Protection of carbon tetrachloride-induced hepatotoxicity by zinc: Role of metallothionein

Cagen, Stuart Z.; Klaassen, Curtis D.

doi:10.1016/0041-008x(79)90013-9

Cited by 129 publications

(42 citation statements)

References 25 publications

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“…Exploiting its abundant intramolecular SH groups, MT reduces the toxicity of alkylating agents (Cagen and Klaassen 1979), -irradiation (Satoh et al 1989), and pesticides (Satoh et al 1992), as well as that of heavy metals such as Cd, and acts as a scavenger of free radicals to protect cells and animals against various types of oxidative stresses (Sato and Bremner 1993). In addition, MT is known to reduce the side eVects of many anticancer drugs (Okazaki et al 1998;Satoh et al 1993b), such as cisplatin (Naganuma et al 1987) and adriamycin (Naganuma et al 1988), and MT-deWcient mice have been shown to be particularly susceptible to toxicity of anticancer drugs (Zhang et al 1998).…”

Section: Resultsmentioning

confidence: 99%

Potential effect on cellular response to cadmium of a single-nucleotide A → G polymorphism in the promoter of the human gene for metallothionein IIA

et al. 2006

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Most people generally ingest cadmium in their food. Cadmium that has accumulated in tissues induces the synthesis of metallothioneins (MTs) which are metal-binding proteins that bind tightly to cadmium to inhibit its renal toxicity. Individuals whose ability to induce the synthesis of MTs is low seem likely to be particularly susceptible to the toxic effects of cadmium. In this study, we analyzed the polymorphism of the promoter region of the gene for MT-IIA, the major species of MT in humans, in 119 adult Japanese subjects. We found that about 18% of the subjects had an A --> G single-nucleotide polymorphism in the core region of the promoter near the TATA box. A reporter-gene assay using HEK293 cells showed that replacement of A by G at position -5 reduced the efficiency of the cadmium-induced transcription of the gene for MT-IIA. This single-nucleotide polymorphism inhibited the binding of nuclear proteins to the core promoter region of the gene for MT-IIA. When the promoter region upstream of the TATA box was replaced by a sequence that contained three dioxin-responsive elements, the reporter-gene assay demonstrated that the A --> G single-nucleotide polymorphism resulted in a marked reduction in the rate of dioxin-induced transcription. These results suggest that the A --> G single-nucleotide polymorphism reduces the efficiency of those aspects of the transcription of the gene for MT-IIA that are controlled by general transcription factors.

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Section: Resultsmentioning

confidence: 99%

Potential effect on cellular response to cadmium of a single-nucleotide A → G polymorphism in the promoter of the human gene for metallothionein IIA

et al. 2006

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“…There are some agents that inhibit CCl 4 -induced liver injury in experimental models. [36][37][38][39][40][41] However, such agents have no effectiveness in the DIC model. GM is the only agent administered for the treatment of patients with DIC.…”

Section: Discussionmentioning

confidence: 98%

Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachloride-induced liver injury in rats

et al. 2005

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“…MT production is induced in many organs, not only by various metals such as Zn, Cu, and Cd but also by nonmetallic compounds (Suzuki and Yamamura, 1980;Onosaka et al, 1984;Min et al, 1991). Due to its sulfhydryl moieties, MT has properties like those of agents that provide detoxification of heavy metal agents, antioxidation against reactive oxygen species (ROS), and scavenging of free radicals (Cagen and Klaassen, 1979;Thornalley and Vasak, 1985;Sato and Bremner, 1993;Sato and Kondoh, 2002). Owing to these abilities, the protective role of MT against metal toxicity has been extensively investigated.…”

Section: Introductionmentioning

confidence: 99%

Carbon tetrachloride-induced lethality in mouse is prevented by multiple pretreatment with zinc sulfate

et al. 2016

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-Carbon tetrachloride (CCl 4 ) is commonly used as a chemical inducer of experimental liver injury. Several compounds have been demonstrated to attenuate the hepatic damage caused by sublethal doses of CCl 4 . However, rescue from lethal toxicity of CCl 4 has not been reported. In the present study, we evaluated the protective effect of metallothionein (MT), an endogenous scavenger of free radicals, on CCl 4 -induced lethal toxicity of mice. To induce MT production in male ddY mice, we administered Zn (as ZnSO 4 ) at 50 mg/kg as a once-daily subcutaneous injection for 3 days prior to a single intraperitoneal administration of 4 g/kg CCl 4 . Animals were observed for mortality every 3 hr for 24 hr after CCl 4 injection. Liver damage was assessed by determining (in a subset of these mice) blood levels of alanine aminotransferase (ALT; a marker of liver injury) and liver histopathology at 6 hr after CCl 4 injection. Our results showed that three times pretreatment with Zn yielded > 40-fold induction of hepatic MT protein levels compared to control group. Zn pretreatment completely abolished the CCl 4 -induced mortality of mice. We also found that pretreatment of mice with Zn significantly decreased the ALT levels and reduced the histological liver damage as assessed at 6 hr post-CCl 4 . These findings suggest that prophylaxis with Zn protects mice from CCl 4 -induced acute hepatic toxicity and mortality, presumably by induction of radical-scavenging MT.

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Protection of carbon tetrachloride-induced hepatotoxicity by zinc: Role of metallothionein

Cited by 129 publications

References 25 publications

Potential effect on cellular response to cadmium of a single-nucleotide A → G polymorphism in the promoter of the human gene for metallothionein IIA

Potential effect on cellular response to cadmium of a single-nucleotide A → G polymorphism in the promoter of the human gene for metallothionein IIA

Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachloride-induced liver injury in rats

Carbon tetrachloride-induced lethality in mouse is prevented by multiple pretreatment with zinc sulfate

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