Reactions of arsenic(III) and arsenic(V) species with glutathione

Scott, Nelson; Hatlelid, Kristina; Mackenzie, Neil E.; Carter, Dean E.

doi:10.1021/tx00031a016

Cited by 437 publications

(284 citation statements)

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“…In the presence of reduced GSH, arsenite conjugates with three molecules of glutathione to form ATG. The monomethyl metabolite of arsenic conjugates with two equivalents of glutathione to form methylarsenic diglutathione (MADG) [27,39]. The dimethyl metabolite of arsenic conjugates with one equivalent of glutathione to form dimethylarsenic glutathione (DMAG) [39,40].…”

Section: Discussionmentioning

confidence: 99%

“…The monomethyl metabolite of arsenic conjugates with two equivalents of glutathione to form methylarsenic diglutathione (MADG) [27,39]. The dimethyl metabolite of arsenic conjugates with one equivalent of glutathione to form dimethylarsenic glutathione (DMAG) [39,40]. Previous study showed that ATG and MADG, but not DMAG, is transported out of hepatocytes via the MRP2/ cMOAT transporter [27].…”

Section: Discussionmentioning

confidence: 99%

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Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

Lu¹,

Tamai²,

Nezu³

et al. 2006

J Biomed Sci

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SummaryArsenic is an established human carcinogen. The role of aquaglyroporins (AQPs) in arsenic disposition was recently identified. In order to examine whether organic anion transporting polypeptide-C (OATP-C) also plays a role in arsenic transport, OATP-C cDNA was transfected into cells of a human embryonic kidney cell line (HEK-293). Transfection increased uptake of the model OATP-C substrate, estradiol-17b-D-glucuronide, by 10-fold. In addition, we measured uptake and cytotoxicity of arsenate, arsenite, monomethylarsonate(MMA V ), and dimethylarsinate (DMA V ). Transfection of OATP-C increased uptake and cytotoxicity of arsenate and arsenite, but not of MMA V or DMA V . Rifampin and taurocholic acid (a substrate of OATP-C) reversed the increased toxicity of arsenate and arsenite seen in OATP-C-transfected cells. The increase in uptake of inorganic arsenic was not as great as that of estradiol-17b-D-glucuronide. Our results suggest that OATP-C can transport inorganic arsenic in a (GSH)-dependent manner. However, this may not be the major pathway for arsenic transport.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

Lu¹,

Tamai²,

Nezu³

et al. 2006

J Biomed Sci

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“…[37][38][39] The sensitivity of tumor cells to As 2 O 3 -induced apoptosis was reported to be inversely related to the intracellular level of glutathione. 23 As shown by Figure 10a, the level of glutathione decreased slightly within the first 3 hr by the treatment with As 2 O 3 .…”

Section: Effects Of As 2 O 3 On Glutathione Content and Superoxide Prmentioning

confidence: 99%

Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide

2001

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The mechanism of the induction of apoptosis by arsenic trioxide (As 2 O 3 ), which was demonstrated recently to be an effective inducer of apoptosis in patients with leukemia, was examined in detail in human leukemia U937 cells. Upon treatment of U937 cells with 50 M of As 2 O 3 , complete inactivation of the kinases ERK1 and ERK2 was detected within 30 min. p38 was activated within 3 hr, and the maximum activity was detected at 6 hr, when DNA fragmentation remained undetectable. Experiments with transfected cells that expressed constitutively activated MEK1 and a specific inhibitor of p38 also suggested that inactivation of ERKs and activation of p38 might be associated with the induction of apoptosis by As 2 O 3 . In contrast to the inactivation of ERKs and the activation of p38, activation of JNK by Key words: arsenic trioxide; apoptosis; leukemia cells; superoxide; tumorArsenic has long been used in traditional Chinese medicine. Arsenic trioxide (As 2 O 3 ) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) and in patients with APL in whom all-trans-retinoic acid (ATRA) and conventional chemotherapy has failed. 1-4 Studies in vitro indicate that As 2 O 3 can induce apoptosis in myeloma cell lines, in plasma cells from myeloma patients, 5 in malignant lymphocytic cell lines 6,7 as well as primary cultures of lymphocytic leukemia and lymphoma cells, 6 in myeloid and B-cell leukemia cell lines, 8 in megakaryocytic leukemia cell lines, 9 in neuroblastoma cell lines 10 and in HPV16-immortalized human cervical epithelial cells. 11 The mechanism responsible for the induction of apoptosis has not been fully characterized, but As 2 O 3 induced apoptosis in NB4 cells, cloned from a relapsed patient with APL, by inducing loss of PML/RAR␣ protein 12 and by suppressing expression of the Bcl-2 protein. 13 Apoptosis induced by As 2 O 3 and by the organic arsenical melarsoprol in myeloid leukemia cell lines, such as the HL-60, KG-1 and U937 cell lines, was found, however, to be independent of the level of expression of PML and PML-RAR␣. 14 In contrast to its apparent curative effects, As 2 O 3 is known to be a carcinogen in human organs, such as skin and lung, and it has serious side effects such as fluid retention in patients. 15 Other chronic side effects include polyneuropathy, palmar keratosis and skin hyperpigmentation. 15 It is, therefore, desirable to develop other drugs that act by a similar mechanism to that of As 2 O 3 but lack the side effect. While the mechanism of the induction of apoptosis in tumor cells by As 2 O 3 is not well understood, As 2 O 3 has been used to mimic the effects of heat shock on cells. 16 When rat fibroblastic 3Y1 cells and rat PC12 cells are treated with As 2 O 3 , stress-induced kinases such as c-Jun N-terminal kinase (JNK) and p38 are activated. 17 To clarify the mechanism of induction of apoptosis in tumor cells by As 2 O 3 , we examined the effects of As 2 O 3 on the activities of mitogen-activated protein (M...

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“…Notably, some of these effects could be the consequence of a direct interaction of arsenic trioxide with GSH and protein thiols (Scott et al. 1993; Hughes 2002; Lu et al. 2007; Zhang et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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Reactions of arsenic(III) and arsenic(V) species with glutathione

Cited by 437 publications

References 9 publications

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide

Role of endoplasmic reticulum stress in drug‐induced toxicity

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