Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 1018, Kansas City, Kansas 66160-7417
Received October 19, 2001; accepted January 8, 2002
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ABSTRACT |
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Key Words: cadmium; liver; hepatotoxicity; necrosis; cytokine; chemokine.
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INTRODUCTION |
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Several reports have addressed the direct mechanism of Cd-induced hepatotoxicity at the subcellular and molecular levels. Subcellular localization of Cd demonstrates that Cd distributes to the nucleus, mitochondria, and endoplasmic reticulum, which localizes Cd in target organelles (Goering and Klaassen, 1983; Kapoor et al., 1961
; Klaassen, 1978
). Cadmium has been shown to cause mitochondrial dysfunction (Diamond and Kench, 1974
) and more specifically inhibition of electron transport (Miccadei and Floridi, 1993
). Cadmium administration also may result in DNA damage (Bagchi et al., 1996
) and lipid peroxidation (Stacey et al., 1980
), although it is disputed whether oxidative stress plays a role in Cd-induced hepatotoxicity (Harvey and Klaassen, 1983
; Muller, 1986
).
Metallothioneins are small, cysteine-rich proteins that bind Cd with high affinity (Klaassen et al., 1999). Pretreatment with low doses of zinc or Cd results in protection from subsequent doses of Cd (Goering and Klaassen, 1984a
,b
). This protection is a result of the induction of MT and subsequent redistribution of Cd to the cytoplasm where it is bound to MT and thus detoxified (Goering and Klaassen, 1983
). In MT-null mice, this protective effect is not seen, thus confirming the requirement of MT in the mechanism of this protective effect (Liu et al., 1996
).
Glutathione (GSH), the primary cellular nonprotein thiol, also plays a role in the detoxication of Cd, although the exact role GSH plays in Cd-induced hepatotoxicity is not accurately defined. Depletion of GSH with phorone, diethyl maleate, or buthionine sulfoximine has been shown to increase sensitivity to both Cd-induced lethality and hepatotoxicity (Dudley and Klaassen, 1984; Singhal et al., 1987
). Glutathione has been shown to be critical for the biliary elimination of Cd from the liver (Dijkstra et al., 1996
). However, the protective effect may also be due to GSH reducing Cd-induced oxidative stress (Shaikh et al., 1999
). Therefore, GSH plays an important and perhaps multifunctional role in Cd-induced liver injury.
There also appears to be an indirect component to Cd-induced liver injury. This indirect component appears to involve Kupffer cell activation and subsequent release of endogenous inflammatory mediators. Kupffer cell activation by Cd was first noted by the identification of cytoplasmic vacuolization (Hoffmann et al., 1975) and an increase in colloidal carbon clearance (Sauer et al., 1997
). Elimination of Kupffer cells with gadolinium chloride alleviates Cd-induced hepatotoxicity in rats (Sauer et al., 1997
; Yamano et al., 1998
), but fails to protect cultured hepatocytes (Badger et al., 1997
). This data strongly supports the role of Kupffer cells in the mechanism of Cd-induced hepatotoxicity.
Limited cohesive information is available about the role of proinflammatory cytokines in Cd-induced hepatotoxicity. Tumor necrosis factor- (TNF-
) is weakly induced by Cd both in vitro (Marth et al., 2000
; Szuster-Ciesielska et al., 2000
) and in vivo (Kayama et al., 1995
). Pretreatment with antibodies against TNF-
mildly decreases Cd-induced hepatotoxicity and abrogated Cd-induced expression of acute phase proteins (Kayama et al., 1995
). In contrast, Yamano and Rikans determined that TNF-
is not increased within 24 h of Cd administration (Yamano et al., 2000
). The concentrations of other cytokines, including interleukin-1
(IL-1
), interleukin-1ß (IL-1ß), interferon-
(IFN-
), and interleukin-6 (IL-6) also increase after Cd treatment, although their relevance is less well defined (Kayama et al., 1995
; Liu et al., 1999
; Marth et al., 2000
; Yamano et al., 2000
).
