Human Lymphocyte Heme Oxygenase 1 as a Response Biomarker to Inorganic Arsenic

Menzel, Daniel B.; Rasmussen, Ronald E.; Lee, E.; Meacher, Dianne; Said, Boctor; Hamadeh, Hisham K.; Vargas, M.; Greene, Howard L.; Roth, Randy Neal

doi:10.1006/bbrc.1998.9363

Cited by 61 publications

(34 citation statements)

References 8 publications

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“…We further showed that hydroxyl radicals, generated through a superoxide-mediated process involving hydrogen peroxide, play an important role in mediating the genotoxic effects of arsenic (13). These findings are consistent with the reports stipulating the functional role of oxidants in mediating the biological effects of arsenite by linking glutathione content (14), heme oxygenase (15,16), oxidative DNA damage (12,17), and metallothionine (18) to the end points being examined. However, the origin of these oxyradical species and the pathways involved in the generation of other secondary radical species are not known.…”

Section: Introductionsupporting

confidence: 88%

Mitochondrial Damage Mediates Genotoxicity of Arsenic in Mammalian Cells

Liu¹,

et al. 2005

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Arsenic is an important environmental carcinogen that affects millions of people worldwide through contaminated water supplies. For decades, arsenic was considered a nongenotoxic carcinogen. Using the highly sensitive A L mutation assay, we previously showed that arsenic is, indeed, a potent gene and chromosomal mutagen and that its effects are mediated through the induction of reactive oxygen species. However, the origin of these radicals and the pathways involved are not known. Here we show that mitochondrial damage plays a crucial role in arsenic mutagenicity. Treatment of enucleated cells with arsenic followed by rescue fusion with karyoplasts from controls resulted in significant mutant induction. In contrast, treatment of mitochondrial DNA-depleted (R 0 ) cells produced few or no mutations. Mitochondrial damage can lead to the release of superoxide anions, which then react with nitric oxide to produce the highly reactive peroxynitrites. The mutagenic damage was dampened by the nitric oxide synthase inhibitor, N G -methyl-L-arginine. These data illustrate that mitochondria are a primary target in arsenic-induced genotoxic response and that a better understanding of the mutagenic/carcinogenic mechanism of arsenic should provide a basis for better interventional approach in both treatment and prevention of arsenic-induced cancer. (Cancer Res 2005; 65(8): 3236-42)

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Section: Introductionsupporting

confidence: 88%

Mitochondrial Damage Mediates Genotoxicity of Arsenic in Mammalian Cells

Liu¹,

et al. 2005

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“…The upregulation of aminolevulinate synthetase 1, ferritin heavy polypeptide 1, and heme oxygenase 1 suggests an increase in heme synthesis and deregulation of iron homeostasis. The induction of heme oxygenase 1 detected in this study has been suggested as a response biomarker for arsenite exposure (40) and an indicator for oxidative stress (5,47). Heme oxygenase 1 is responsible for the aerobic breakdown of heme to biliverdin, carbon monoxide, and iron, which has important effects on the liver (25).…”

Section: Identification Of Biologically Relevant Genes Important For mentioning

confidence: 81%

Transcriptome kinetics of arsenic-induced adaptive response in zebrafish liver

Lam

Winata

Tong

et al. 2006

Physiological Genomics

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-Arsenic is a prominent environmental toxicant and carcinogen; however, its molecular mechanism of toxicity and carcinogenicity remains poorly understood. In this study, we performed microarray-based expression profiling on liver of zebrafish exposed to 15 parts/million (ppm) arsenic [As(V)] for 8 -96 h to identify global transcriptional changes and biological networks involved in arsenic-induced adaptive responses in vivo. We found that there was an increase of transcriptional activity associated with metabolism, especially for biosyntheses, membrane transporter activities, cytoplasm, and endoplasmic reticulum in the 96 h of arsenic treatment, while transcriptional programs for proteins in catabolism, energy derivation, and stress response remained active throughout the arsenic treatment. Many differentially expressed genes encoding proteins involved in heat shock proteins, DNA damage/repair, antioxidant activity, hypoxia induction, iron homeostasis, arsenic metabolism, and ubiquitin-dependent protein degradation were identified, suggesting strongly that DNA and protein damage as a result of arsenic metabolism and oxidative stress caused major cellular injury. These findings were comparable with those reported in mammalian systems, suggesting that the zebrafish liver coupled with the available microarray technology present an excellent in vivo toxicogenomic model for investigating arsenic toxicity. We proposed an in vivo, acute arsenic-induced adaptive response model of the zebrafish liver illustrating the relevance of many transcriptional activities that provide both global and specific information of a coordinated adaptive response to arsenic in the liver. microarray expression profiling; arsenic toxicity; oxidative stress; fish toxicogenomics ARSENIC IS AN IMPORTANT and ubiquitous environmental toxicant, and the risk of arsenic poisoning in humans is a public health issue worldwide (1,23,27,46,54). In addition, arsenic is classified as a human carcinogen based on several epidemiological studies showing an association of arsenic exposure with cancers in lung, bladder, kidney, and liver (33, 54). Aside from cancers, arsenic ingestion is also associated with other human diseases such as blackfoot disease, atherosclerosis, hypertension, diabetes mellitus, skin lesions, and liver injury (19,20,37,54,62). Despite these findings and the fact that arsenic is the most extensively studied of the metals and metalloids in drinking water, the molecular mechanisms of arsenic toxicity and carcinogenicity are poorly understood (34,46). This is partly due to the difficulty of inducing cancer with arsenic in animal models and the complex effects induced by arsenic through a variety of mechanisms that influence numerous signal transduction pathways, as these effects vary depending on cell type, dosage, and form of arsenic used (7, 60). Thus many different modes of action have been proposed, and these include both genotoxic and nongenotoxic effects (33,34,46). Some of the genotoxic effects include induction of chromosomal abnor...

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“…47 Arsenic intoxication caused a significant increase in lipid peroxidation in the testes of the experimental animals in our studies. Menzel et al 48 reported that arsenic can stimulate the release of free iron via the activation of heme oxygenase. The free iron is believed to be involved in classical Fenton-type reactions leading to enhancement of lipid peroxidation.…”

Section: A B Cmentioning

confidence: 99%