Induction of metallothionein by steroids in rat primary hepatocyte cultures

Bracken, William M.; Klaassen, Curtis D.

doi:10.1016/0041-008x(87)90242-0

Cited by 37 publications

(17 citation statements)

References 20 publications

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“…That is, hepatocyte MT content showed little dependence on the extracellular Zn content, even when this was much higher than a physiological plasma Zn concentration (approximately 10 p,mol/L). This is in disagreement with previous reports (41,42), which indicated a higher MT induction in hepatocytes cultured with Zn concentrations similar to those reported here. However, some of these studies were made without albumin present in the medium (41,42).…”

Section: Discussioncontrasting

confidence: 73%

“…This is in disagreement with previous reports (41,42), which indicated a higher MT induction in hepatocytes cultured with Zn concentrations similar to those reported here. However, some of these studies were made without albumin present in the medium (41,42). Absence of albumin in the medium could cause an unphysiological Zn accumulation in the hepatocyte, which in turn would increase MT levels.…”

Section: Discussioncontrasting

confidence: 73%

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Role of extracellular zinc and copper on metallothionein regulation in cultured rat hepatocytes

1991

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Cellular and extracellular metallothionein contents of rat hepatocytes cultured in the presence of albumin (30 pmoVL) with zinc (1,10,50 and 100 pmol/L), copper (1, 10 and 50 pmol/L), zinc and copper (1, 10 and 50 pmol/L of each metal) or no metals in the culture medium have been measured by radioimmunoassay. Cellular metallothionein levels increased steadily with culture time regardless of the metal treatment and showed little dependence (only a twofold increase) on extracellular zinc or copper at all metal concentrations and times (up to 3 days) studied. In contrast, the presence of both metals simultaneously in the culture medium strongly increased cellular metallothionein contents, acting synergistically in some cases. Significant extracellular metallothionein was observed when copper or zinc and copper were present in the culture medium, most of which is likely a consequence of cell leakage because no evidence of physiological secretion was observed. Total metallothionein production (cellular and extracellular metallothionein levels) indicated that copper was a better metallothionein inducer than zinc in these experimental conditions. These results indicate that metallothionein regulation in the hepatocyte is different depending on the extracellular metal levels and composition and that attention must be given to metallothionein release from the hepatocyte. (HEPATOLOGY 1991;14:648-654.)The liver is believed to be a central organ in zinc (Zn) and copper (Cu) homeostasis in the organism (1, 2). To characterize how the liver regulates the metabolism of these essential heavy metals, the use of cultured hepatocytes has proved to be a useful tool. Several comprehensive studies on the hepatocyte metabolism of Zn and Cu have been published (3-11). In these studies metallothionein (MT), a low molecular weight heavy metal-binding protein, was usually considered to play a central role. However, its levels were either not measured or measured by rather insensitive or nonspecific The putative secretion of MT by cultured hepatocytes has never been studied in detail. This is noteworthy because experimental studies suggest a normal presence of circulating MT (12-21), the source of which, at least in part, might be the liver (22). Biliary excretion of MT has also been reported (16, 23). Studies on the putative secretion of MT by hepatocytes therefore are needed to establish such a possibility.Therefore the aim of this work was to study the effect of physiological (10 p,moliL) and nonphysiological (0, 1, 50 and 100 FmoVL) concentrations of Zn and/or Cu in the culture medium (in the presence of the physiological chelator albumin) on hepatocyte MT content and the putative MT secretion in those conditions (the terms physiological and nonphysiological for metal concentrations are relative; see Discussion). MATERIALS AND METHODSIsolation and Maintenance of Hepatocytes. Isolated liver parenchymal cells were prepared from adult male Lou rats by using the three-step perfusion technique of Garvey and Heil (24) as modified from Seglen ...