Chemokines are a specific subset of cytokines that primarily function to recruit leukocytes to sites of inflammation. Interleukin-8 and CINC-1 (cytokine-inducible chemoattractant factor-1) are the prototypical neutrophil-specific chemokines for humans and rats, respectively. Because neutrophil accumulation has been reported in sites of inflammation after Cd-administration (Dudley et al., 1982; Hoffmann et al., 1975
; Kayama et al., 1995
), it is plausible to investigate whether Cd increases expression of neutrophil-specific chemokines. Neutrophil chemokines are induced after Cd treatment of cultured mouse and rat hepatocytes as well as cultured human cells (Dong et al., 1998
; Horiguchi et al., 1993
). In addition, CINC-1 protein increases in parallel with increased hepatotoxicity (Yamano et al., 2000
).
It has been known for some time that sensitivity to Cd-induced hepatotoxicity is dependent upon the strain of mice studied (Nolan et al., 1986; Quaife et al., 1984). This strain difference does not appear to be due to a difference in Cd uptake by the liver or induction of MT (Kershaw and Klaassen, 1991
; Liu et al., 1992
). The sensitivity of rats to various hepatotoxins is also strain dependent. Fischer 344 (F344) rats are more sensitive than Sprague-Dawley (SD) rats to several chemical hepatotoxins, including 1,2 dichlorobenzene (Stine et al., 1991
), carbon tetrachloride (Steup et al., 1991
), diquat (Gupta et al., 1994
), and paraffin wax (Hoglen et al., 1998
). Recently, a preliminary report noted that F344 rats are also more sensitive than SD rats to Cd-induced hepatotoxicity (Keuster et al., 1999
). That study suggested that the rate of MT induction might be causative in the rat strain difference, however, the data was not conclusive.
Therefore this study was conducted to achieve two goals: first, to define and examine the dose- and time-related rat strain difference in sensitivity to Cd-induced hepatotoxicity; and second, to utilize this strain difference to help elucidate the direct versus indirect mechanisms of Cd-induced hepatotoxicity.
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MATERIALS AND METHODS |
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Chemicals.
Tris-HCl and CdCl2 were purchased from Fisher Scientific (St. Louis, MO) and 109Cd was purchased from New England Nuclear (Boston, MA). All other chemicals were purchased from Sigma Chemical Company (St. Louis, MO).
Serum enzyme activity assays.
Biochemical evaluation of liver injury was performed by quantifying serum activities of alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) spectrophotometrically, using commercially available test kits (UV detection, kinetic endpoint, Sigma Diagnostics, St. Louis, MO) according to the manufacturer's instructions.
Histopathology.
Liver samples were taken consistently from the left lobe of the liver and processed by standard histological techniques. Briefly, samples were fixed in formalin for 24 h, then switched to ethanol for storage. Liver sections were then processed routinely and embedded in paraffin blocks. Slides were prepared (5 µm thick), stained with hematoxylin and eosin, and analyzed by light microscopy for liver injury.
Hepatic Cd content.
Liver samples ( 1.0 g) were digested 1:3 (w/v) in concentrated HNO3 at 100°C for 60 min. The digested samples were assayed for Cd content using a Perkin-Elmer atomic absorption spectrophotometer (Norwalk, CT) using an analytical wavelength of 228.8 nm. Sample Cd content was determined by comparing absorbance values to a standard curve of Cd solutions.
Metallothionein assay.
Liver samples were prepared by homogenizing 1:3 (w/v) in 10 mM Tris-HCl buffer (pH 7.4), centrifuged at 13,000 x g, and the supernatant fractions were retained. Protein concentration in supernatants was determined using the bicinchoninic acid method using a BCATM kit (Pierce, Rockford, IL). Supernatants were assayed and hepatic MT content was determined using the Cd-hemoglobin method as previously described (Eaton and Toal, 1982).
Hepatic nonprotein thiol (NPSH) content.
