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Shinya Toyokuni - One of the best experts on this subject based on the ideXlab platform.

  • histological detection of catalytic ferrous Iron with the selective turn on fluorescent probe rhonox 1 in a fenton reaction based rat renal carcinogenesis model
    Free Radical Research, 2014
    Co-Authors: Takahiro Mukaide, Yuka Hattori, Nobuaki Misawa, Satomi Funahashi, Li Jiang, Tasuku Hirayama, Hideko Nagasawa, Shinya Toyokuni
    Abstract:

    AbstractIron overload of a chronic nature has been associated with a wide variety of human diseases, including infection, carcinogenesis, and atherosclerosis. Recently, a highly specific turn-on fluorescent probe (RhoNox-1) specific to labile ferrous Iron [Fe(II)], but not to labile ferric Iron [Fe(III)], was developed. The evaluation of Fe(II) is more important than Fe(III) in vivo in that Fe(II) is an initiating component of the Fenton reaction. In this study, we applied this probe to frozen sections of an established Fenton reaction-based rat renal carcinogenesis model with an Iron Chelate, ferric nitrilotriacetate (Fe-NTA), in which catalytic Iron induces the Fenton reaction specifically in the renal proximal tubules, presumably after Iron reduction. Notably, this probe reacted with Fe(II) but with neither Fe(II)-NTA, Fe(III) nor Fe(III)-NTA in vitro. Prominent red fluorescent color was explicitly observed in and around the lumina of renal proximal tubules 1 h after an intraperitoneal injection of 10–...

  • Lipid Peroxidation Generates Body Odor Component trans-2-Nonenal Covalently Bound to Protein in Vivo
    Journal of Biological Chemistry, 2010
    Co-Authors: Kousuke Ishino, Chika Wakita, Takahiro Shibata, Shinya Toyokuni, Sachiko Machida, Shun Matsuda, Tomonari Matsuda, Koji Uchida
    Abstract:

    trans-2-Nonenal is an unsaturated aldehyde with an unpleasant greasy and grassy odor endogenously generated during the peroxidation of polyunsaturated fatty acids. 2-Nonenal covalently modified human serum albumin through a reaction in which the aldehyde preferentially reacted with the lysine residues. Modified proteins were immunogenic, and a specific monoclonal antibody (mAb) 27Q4 that cross-reacted with the protein covalently modified with 2-nonenal was raised from mouse. To verify the presence of the protein-bound 2-nonenal in vivo, the mAb 27Q4 against the 2-nonenal-modified keyhole limpet hemocyanin was raised. It was found that a novel 2-nonenal-lysine adduct, cis- and trans-Nϵ-3-[(hept-1-enyl)-4-hexylpyridinium]lysine (HHP-lysine), constitutes an epitope of the antibody. The immunoreactive materials with mAb 27Q4 were detected in the kidney of rats exposed to ferric nitrilotriacetate, an Iron Chelate that induces free radical-mediated oxidative tissue damage. Using high performance liquid chromatography with on-line electrospray ionization tandem mass spectrometry, we also established a highly sensitive method for detection of the cis- and trans-HHP-lysine and confirmed that the 2-nonenal-lysine adducts were indeed formed during the lipid peroxidation-mediated modification of protein in vitro and in vivo. Furthermore, we examined the involvement of the scavenger receptor lectin-like oxidized low density lipoprotein receptor-1 in the recognition of 2-nonenal-modified proteins and established that the receptor recognized the HHP-lysine adducts as a ligand.

