Effect of heme oxygenase-1 on the vulnerability of astrocytes and neurons to hemoglobin

Chen-Roetling, Jing; Regan, Raymond F.

doi:10.1016/j.bbrc.2006.09.036

Cited by 43 publications

(42 citation statements)

References 45 publications

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“…This novel finding suggests that hemin toxicity is due to other mechanisms such as membrane cation leakage, or to the breakdown products of hemin. A deeper understanding of hemin metabolism, and the roles of bilirubin and CO may help to elucidate why some studies find the actions of HO beneficial to cells (Benvenisti-Zarom and Regan, 2007;Chen-Roetling and Regan, 2006) while others find it detrimental (Koeppen et al, 2004;Wang and Dore, 2007). Investiga-tions of whether CO or bilirubin mediate hemin toxicity may aid the development of new therapeutic interventions for hemorrhagic stroke.…”

Section: Discussionmentioning

confidence: 97%

The metabolism and toxicity of hemin in astrocytes

Dang

Bishop

Dringen

et al. 2011

Glia

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Hemin is cytotoxic, and contributes to the brain damage that accompanies hemorrhagic stroke. In order to better understand the basis of hemin toxicity in astrocytes, the present study quantified hemin metabolism and compared it to the pattern of cell death. Heme oxygenase-1 (HO-1) expression was first evident after 2 h incubation with hemin, with maximal expression being observed by 24 h. Despite the induction of HO-1, it was found that the proportion of hemin metabolized by astrocytes remained fairly constant throughout the 24 h period, with 70-80% of intracellular hemin remaining intact. A period of cell loss began after 2 h exposure to hemin, which gradually increased in severity to reach a maximum by 24 h. This cell loss could not be attenuated by the iron chelator, 1,10-phenanthroline, or by several antioxidant compounds (Trolox, N-acetyl-L-cysteine and N-tert-butyl-α-phenylnitrone), indicating that the mechanism of hemin toxicity does not involve iron. While these results make it unlikely that hemin toxicity is due to interactions with endogenous H(2)O(2), hemin toxicity was increased in the presence of supraphysiological levels of H(2)O(2) and this increase was ameliorated by PHEN, indicating that the iron released from hemin can be toxic under some pathological conditions. However, when H(2)O(2) is present at physiological levels, the toxicity of hemin appears to be caused by other mechanisms that may involve bilirubin and carbon monoxide in this model system.

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Section: Discussionmentioning

confidence: 97%

The metabolism and toxicity of hemin in astrocytes

Dang

Bishop

Dringen

et al. 2011

Glia

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“…While this protective mechanism may be highly relevant to neurons and perhaps other cell types (Doré et al, 1999), prior studies in astrocytes have demonstrated that exogenous bilirubin has no effect on heme-mediated oxidative injury (Regan et al, 2000;Chen-Roetling and Regan, 2006). Although bilirubin is clearly a potent antioxidant (Stocker et al, 1987), its efficacy in astrocytes may be specifically limited by two mechanisms: rapid mitochondrial catabolism and rapid export from cells via multi-drug resistance protein-1 (Hansen and Allen, 1997;Gennuso et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with the benefit provided by HO in ischemia and trauma models (Doré et al, 1999;Chang et al, 2003), HO-1 knockout astrocytes were more vulnerable to Hb or hemin (Chen-Roetling et al, 2005;Chen-Roetling and Regan, 2006), while increasing astrocyte expression by genetic or pharmacologic means was protective (Teng et al, 2004;. Putative protective mechanisms include the antioxidant effect of bilirubin production (Doré et al, 1999), and also the conversion of a lipid soluble oxidant, hemin, to iron, which is then sequestered in ferritin (Balla et al, 1992).…”

Section: Introductionmentioning

confidence: 87%

“…However, it increases significantly in CNS cells exposed to micromolar concentrations of extracellular Hb or hemin (Chen-Roetling et al, 2005;Chen-Roetling and Regan, 2006), suggesting that endogenous catabolic mechanisms may be insufficient to maintain homeostasis in cells adjacent to an intracerebral hematoma. Heme breakdown is mediated by the heme oxygenases (HO), which catalyze the rate-limiting step in its conversion to bilirubin, carbon monoxide, and iron.…”

Section: Introductionmentioning

confidence: 99%

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Astrocyte-specific heme oxygenase-1 hyperexpression attenuates heme-mediated oxidative injury

