidant porphyrin manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) could protect mice against bleomycin-induced lung fibrosis. A 10 mg/kg intraperitoneal dose of MnTBAP was established as safe and had a serum and lung half-life of 9.5 h in mice. Based on this data, four groups of mice were given one dose of bleomycin (3.2 U/kg, intratracheal) or saline and MnTBAP (5 mg/kg, intraperitoneal) or saline twice daily for 14 d. Lung fibrosis was assessed by measuring (1) lung hydroxyproline content as an index of collagen accumulation, (2) airway dysfunction by whole body plethysmography, and (3) histopathology. Bleomycin produced a 20% loss in body weight that was only 10% in the bleomycin/MnTBAP group. Bleomycin produced a twofold increase in hydroxyproline content that was decreased 23% by MnTBAP. Bleomycin produced a twofold increase in airway dysfunction that was also attenuated 30% by MnTBAP. Histopathologic analysis of the lungs of mice treated with bleomycin demonstrated a severe fibrotic response that was attenuated 28% by MnTBAP. Future studies on the oxidant mechanisms that MnTBAP is affecting in this bleomycin model of lung fibrosis may shed light on potential new therapeutic approaches for treating interstitial lung diseases.

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“…Single colonies of D7 cells [18] were inoculated in 20 9 3 ml YPD with and without 0.75 mM CoCl 2 and allowed to grow for 48 h at 30°C. Approximately 750 cells from each culture (based on OD 600 nm ) were plated on YPD plates and the number of red, pink, red-white, pink-white and red-pink twin sectored colonies was counted following incubation at 28°C for 6 days followed by incubation at 4°C for 2 days [19]. For acute exposure to CoCl 2 , 20 9 3 ml log phase cultures grown from single colonies were exposed to 0.75 mM CoCl 2 for 1 h, plating and subsequent incubation were as above.…”

Section: Rate Of Mitotic Recombinationmentioning

confidence: 99%

Homologous Recombination is Activated at Early Time Points Following Exposure to Cobalt Chloride Induced Hypoxic Conditions in Saccharomyces cerevisiae

2011

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DNA repair functions are essential for the maintenance of genetic integrity and are regulated in response to both environmental and chemical stressors in mammalian and yeast cells in culture. The inhibitory effect of limited O 2 availability on DNA repair functions in general and on homologous recombination (HR) in particular, correlates with increased chromosomal abnormalities in hypoxic cancer cells. Given the above, we have investigated the effects of CoCl 2 ,--a hypoxia mimetic agent on HR and genetic aberrations in Saccharomyces cerevisiae. Our studies demonstrate that both acute and chronic exposure to CoCl 2 activated HR and increased genetic aberrations in S. cerevisiae D7 cells. At early time points following addition of CoCl 2 to the growth media, cells were briefly arrested in the G1-S boundary concomitant with a transient increase in Rad52-GFP foci formation and induction of low levels of DNA damage. The mode of action of CoCl 2 is thus similar to that of DNA synthesis inhibitors, the later are known to induce HR and cause G1-S arrest. We propose that the activation of HR in the presence of the hypoxia mimetic agent may be attributed to the replication stress and/or DNA damage induced by the stressor.Keywords Saccharomyces cerevisiae Á Hypoxia mimetic Á Homologous recombination Á DNA damage Á G1-S arrest Intracellular DNA double-strand breaks (DSB) generated by exposure to ionizing radiation, chemotherapeutic drugs and reactive oxygen species, as well as during V(D)J recombination and immunoglobulin class switching are repaired by homologous recombination (HR) and nonhomologous end joining (NHEJ). Failure to repair DSBs results in various chromosomal abnormalities that may ultimately lead to neoplastic transformation [1]. In S. cerevisiae, HR is the major pathway for DNA double strand break repair (DSBR) and is carried out by members of the RAD52 epistasis group that include RAD52, RAD50, RAD51, RAD54, RAD55, RAD57, RAD59, MRE11 and XRS2 and requires extensive DNA sequence homology between the DNA molecules involved in recombination. HR is initiated by DSBs followed by 5 0 to 3 0 resection of the ends. The 3 0 ends thus formed are recombinogenic that bind Rad51 in an ATP dependent reaction and invades homologous template to initiate DNA replication by strand displacement. The inhibitory effect of RPA on Rad51 binding to DNA is overcome by Rad52. Broken ends are then joined by ligation leading to the formation of two Holliday junctions that are subsequently resolved to yield either crossover or non-crossover products [2]. DSBR by NHEJ requires little or no sequence homology and is carried out by the MRX complex along with Yku80, Yku70, DNA Pol4 and DNA ligase IV [3]. While DSB repair by HR is error-proof, that by NHEJ is an error-prone process.DNA replication and repair functions are regulated in response to environmental stress conditions in S. cerevisiae. Hypoxic stress results in transient down-regulation in the expression of MCB and SCB regulated genes required

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Bleomycin genotoxicity alteration by glutathione and cytochrome P-450 cellular content in respiratory proficient and deficient strains of Saccharomyces cerevisiae

Cited by 18 publications

References 28 publications

The transcription factor NRF2 protects against pulmonary fibrosis

The transcription factor NRF2 protects against pulmonary fibrosis

Attenuation of Bleomycin-Induced Pulmonary Fibrosis by a Catalytic Antioxidant Metalloporphyrin

Homologous Recombination is Activated at Early Time Points Following Exposure to Cobalt Chloride Induced Hypoxic Conditions in Saccharomyces cerevisiae

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