  • deletion and single nucleotide substitution at g c in the kidney of gpt delta transgenic mice after ferric nitrilotriacetate treatment
    Cancer Science, 2006
    Co-Authors: Li Jiang, Yi Zhong, Shinya Akatsuka, Yuting Liu, Khokon Kuma Dutta, Wenhua Lee, Janice Onuki, Kenichi Masumura, Takehiko Nohmi, Shinya Toyokuni
    Abstract:

    An Iron Chelate, ferric nitrilotriacetate (Fe-NTA), induces oxidative renal proximal tubular damage that subsequently leads to a high incidence of renal cell carcinoma in rodents, presenting an intriguing model of free radical-induced carcinogenesis. In the present study, we used gpt delta transgenic mice, which allow efficient detection of point mutations and deletions in vivo, to evaluate the mutation spectra, in association with the formation of 8-oxoguanine and acrolein-modified adenine during the first 3 weeks of carcinogenesis. Immunohistochemical analysis revealed the highest levels of 8-oxoguanine and acrolein-modifed adenine in the renal proximal tubules after 1 week of repeated administration. DNA immunoprecipitation and quantitative polymerase chain reaction analysis showed that the relative abundance of 8-oxoguanine and acrolein-modified adenine at the gpt reporter gene were increased at the first week in the kidney. Similarly, in both 6-thioguanine and Spi− selections performed on the renal specimens after Fe-NTA administration, the mutant frequencies were increased in the Fe-NTA-treated mice at the first week. Further analyzes of 79 mutant clones and 93 positive plaques showed a high frequency of G:C pairs as preferred targets for point mutation, notably G:C to C:G transversion-type mutation followed by deletion, and of large-size (>1 kilobase) deletions with short homologous sequences in proximity to repeated sequences at the junctions. The results demonstrate that the Iron-based Fenton reaction is mutagenic in vivo in the renal tubular cells and induces characteristic mutations. (Cancer Sci 2006; 97: 1159–1167)

  • formation of acrolein derived 2 deoxyadenosine adduct in an Iron induced carcinogenesis model
    Journal of Biological Chemistry, 2003
    Co-Authors: Yoshichika Kawai, Shinya Toyokuni, Atsunori Furuhata, Yasuaki Aratani, Koji Uchida
    Abstract:

    Abstract Acrolein is a representative carcinogenic aldehyde found ubiquitously in the envIronment and formed endogenously through oxidation reactions, such as lipid peroxidation and myeloperoxidase-catalyzed amino acid oxidation. It shows facile reactivity toward DNA to form an exocyclic DNA adduct. To verify the formation of acrolein-derived DNA adduct under oxidative stress in vivo, we raised a novel monoclonal antibody (mAb21) against the acrolein-modified DNA and found that the antibody most significantly recognized an acrolein-modified 2′ -deoxyadenosine. On the basis of chemical and spectroscopic evidence, the major antigenic product of mAb21 was the 1,N6-propano-2′ -deoxyadenosine adduct. The exposure of rat liver epithelial RL34 cells to acrolein resulted in a significant accumulation of the acrolein-2′ -deoxyadenosine adduct in the nuclei. Formation of this adduct under oxidative stress in vivo was immunohistochemically examined in rats exposed to ferric nitrilotriacetate, a carcinogenic Iron Chelate that specifically induces oxidative stress in the kidneys of rodents. It was observed that the acrolein-2′ -deoxyadenosine adduct was formed in the nuclei of the proximal tubular cells, the target cells of this carcinogenesis model. The same cells were stained with a monoclonal antibody 5F6 that recognizes an acrolein-lysine adduct, by which cytosolic accumulation of acrolein-modified proteins appeared. Similar results were also obtained from myeloperoxidase knockout mice exposed to the Iron complex, suggesting that the myeloperoxidase-catalyzed oxidation system might not be essential for the generation of acrolein in this experimental animal carcinogenesis model. The data obtained in this study suggest that the formation of a carcinogenic aldehyde through lipid peroxidation may be causally involved in the pathophysiological effects associated with oxidative stress.