Hepatic NPSH was quantified using the DTNB method (Ellman, 1959). Briefly, 100 mg liver samples were homogenized using a Kinematica Polytron homogenizer (Littau, Switzerland) in 5% TCA/EDTA, separated by centrifugation at 13,000 x g, and the supernatants retained for NPSH analysis. Each reaction contained 176 µl 0.1 M phosphate buffer (pH 8), 16 µl supernatant, and 8 µl 5 mM 5,5`-dithio-bis(2-nitrobenzoic acid). Absorbance was quantified using a Biotek microtiter plate spectrophotometer (Winooski, VT) at 405 nm (analytical wavelength) and 690 nm (reference wavelength), and compared with a standard curve of known GSH concentrations.
Isolation of total RNA and quantification of specific mRNAs using the branched-DNA (bDNA) method.
Total RNA was isolated using RNAzol B reagent (Tel-Test, Inc., Friendswood, TX) as per the manufacturer's protocol. Each RNA pellet was resuspended in RNase-free water and stored at 80°C. The concentration of total RNA in each sample was quantified spectrophotometrically and RNA integrity was determined by illuminating the 28S and 18S rRNA bands with ethidium bromide after separation by agarose gel electrophoresis. Specific mRNAs encoding individual cytokines were quantified using the QuantigeneTM bDNA signal amplification method (Bayer Diagnostics, East Walpole, MA, www.quantigene.com) as per the manufacturer's protocol. Briefly, 10 µg samples of total RNA were loaded per well of a 96-well microtiter plate containing hybridization buffer and 50 fmol/µl of each probe set. Complimentary probes were designed (see next section) and hybridized to mRNAs encoding for individual cytokines overnight at 53°C. Following hybridization, excess probes were removed by washing with hybridization buffer. The captured mRNAs were then hybridized to branched DNA molecules that contain alkaline phosphatase molecules. After incubation with the chemiluminescent substrate, luminescence was quantified with a Quantiplex 320 bDNA luminometer.
Development of specific oligonucleotide probe sets for bDNA analysis of cytokines.
The gene sequences of interest were accessed from GenBank (www.ncbi.nlm.nih.gov). These target sequences were analyzed by ProbeDesignerTM Software Version 1.0. Multiple, specific probes were developed to each mRNA transcript (Table 1). Oligonucleotide probes designed in this manner were specific to a single cytokine transcript. All oligonucleotide probes were designed to have a Tm of approximately 63°C. This feature allows hybridization conditions to be held constant (i.e., 53°C) during each hybridization step for each olignucleotide probe set. Each probe developed in ProbeDesignerTM was submitted to the National Center for Biotechnological Information (NCBI) for nucleotide comparison by the basic logarithmic alignment search tool (BLASTn) to ensure minimal cross-reactivity with other rat sequences. Oligonucleotides with a high degree of similarity (> 80%) to other known rat sequences were eliminated from the design.
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RESULTS |
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Lipopolysaccharide treatment caused a 32-fold increase in CINC-1 mRNA levels at 1 h that decreased 70% by 6 h (Fig. 6A). Cadmium treatment increased CINC-1 levels only about 1020% of the LPS response. This increase was not observed until 18 and 24 h after dosing with 2.0 mg Cd/kg in both F344 and SD rats. The hepatotoxic dose of 3.0 mg Cd/kg in SD rats only increased CINC-1 mRNA levels at 24 h (Fig. 6B
).
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Lipopolysaccharide treatment resulted in a 150-fold increase of TNF- mRNA levels at 1 h that decreased 80% by 6 h (Fig. 7A
). Cadmium treatment caused an increase in TNF-
mRNA levels that was only 515% of the response produced by LPS at 3, 6, 10, and 18 h in F344 rats after 2.0 mg Cd/kg, at 3 and 6 h in SD rats after 2.0 mg Cd/kg, and at 3, 6, and 10 h in SD rats after 3.0 mg Cd/kg (Fig. 7B
).