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Section: Discussioncontrasting

confidence: 73%

Section: Discussioncontrasting

confidence: 73%

Role of extracellular zinc and copper on metallothionein regulation in cultured rat hepatocytes

1991

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“…However, in this study, progesterone pretreatment had no effect on hepatic MT and MT-mRNA levels. Previously, Bracken and Klaassen (14) reported that sex steroids (j-estradiol, progesterone, and testosterone) were ineffective as inducers of MT in rat hepatocytes. From these results, we conclude that progesterone alone is not even a weak inducer of hepatic MT in rats.…”

Section: Discussionmentioning

confidence: 99%

Effect of Progesterone Pretreatment on Cadmium Toxicity in Male Fischer (F344/NCr) and Wistar (WF/NCr) Rats

Shiraishi¹,

Barter²,

Uno³

et al. 1994

Environmental Health Perspectives

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A previous report indicated that progesterone pretreatment can markedly reduce cadmium (Cd) toxicity in male NAW mice. Therefore we examined the effects of progesterone pretreatment on Cd toxicity in male Fischer (F344) and Wistar (WF) rats. A single subcutaneous injection of 10 or 30 pmole (CdCI2)/kg proved nonlethal over 24 hr but caused the typical spectrum of testicular lesions in these rats. Moreover, when F344 rats were pretreated with progesterone (100 mg/kg, sc, at -48, -24, and 0 hr) and then given cadmium (20 pmole CdCI2/kg, 0 hr), this dose of cadmium proved very toxic, unexpectedly causing 53% mortality. Progesterone pretreatment had no effect on cadmium-induced lethality in WF rats or on testicular lesions in either strain. Significant elevations in serum lactate dehydrogenase (LDH) activity, indicative of hepatotoxicity, were also observed in progesterone-pretreated F344 rats given cadmium as compared to rats given Cd alone. Progesterone did not induce increases in hepatic or renal metallothionein (MT) and hepatic or testicular MT-I mRNA levels in F344 rats. In contrast, levels of the testicular cadmium-binding protein (TCBP) in progesterone-pretreated F344 rats were doubled. This increase in TCBP provided no protection against cadmium toxicity in the testes. These results indicate that, in contrast to previously reported data for mice, progesterone pretreatment increased the lethality of cadmium in male F344 rats and had no effect on cadmium-induced testicular toxicity in F344 and WF rats. -Environ Health Perspect 1 02(Suppl 3): 277-280 (1994).

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“…Other steroids also regulate the synthesis of MTs. In rat hepatocyte primary cell lines, the glucocorticoid corticosterone induces the synthesis of MTs, and the synthetic glucocorticoid dexamethasone is a more potent MT inductor than is Zn 2+ and Cd 2+ (Bracken and Klaassen 1987). Taking into account the above-mentioned studies and our results, we can conclude that the effects of E 2 on development are complex, depending on the mechanisms of toxicity of other substances as well the susceptibility of certain cell differentiation processes such as the neuralcrest-derived melanocytes reported in the case of Xenopus laevis embryos (Bevan et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Estradiol uptake, toxicity, metabolism, and adverse effects on cadmium-treated amphibian embryos.

Fridman

Corró

Herkovits

2004

Environ Health Perspect

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The exposure of Bufo arenarum embryos to 25 µmol/L 17β-estradiol (E 2 ) resulted in 100% lethality within 48 hr, whereas 10 µmol//L E 2 was the no observed effect concentration value for shortterm chronic (7 days) exposure. The toxicity profile curves show that lethal effects were proportional to the E 2 concentration and the time of exposure. The E 2 uptake resulted in 20.1 ng E 2 /mg embryo at 8 hr posttreatment, but 67.3% of this value was achieved during the first 30 min of incubation with this estrogen. Regarding metabolism, the embryos synthesize estrone (E 1 ) from E 2 by means of 17β-hydroxysteroid dehydrogenase. Simultaneous treatments of Bufo arenarum embryos with 1 mg/L Cd 2+ and 0.1, 1, or 10 µmol/L E 2 enhanced the lethality exerted by cadmium in 76.7, 80, and 83.3% of embryos, respectively. The results indicate that estrogenic endocrine disruptors could have an adverse effect on amphibian embryos and enhance the toxic effect of Cd on amphibian embryos. This study points to the possibility of using the AMPHITOX test as a screening method for potential endocrine disruption as well as the combined effects of chemical mixtures.

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Induction of metallothionein by steroids in rat primary hepatocyte cultures

Cited by 37 publications

References 20 publications

Role of extracellular zinc and copper on metallothionein regulation in cultured rat hepatocytes

Role of extracellular zinc and copper on metallothionein regulation in cultured rat hepatocytes

Effect of Progesterone Pretreatment on Cadmium Toxicity in Male Fischer (F344/NCr) and Wistar (WF/NCr) Rats

Estradiol uptake, toxicity, metabolism, and adverse effects on cadmium-treated amphibian embryos.

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