  • oxidative stress response in Iron induced renal carcinogenesis acute nephrotoxicity mediates the enhanced expression of glutathione s transferase yp isozyme
    Archives of Biochemistry and Biophysics, 1996
    Co-Authors: Aya Fukuda, Shinya Toyokuni, Toshihiko Osawa, Hiroaki Oda, Kimihiko Satoh, Koji Uchida
    Abstract:

    Abstract An Iron Chelate, ferric nitrilotriacetate (Fe-NTA), induces acute renal proximal tubular necrosis, a consequence of free radical-mediated oxidative tissue damage, that eventually leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we investigated the free radical-induced oxidative stress response in this carcinogenesis model, focusing on the expression of glutathione S -transferases (GSTs) which catalyze the conjugation of reactive chemicals with glutathione and play an important role in protecting cells. A single intraperitoneal Fe-NTA treatment (15 mg Fe/kg body weight) induced a rapid oxidative stress, which was monitored by the accumulation of lipid peroxidation products and the loss of sulfhydryl contents in the kidneys, resulting in a 30% reduction of GST activity 1 h after an Fe-NTA treatment. The enzyme activity returned to the control level after 16 h. The immunoblot analysis of GST isozymes demonstrated that the level of α-class GSTs (GST-Ya and GST-Yc) and π-class GST (GST-Yp), major GST isozymes constitutively produced in the kidney, decreased immediately within 1 h of the Fe-NTA treatment. The onset of the recovery of GST-Yp protein levels was detected 3 h after the Fe-NTA treatment. The enhanced production of GST-Yp in gene expression was evident in the drastic elevation of mRNA levels and these increases coincided with a substantial rise in the GST activity and protein levels. The α-class GSTs were not inducible by treatment with Fe-NTA. The immunohistochemical analysis demonstrated that the expression of GST-Yp was strongly induced in the regenerating proximal tubular cells. A steady accumulation of GST-Yp protein was observed in the subacute toxicity experiments with multiple injections of Fe-NTA. These results suggest that the enhanced expression of GST-Yp is important in mediating cell repairs or increasing the resistance to subsequent injury.

Koji Uchida - One of the best experts on this subject based on the ideXlab platform.

  • Lipid Peroxidation Generates Body Odor Component trans-2-Nonenal Covalently Bound to Protein in Vivo
    Journal of Biological Chemistry, 2010
    Co-Authors: Kousuke Ishino, Chika Wakita, Takahiro Shibata, Shinya Toyokuni, Sachiko Machida, Shun Matsuda, Tomonari Matsuda, Koji Uchida
    Abstract:

    trans-2-Nonenal is an unsaturated aldehyde with an unpleasant greasy and grassy odor endogenously generated during the peroxidation of polyunsaturated fatty acids. 2-Nonenal covalently modified human serum albumin through a reaction in which the aldehyde preferentially reacted with the lysine residues. Modified proteins were immunogenic, and a specific monoclonal antibody (mAb) 27Q4 that cross-reacted with the protein covalently modified with 2-nonenal was raised from mouse. To verify the presence of the protein-bound 2-nonenal in vivo, the mAb 27Q4 against the 2-nonenal-modified keyhole limpet hemocyanin was raised. It was found that a novel 2-nonenal-lysine adduct, cis- and trans-Nϵ-3-[(hept-1-enyl)-4-hexylpyridinium]lysine (HHP-lysine), constitutes an epitope of the antibody. The immunoreactive materials with mAb 27Q4 were detected in the kidney of rats exposed to ferric nitrilotriacetate, an Iron Chelate that induces free radical-mediated oxidative tissue damage. Using high performance liquid chromatography with on-line electrospray ionization tandem mass spectrometry, we also established a highly sensitive method for detection of the cis- and trans-HHP-lysine and confirmed that the 2-nonenal-lysine adducts were indeed formed during the lipid peroxidation-mediated modification of protein in vitro and in vivo. Furthermore, we examined the involvement of the scavenger receptor lectin-like oxidized low density lipoprotein receptor-1 in the recognition of 2-nonenal-modified proteins and established that the receptor recognized the HHP-lysine adducts as a ligand.

