Enhancement of oxygen toxicity by diethyldithiocarbamate on chinese hamster and mouse cells

Lin, Peck Sun; Kwock, Lester; Lui, P. S.; Hefter, K.

doi:10.1016/0360-3016(79)90800-9

Cited by 13 publications

(4 citation statements)

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“…This may explain why SOD is the most effective in counteracting the deleterious ac tion of DDC on alkaline secretion. On the other hand, since alkaline secretion depends on active, energy-requiring process (23), it might be possible that the observed effect of DDC on HCO3 secretion is due to more general cellular toxicity caused by this agent (22,24). Yet, since the duodenal mucosa re sponded to dmPGE2 in the presence of DDC by a similar magnitude of increase in HCO3 output as that induced by this agent in normal rats, the general toxicity of DDC cannot total ly explain the secretory disorder observed in the present study.…”

Section: Discussionmentioning

confidence: 99%

Duodenal Ulcers Induced by Diethyldithiocarbamate, a Superoxide Dismutase Inhibitor, in the Rat: Role of Antioxidative System in the Pathogenesis.

et al. 1991

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ABSTRACT-Pathogenesis of duodenal ulcers induced by diethyldithiocarbamate (DDC), a superoxide dismutase (SOD) inhibitor, was investigated in the rat. Repeat ed s.c. administration of DDC (750 mg/kg) every 12 hr induced duodenal ulcers in the fed rats, and the severity of the ulcers reached the maximum after three injections. DDC not only reduced basal acid output but also impaired duodenal alkaline secre tion. These ulcers were significantly prevented by antioxidative agents such as SOD (50000 units/kg, s.c.), allopurinol (50 mg/kg, s.c.) or glutathione (200 mg/kg, s.c.) as well as the antisecretory agent cimetidine (100 mg/kg, s.c.). The impaired HCO3 re sponse caused by DDC was partially but significantly reversed by either SOD (15000 units/kg/hr, i.v.), allopurinol or glutathione; and SOD by itself significantly elevated the rate of basal alkaline secretion. 16,16-Dimethyl prostaglandin E2 (10 ,ug/kg, s.c.) increased duodenal HCO3 output in the presence of DDC and significantly prevented the development of duodenal ulcers in response to DDC. These results suggest that the mucosal antioxidative system including SOD may play a role in the regulatory process of alkaline secretion and contribute to the mucosal defensive ability in the duodenum. The insufficiency of this system may be involved in the pathogenesis of DDC-induced duodenal ulcers. Diethyldithiocarbamate (DDC), a potent metal chelator, is known to induce damage in the gastrointestinal mucosa in rats (1, 2). Re cently, we found that repeated administration of DDC to fed rats produced penetrating ulcers in the duodenum with a high incidence (3). Although inhibition of copper modulated cytosolic superoxide dismutase (SOD) is thought to be a significant factor in the pathogenesis of this toxicity, the precise mechanism remains unknown. Since the anti oxidative system including SOD may play a role in maintaining the functional integrity of these organs, the pathogenesis of DDC-in duced toxicity might involve the functional dis orders related to the insufficiency of this sys tem. We have previously shown that the im pairment of alkaline secretion is commonly in volved in the mechanism of experimental pro duction of duodenal ulcers as induced by mepirizole, antiinflammatory drugs or digi toxin (4-7). Thus, it is of interest to study the relationship between the antioxidative system and duodenal alkaline secretion.In the present study, we examined the effects of DDC and antioxidative drugs on duodenal alkaline secretion in the rat to in vestigate (a) the pathogenesis of DDC-induced duodenal ulcers and (b) the role of the anti oxidative system in duodenal alkaline secretion.