Benvenisti-Zarom

Regan

2007

Neurobiology of Disease

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In prior studies, we have observed that HO activity protects astrocytes from heme-mediated injury, but paradoxically increases neuronal injury. In this study, we tested the hypothesis that an adenovirus encoding the human HO-1 gene driven by an enhanced glial fibrillary acidic protein promoter (Ad-GFAP-HO-1) would increase HO-1 expression selectively in astrocytes, and provide cytoprotection. Treatment with 100 MOI Ad-GFAP-HO-1 for 24h resulted in HO-1 expression that was 6.4-fold higher in cultured primary astrocytes than in neurons. Astrocyte HO activity was increased by approximately fourfold over baseline, which was sufficient to reduce cell death after 24 h hemin exposure by 60%, as assessed by both MTT and LDH release assays. A similar reduction in cell protein oxidation, quantified by carbonyl assay, was also observed. These results suggest that HO-1 transgene expression regulated by an enhanced GFAP promoter selectively increases HO-1 expression in astrocytes, and is cytoprotective. Further investigation of this strategy in vivo is warranted.

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“…Bioactivity of Compounds 1-9 Compounds 1-9 were screened against breast (MCF-7), colon (CKCO-1), lung (H-1299) and skin (HT-144) human cancer cell lines using MTT assay 11) and found to exhibit modest cytotoxcity against the aforementioned cell lines. For breast cancer cell lines (MCF-7), the IC 50 values of compounds 1, 2, 3, 4, 5, 6, 7, 8 and 9 were found to be 48, 43, 35, 46, 28, 45, 55, 67 and 42 mM, respectively.…”

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confidence: 99%

Novel Microbial Transformations of Sclareolide

Ata

Conci

Betteridge

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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Microorganisms such as bacteria and fungi are capable to perform regio-and stereo-selective reactions on organic compounds. The different possible microbial reactions include oxidation, reduction, and degradative reactions.1) Many of these reactions allow the production of new compounds that would be extremely difficult to synthesize chemically. 2)For instance hydroxylation at inactivated methylene is a very common microbial reaction.3) The results obtained from microbial transformations are quite often similar to those obtained from mammal biotransformations.4) The parallel relationship between mammals and microbial transformations is due to the fact that many fungi, such as the filamentous fungus Cunninghamella, utilize the enzyme cytochrome P-450 monoxygenase in the metabolism of xenobiotics.5) This enzyme system is analogous to the enzyme system used by mammals, allowing microbial transformations to be used successfully as in vitro models for mammalian drug metabolism.6) A lead bioactive compounds can also be generated through microbial transformations of natural products. The metabolic products often have improved bioactivity with minimal toxicity compared to the parent natural product. 7)In our continuing effort to discover new bioactive natural products, we decided to do biotransformation studies of sclareolide (1) using whole cell cultures of different fungi. Sclareolide (1) is a minor constituent of the vascular plant Arnica angustifolia and is commercially available.8) Compound 1 has shown modest cytotoxcity against breast (MCF-7), colon (CKCO-1), lung (H-1299) and skin (HT-144) human cancer cell lines. 8) For this project, we screened five different fungi, namely Mucor plumbeus (ATCC 4740), Cunninghamella blakesleeana (ATCC 9245), Cunninghamella echinulata (ATCC 9244), Curvularia lunata (ATCC 12017) and Aspergillus niger (ATCC 1004), for their capability to metabolize compound 1. During these biotransformation experiments, we discovered that Cunninghamella blakesleeana (ATCC 9245) metabolized compound 1 into O 6 -sclareolide (2), 3b,6a-dihydroxysclareolide (3) and 9-hydroxysclareolide (4), along with three known metabolites, 1b,3b-dihydroxysclareolide (5), 3-oxosclareolide (6) and 3b-hydroxysclareolide (7). Biotransformation experiments of compound 1 with Cunninghamella echinulata (ATCC 9244) also yielded two new compounds, 5-hydroxysclareolide (8), and 7b-hydroxysclareolide (9) along with two known compounds 5 and 7. NMR spectroscopic methods were used to establish the structures of compounds 2-9. Compounds 2-9 were found to exhibit modest acetylcholinesterase inhibitory activity. To the best of our knowledge, biotransformation of 1 into 2 is a novel ether-forming microbial reaction. In this paper we report the biotransformations of 1 and structure elucidation of compounds 2-9 as well as their bioactivity data. Results and DiscussionOur first biotransformed product, O 6-sclareolide was obtained as a colorless gum. Its UV spectrum showed terminal absorption indicating the lack of a conjugated p system...

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Effect of heme oxygenase-1 on the vulnerability of astrocytes and neurons to hemoglobin

Cited by 43 publications

References 45 publications

The metabolism and toxicity of hemin in astrocytes

The metabolism and toxicity of hemin in astrocytes

Astrocyte-specific heme oxygenase-1 hyperexpression attenuates heme-mediated oxidative injury

Novel Microbial Transformations of Sclareolide

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