  • formation of acrolein derived 2 deoxyadenosine adduct in an Iron induced carcinogenesis model
    Journal of Biological Chemistry, 2003
    Co-Authors: Yoshichika Kawai, Shinya Toyokuni, Atsunori Furuhata, Yasuaki Aratani, Koji Uchida
    Abstract:

    Abstract Acrolein is a representative carcinogenic aldehyde found ubiquitously in the envIronment and formed endogenously through oxidation reactions, such as lipid peroxidation and myeloperoxidase-catalyzed amino acid oxidation. It shows facile reactivity toward DNA to form an exocyclic DNA adduct. To verify the formation of acrolein-derived DNA adduct under oxidative stress in vivo, we raised a novel monoclonal antibody (mAb21) against the acrolein-modified DNA and found that the antibody most significantly recognized an acrolein-modified 2′ -deoxyadenosine. On the basis of chemical and spectroscopic evidence, the major antigenic product of mAb21 was the 1,N6-propano-2′ -deoxyadenosine adduct. The exposure of rat liver epithelial RL34 cells to acrolein resulted in a significant accumulation of the acrolein-2′ -deoxyadenosine adduct in the nuclei. Formation of this adduct under oxidative stress in vivo was immunohistochemically examined in rats exposed to ferric nitrilotriacetate, a carcinogenic Iron Chelate that specifically induces oxidative stress in the kidneys of rodents. It was observed that the acrolein-2′ -deoxyadenosine adduct was formed in the nuclei of the proximal tubular cells, the target cells of this carcinogenesis model. The same cells were stained with a monoclonal antibody 5F6 that recognizes an acrolein-lysine adduct, by which cytosolic accumulation of acrolein-modified proteins appeared. Similar results were also obtained from myeloperoxidase knockout mice exposed to the Iron complex, suggesting that the myeloperoxidase-catalyzed oxidation system might not be essential for the generation of acrolein in this experimental animal carcinogenesis model. The data obtained in this study suggest that the formation of a carcinogenic aldehyde through lipid peroxidation may be causally involved in the pathophysiological effects associated with oxidative stress.

  • oxidative stress response in Iron induced renal carcinogenesis acute nephrotoxicity mediates the enhanced expression of glutathione s transferase yp isozyme
    Archives of Biochemistry and Biophysics, 1996
    Co-Authors: Aya Fukuda, Shinya Toyokuni, Toshihiko Osawa, Hiroaki Oda, Kimihiko Satoh, Koji Uchida
    Abstract:

    Abstract An Iron Chelate, ferric nitrilotriacetate (Fe-NTA), induces acute renal proximal tubular necrosis, a consequence of free radical-mediated oxidative tissue damage, that eventually leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we investigated the free radical-induced oxidative stress response in this carcinogenesis model, focusing on the expression of glutathione S -transferases (GSTs) which catalyze the conjugation of reactive chemicals with glutathione and play an important role in protecting cells. A single intraperitoneal Fe-NTA treatment (15 mg Fe/kg body weight) induced a rapid oxidative stress, which was monitored by the accumulation of lipid peroxidation products and the loss of sulfhydryl contents in the kidneys, resulting in a 30% reduction of GST activity 1 h after an Fe-NTA treatment. The enzyme activity returned to the control level after 16 h. The immunoblot analysis of GST isozymes demonstrated that the level of α-class GSTs (GST-Ya and GST-Yc) and π-class GST (GST-Yp), major GST isozymes constitutively produced in the kidney, decreased immediately within 1 h of the Fe-NTA treatment. The onset of the recovery of GST-Yp protein levels was detected 3 h after the Fe-NTA treatment. The enhanced production of GST-Yp in gene expression was evident in the drastic elevation of mRNA levels and these increases coincided with a substantial rise in the GST activity and protein levels. The α-class GSTs were not inducible by treatment with Fe-NTA. The immunohistochemical analysis demonstrated that the expression of GST-Yp was strongly induced in the regenerating proximal tubular cells. A steady accumulation of GST-Yp protein was observed in the subacute toxicity experiments with multiple injections of Fe-NTA. These results suggest that the enhanced expression of GST-Yp is important in mediating cell repairs or increasing the resistance to subsequent injury.