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Lipopolysaccharide treatment caused a 110-fold increase in IL-6 mRNA levels at 1 h that decreased 55% by 6 h (Fig. 7E). Cadmium administration resulted in increased IL-6 mRNA levels in SD rats after 3.0 mg Cd/kg at 6, 10, 18, and 24 h that did not exceed 25% of the LPS response. No significant increases in IL-6 mRNA levels were noted after administration of 2.0 mg Cd/kg to either F344 or SD rats (Fig. 7F
).
Lipopolysaccharide treatment caused a 15-fold increase in IL-10 mRNA levels at 1 h that continued to increase to 19-fold by 6 h (Fig. 7G). Cadmium treatment did not increase IL-10 mRNA levels over control in any dose group at any time point (Fig. 7H
).
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DISCUSSION |
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It is well documented that mouse strains vary widely in their sensitivity to cadmium-induced hepatotoxicity (Nolan and Shaikh, 1986; Quaife et al., 1984
). The mouse strain differences did not appear to be due to differential accumulation of Cd in the liver or induction of MT (Kershaw and Klaassen, 1991
; Liu et al., 1992
). However, it is unknown whether there are any strain-related differences in the indirect components of Cd-induced hepatotoxicity.
Therefore, this study was conducted to utilize this rat strain difference in susceptibility to Cd to elucidate the role of cytokines in Cd-induced hepatotoxicity. The first aim of this study was to fully characterize the dose response and time course of Cd-induced liver injury in both F344 and SD rats. These data clearly demonstrate that F344 rats are more sensitive to Cd-induced hepatotoxicity with respect to dose. Cadmium has a similar temporal toxicity in both strains of rats, beginning at about 3 h and becoming maximal between 18 and 24 h. Unfortunately, hepatotoxic doses of Cd could not be compared between F344 and SD rats 48 h after Cd administration due to significant lethality in the SD rats. These data demonstrate a dose-dependent strain difference in sensitivity to Cd-induced hepatotoxicity.
The next aim of this study was to determine whether Cd accumulation was causative for the strain difference. The data show that an equal dosage of Cd (2.0 mg Cd/kg) results in similar hepatic Cd content in the 2 strains during the first 18 h after Cd administration. At later time points there is more Cd in the SD rat livers than F344 rat livers after equal dosages of 2.0 mg Cd/kg. It is plausible that this may simply be due to release of Cd as a result of necrosis in F344 rat livers. Higher dosages of Cd (3.0 mg Cd/kg) in SD rats resulted in higher hepatic cadmium content. Therefore, hepatic Cd accumulation in F344 and SD rats appears to be dependent upon the dose of Cd rather than the strain of rat. These data clearly show that differences in Cd accumulation in the liver do not account for the strain difference in Cd-induced hepatotoxicity.
Thiols are important in Cd toxicity, both as targets for toxicity as well as buffers against toxicity. Metallothionein (MT) is a highly inducible, cysteine-rich protein that binds Cd with high affinity, thus sequestering and detoxifying Cd (Klaassen et al., 1999). Therefore, MT was quantified over time after Cd administration. MT was significantly induced in a time-dependent manner, beginning at 6 h after Cd and continuing to increase throughout the time course. However, hepatic MT was not significantly different between the 3 treatment groups at any time point during the study. Nonprotein thiols, such as glutathione, are also known to be important in the detoxification and excretion of Cd (Singhal et al., 1987
). Therefore, total hepatic nonprotein sulfhydryls (NPSH) were quantified in the time course samples. Hepatic NPSH was similar in naïve F344 and SD rats and remained unchanged from controls through the first 10 h of the study. At and after 18 h, hepatic NPSH was decreased only after hepatotoxic doses of Cd in both F344 and SD rats. NPSH remained unchanged with the lower dose in SD rats. These data indicate that the decrease in NPSH is a result of toxicity rather than a factor that results in the sensitivity of the F344 rats. Therefore, the strain difference in Cd-induced hepatotoxicity is not due to MT induction or alteration in NPSH concentration.