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Section: Discussionmentioning

confidence: 99%

Duodenal Ulcers Induced by Diethyldithiocarbamate, a Superoxide Dismutase Inhibitor, in the Rat: Role of Antioxidative System in the Pathogenesis.

et al. 1991

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“…Because copper complexes are often lipophilic, intracellular copper and Tira concentrations may increase. From the cytotoxicity result, it is reasonable to assume that one of the major forms of action of Tira copper complex is likely to be in relevant redox reactivity in cells [28,29]. Cycling of copper in its two oxidative states must catalytically consume oxygen as has been reported in Tira treated cells [8,30,31].…”

Section: Complex Of Tira and Coppermentioning

confidence: 99%

“…Compared to control, mice treated with the copper chelator, D-penicillamine, lost as much as 50% of CCO activity in their brains [27]. We have previously observed that another copper chelator, diethyldithiocarbamate (DDC), can enhance radiation effect and induce electron microscopy detectable mitochondria damages [28]. DDC has recently been found to induce apoptosis in thymocytes by raising the intracellular level of redox-active copper [29].…”

Section: Chemistry Of Tiramentioning

confidence: 99%

New cytotoxic mechanism of the bioreductive agent Tirapazamine (SR 4233) mediated by forming complex with copper

Lin

1996

Radiat. Oncol. Investig.

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Tirapazamine (Tira, SR 4233), a Bioreductive agent, is highly toxic to cells under low oxygen conditions because it produces a toxic oxidizing radical intermediate. The mechanisms for its toxicity under aerobic conditions have not been fully established but involve reactive oxygen species production. In an earlier study, we observed that the cytotoxic effect of Tira under aerobic conditions varied in a series of experiments. We suspected that some unknown property or properties of this agent was responsible for causing the variation in our study. We have reason to believe that one property is due to Tira forming a complex with copper. Depending on the copper concentration, the cytotoxic potency of Tira under aerobic conditions may increase 2‐ to 10‐fold while its effect under low oxygen conditions remains high. The Tira copper complex's stereochemistry likely has a ratio of 2 to 1. Several of the theoretical properties of this complex may lead to a new fundamental understanding of Tira effects in vitro and in vivo. Radiat. Oncol. Invest. 4:211–220, 1996. © 1997 Wiley‐Liss, Inc.

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“…If one accepts that DNA is one of the important targets of bleomycin, then the cellular effects of bleomycin can be greatly altered by the concentrations of 0,-and/or the level of superoxide dismutase (SOD) activity within the cell. Superoxide dismutase is a copper-containing enzyme that is present in all respiring cells to protect the cells from excess levels of O,-.x We have recently studied the cytotoxic effect of raising cellular 0,levels in the Chinese hamster cell line (Don) by using the copper chelator, diethyldithiocarbamate (DDC) to inhibit SOD.12, 13 We observed that DDC could inhibit superoxide dismutase activity as reported by others7,'" and reduce the cellular clonogenic ability in this cell line in a concentration-dependent fashion. 'Z,'J These results suggest that DDC-treated cells are more vulnerable to 0,related injuries.…”

mentioning

confidence: 99%

Copper chelator enhancement of bleomycin cytotoxicity

Lin¹,

Kwock²,

Goodchild³

1980

Cancer

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Bleomycin's effects on DNA strand scission are inhibited by low concentration of some metal ions (including copper), greatly stimulated by ferrous (Fe+2) ions, and increased and probably mediated by the production of superoxide radicals (O2-), hydroxyl radicals (OH), and hydrogen peroxide (H2O2). However, the role of these mechanisms in overall bleomycin cytotoxicity is not known. For this reason, we have treated the Chinese hamster cell line (V79) cells with a copper chelator, diethyldithiocarbamate (DDC) and bleomycin in vitro DDC is known to inhibit superoxide dismutase (SOD), an enzyme responsible for the scavenging of O2-. The cytotoxicity is determined by the standard clonogenic survival method, which shows that DDC treated cells are more susceptible to bleomycin either as a function of bleomycin dose or as a function of bleomycin treatment time. These results support the notion that reducing Cu2+ levels and/or increasing O2- concentrations can modify the cytotoxicity of bleomycin.

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Enhancement of oxygen toxicity by diethyldithiocarbamate on chinese hamster and mouse cells

Cited by 13 publications

References 14 publications

Duodenal Ulcers Induced by Diethyldithiocarbamate, a Superoxide Dismutase Inhibitor, in the Rat: Role of Antioxidative System in the Pathogenesis.

Duodenal Ulcers Induced by Diethyldithiocarbamate, a Superoxide Dismutase Inhibitor, in the Rat: Role of Antioxidative System in the Pathogenesis.

New cytotoxic mechanism of the bioreductive agent Tirapazamine (SR 4233) mediated by forming complex with copper

Copper chelator enhancement of bleomycin cytotoxicity

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