  • formation of 4 hydroxy 2 nonenal modified proteins in the renal proximal tubules of rats treated with a renal carcinogen ferric nitrilotriacetate
    Proceedings of the National Academy of Sciences of the United States of America, 1994
    Co-Authors: Shinya Toyokuni, Koji Uchida, Keisei Okamoto, Yukari Hattorinakakuki, Hiroshi Hiai, E R Stadtman
    Abstract:

    Abstract An Iron Chelate, ferric nitrilotriacetate (Fe-NTA), induces proximal tubular necrosis, a consequence of lipid peroxidation, that finally leads to a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation as monitored by formation of thiobarbituric acid-reactive substances and free 4-hydroxy-2-nonenal (HNE) was observed in the kidney homogenates of rats treated with Fe-NTA. Based on the fact that HNE is capable of reacting with cellular proteins, we attempted to detect the localization of HNE-modified proteins in rat kidney tissues with an immunohistochemical procedure. By means of an immunohistochemical technique using polyclonal antibody against the HNE-modified proteins, it was shown that HNE-modified proteins are formed in the target cells of this carcinogenesis model. HNE-modified proteins were detected in the renal proximal tubules 1 hr after i.p. administration of Fe-NTA (15 mg of Iron per kg). Intense positivity was found in the cells with degeneration. After 6 hr, the level of HNE-protein conjugates decreased due to the subsequent necrosis. The intensity of the immunochemical reaction with HNE-modified proteins increased in parallel with an increase in the amounts of thiobartituric acid-reactive substances and free HNE that were found. Furthermore, histochemical detection of aldehydes by cold Schiff's reagent demonstrated that location of aldehydes was identical to that of the HNE-modified proteins determined by immunohistochemical procedures. It would thus appear that the production of HNE, a genotoxic and mutagenic aldehyde, and its reaction with proteins may play a role in Fe-NTA-induced renal carcinogenesis.

Rex M Tyrrell - One of the best experts on this subject based on the ideXlab platform.

  • the heme synthesis and degradation pathways role in oxidant sensitivity heme oxygenase has both pro and antioxidant properties
    Free Radical Biology and Medicine, 2000
    Co-Authors: Stefan W Ryter, Rex M Tyrrell
    Abstract:

    The heme biosynthetic and catabolic pathways generate pro- and antioxidant compounds, and consequently, influence cellular sensitivity to oxidants. Heme precursors (delta-aminolevulinic acid, porphyrins) generate reactive oxygen species (ROS), from autoxidation and photochemical reactions, respectively. Heme, an essential Iron Chelate, serves in respiration, oxygen transport, detoxification, and signal transduction processes. The potential toxicity of heme and hemoproteins points to a critical role for heme degradation in cellular metabolism. The heme oxygenases (HOs) provide this function and participate in cellular defense. This hypothesis emerges from the observation that the activation of HO-1 is an ubiquitous cellular response to oxidative stress. The reaction products of HO activity, biliverdin, and its subsequent metabolite bilirubin, have antioxidant properties. Furthermore, Iron released from HO activity stimulates ferritin synthesis, which ultimately provides an Iron detoxification mechanism that may account for long-term cytoprotection observed after HO induction. However, such models have overlooked potential pro-oxidant consequences of HO activity. The HO reaction releases Iron, which could be involved in deleterious reactions that compete with Iron reutilization and sequestration pathways. Indeed, the induction of HO activity may have both pro- and antioxidant sequelae depending on cellular redox potential, and the metabolic fate of the heme Iron.

  • the heme synthesis and degradation pathways role in oxidant sensitivity heme oxygenase has both pro and antioxidant properties
    Free Radical Biology and Medicine, 2000
    Co-Authors: Stefan W Ryter, Rex M Tyrrell
    Abstract:

    Abstract The heme biosynthetic and catabolic pathways generate pro- and antioxidant compounds, and consequently, influence cellular sensitivity to oxidants. Heme precursors (δ-aminolevulinic acid, porphyrins) generate reactive oxygen species (ROS), from autoxidation and photochemical reactions, respectively. Heme, an essential Iron Chelate, serves in respiration, oxygen transport, detoxification, and signal transduction processes. The potential toxicity of heme and hemoproteins points to a critical role for heme degradation in cellular metabolism. The heme oxygenases (HOs) provide this function and participate in cellular defense. This hypothesis emerges from the observation that the activation of HO-1 is an ubiquitous cellular response to oxidative stress. The reaction products of HO activity, biliverdin, and its subsequent metabolite bilirubin, have antioxidant properties. Furthermore, Iron released from HO activity stimulates ferritin synthesis, which ultimately provides an Iron detoxification mechanism that may account for long-term cytoprotection observed after HO induction. However, such models have overlooked potential pro-oxidant consequences of HO activity. The HO reaction releases Iron, which could be involved in deleterious reactions that compete with Iron reutilization and sequestration pathways. Indeed, the induction of HO activity may have both pro- and antioxidant sequelae depending on cellular redox potential, and the metabolic fate of the heme Iron.

Naoko K Nishizawa - One of the best experts on this subject based on the ideXlab platform.

  • Iron transport and its regulation in plants
    Free Radical Biology and Medicine, 2019
    Co-Authors: Takanori Kobayashi, Tomoko Nozoye, Naoko K Nishizawa
    Abstract:

    Iron is an essential element for plants as well as other organisms, functioning in various cellular processes, including respiration, chlorophyll biosynthesis, and photosynthesis. Plants take up Iron from soil in which Iron solubility is extremely low especially under aerobic conditions at high-pH range. Therefore, plants have evolved efficient Iron-uptake mechanisms. Because Iron is prone to being precipitated and excess ionic Iron is cytotoxic, plants also have sophisticated internal Iron-transport mechanisms. These transport mechanisms comprise Iron chelators including nicotianamine, mugineic acid family phytosiderophores and citrate, and various types of transporters of these chelators, Iron-Chelate complexes, or free Iron ions. To maintain Iron homeostasis, plants have developed mechanisms for regulating gene expression in response to Iron availability. Expression of various genes involved in Iron uptake and translocation is induced under Iron deficiency by transcription factor networks and is negatively regulated by the ubiquitin ligase HRZ/BTS. This response is deduced to be mediated by cellular Iron sensing as well as long-distance Iron signaling. The ubiquitin ligase HRZ/BTS is a candidate intracellular Iron sensor because it binds to Iron and zinc, and its activity is affected by Iron availability. The Iron-excess response of plants is thought to be partially independent of the Iron-deficiency response. In this review, we summarize and discuss extant knowledge of plant Iron transport and its regulation.

  • the Iron Chelate transporter osysl9 plays a role in Iron distribution in developing rice grains
    Plant Molecular Biology, 2017
    Co-Authors: Takeshi Senoura, Takanori Kobayashi, Naoko K Nishizawa, Emi Sakashita, Michiko Takahashi, May Sann Aung, Hiroshi Masuda, Hiromi Nakanishi
    Abstract:

    Rice OsYSL9 is a novel transporter for Fe(II)-nicotianamine and Fe(III)-deoxymugineic acid that is responsible for internal Iron transport, especially from endosperm to embryo in developing seeds. Metal chelators are essential for safe and efficient metal translocation in plants. Graminaceous plants utilize specific ferric Iron chelators, mugineic acid family phytosiderophores, to take up sparingly soluble Iron from the soil. Yellow Stripe 1-Like (YSL) family transporters are responsible for transport of metal-phytosiderophores and structurally similar metal-nicotianamine complexes. Among the rice YSL family members (OsYSL) whose functions have not yet been clarified, OsYSL9 belongs to an uncharacterized subgroup containing highly conserved homologs in graminaceous species. In the present report, we showed that OsYSL9 localizes mainly to the plasma membrane and transports both Iron(II)-nicotianamine and Iron(III)-deoxymugineic acid into the cell. Expression of OsYSL9 was induced in the roots but repressed in the nonjuvenile leaves in response to Iron deficiency. In Iron-deficient roots, OsYSL9 was induced in the vascular cylinder but not in epidermal cells. Although OsYSL9-knockdown plants did not show a growth defect under Iron-sufficient conditions, these plants were more sensitive to Iron deficiency in the nonjuvenile stage compared with non-transgenic plants. At the grain-filling stage, OsYSL9 expression was strongly and transiently induced in the scutellum of the embryo and in endosperm cells surrounding the embryo. The Iron concentration was decreased in embryos of OsYSL9-knockdown plants but was increased in residual parts of brown seeds. These results suggested that OsYSL9 is involved in Iron translocation within plant parts and particularly Iron translocation from endosperm to embryo in developing seeds.

Stefan W Ryter - One of the best experts on this subject based on the ideXlab platform.

  • the heme synthesis and degradation pathways role in oxidant sensitivity heme oxygenase has both pro and antioxidant properties
    Free Radical Biology and Medicine, 2000
    Co-Authors: Stefan W Ryter, Rex M Tyrrell
    Abstract:

    The heme biosynthetic and catabolic pathways generate pro- and antioxidant compounds, and consequently, influence cellular sensitivity to oxidants. Heme precursors (delta-aminolevulinic acid, porphyrins) generate reactive oxygen species (ROS), from autoxidation and photochemical reactions, respectively. Heme, an essential Iron Chelate, serves in respiration, oxygen transport, detoxification, and signal transduction processes. The potential toxicity of heme and hemoproteins points to a critical role for heme degradation in cellular metabolism. The heme oxygenases (HOs) provide this function and participate in cellular defense. This hypothesis emerges from the observation that the activation of HO-1 is an ubiquitous cellular response to oxidative stress. The reaction products of HO activity, biliverdin, and its subsequent metabolite bilirubin, have antioxidant properties. Furthermore, Iron released from HO activity stimulates ferritin synthesis, which ultimately provides an Iron detoxification mechanism that may account for long-term cytoprotection observed after HO induction. However, such models have overlooked potential pro-oxidant consequences of HO activity. The HO reaction releases Iron, which could be involved in deleterious reactions that compete with Iron reutilization and sequestration pathways. Indeed, the induction of HO activity may have both pro- and antioxidant sequelae depending on cellular redox potential, and the metabolic fate of the heme Iron.

  • the heme synthesis and degradation pathways role in oxidant sensitivity heme oxygenase has both pro and antioxidant properties
    Free Radical Biology and Medicine, 2000
    Co-Authors: Stefan W Ryter, Rex M Tyrrell
    Abstract:

    Abstract The heme biosynthetic and catabolic pathways generate pro- and antioxidant compounds, and consequently, influence cellular sensitivity to oxidants. Heme precursors (δ-aminolevulinic acid, porphyrins) generate reactive oxygen species (ROS), from autoxidation and photochemical reactions, respectively. Heme, an essential Iron Chelate, serves in respiration, oxygen transport, detoxification, and signal transduction processes. The potential toxicity of heme and hemoproteins points to a critical role for heme degradation in cellular metabolism. The heme oxygenases (HOs) provide this function and participate in cellular defense. This hypothesis emerges from the observation that the activation of HO-1 is an ubiquitous cellular response to oxidative stress. The reaction products of HO activity, biliverdin, and its subsequent metabolite bilirubin, have antioxidant properties. Furthermore, Iron released from HO activity stimulates ferritin synthesis, which ultimately provides an Iron detoxification mechanism that may account for long-term cytoprotection observed after HO induction. However, such models have overlooked potential pro-oxidant consequences of HO activity. The HO reaction releases Iron, which could be involved in deleterious reactions that compete with Iron reutilization and sequestration pathways. Indeed, the induction of HO activity may have both pro- and antioxidant sequelae depending on cellular redox potential, and the metabolic fate of the heme Iron.