It has been proposed that Kupffer cells are involved in the indirect component of the mechanism of Cd toxicity (Hoffmann et al., 1975; Sauer et al., 1997
; Yamano et al., 1998
, 2000
). Kupffer cells have been implicated as the source of the inflammatory response, because they are known to produce proinflammatory mediators such as cytokines and chemokines when activated. Lipopolysaccharide (LPS) is the prototypical activator of Kupffer cells and has been well documented to robustly increase gene expression for proinflammatory cytokines and thus produce liver injury. LPS was used in this study as a positive control to quantify Cd-induced cytokine expression with regard to magnitude and time.
CINC-1 and MCP-1 are the prototypical neutrophil and monocyte chemokines that specifically recruit neutrophils and monocytic macrophages, respectively, to sites of inflammation. The results demonstrate that Cd elicits small increases, relative to LPS, in CINC-1 gene expression that are not substantially different in F344 and SD rats after hepatotoxic dosages of Cd. Moreover, the increases in CINC-1 mRNA did not precede toxicity, and were more likely an effect of, or response to the toxicity. MCP-1 mRNA is increased in F344 rats at slightly earlier time points than in SD rats. While this may contribute to Cd-induced hepatotoxicity, the magnitude of the response is unlikely to be substantial enough to account for the strain difference in toxicity.
Particular attention has been paid to the role of TNF- in Cd toxicity, with several reports suggesting that TNF-
plays a role in the mechanism of hepatotoxicity (Kayama et al., 1995
; Marth et al., 2000
; Szuster-Ciesielska et al., 2000
). In the present study, Cd treatment, when compared to LPS treatment, only mildly increased TNF-
gene expression in either F344 or SD rats. In addition, the pattern of increased TNF-
mRNA levels after Cd treatment is not similar to the pattern observed after LPS treatment. Moreover, the strain-related differences in TNF-
gene expression do not parallel the strain-related differences in hepatotoxicity. Therefore, expression of the TNF-
gene does not appear to account for the strain difference in sensitivity to Cd-induced hepatotoxicity. Furthermore, these increases are not robust when compared to LPS, and therefore may only be a minor factor in Cd toxicity.
Interleukin-1ß and IL-6 have also been implicated in the mechanism of Cd toxicity (Kayama et al., 1995; Marth et al., 2000
; Yamano et al., 2000
). Examination of these interleukins in the present study shows that the levels of IL-1ß and IL-6 mRNAs are increased selectively in SD rats after hepatotoxic dosages of Cd. Because IL-1ß and IL-6 are increased in SD rats and not in F344 rats, they can be ruled out as candidates for sensitizing F344 rats to Cd-induced hepatotoxicity. Interleukin-10, the prototypical anti-inflammatory cytokine, was not significantly increased at any time point.
From these data, as well as literature citations, it is clear that Cd toxicity is an extremely complex process. This study was designed to specifically address several potential components of this complex mechanism of hepatotoxicity. This study attempted to utilize this strain difference in sensitivity to Cd-induced hepatotoxicity to tease out important factors in the mechanism of toxicity. Hepatic Cd accumulation, MT induction, and NPSH alteration are similar in both strains and thus do not appear to contribute to the strain difference. More interestingly, this study establishes cytokine profiles over time with regard to both time and magnitude of response. Thus, these chemokines and cytokines may participate in the mechanism of Cd-induced hepatotoxicity; however, it is likely to be only a minor component of the toxicity and does not account for the strain difference in Cd-induced hepatotoxicity.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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Bagchi, D., Bagchi, M., Hassoun, E. A., and Stohs, S. J. (1996). Cadmium-induced excretion of urinary lipid metabolites, DNA damage, glutathione depletion, and hepatic lipid peroxidation in Sprague-Dawley rats. Biol. Trace Elem. Res. 52, 143154.[ISI][Medline]
Diamond, E. M., and Kench, J. E. (1974). Effects of cadmium on the respiration of rat liver mitochondria. Environ. Physiol. Biochem. 4, 280283.[ISI][Medline]
Dijkstra, M., Havinga, R., Vonk, R. J., and Kuipers, F. (1996). Bile secretion of cadmium, silver, zinc and copper in the rat. Involvement of various transport systems. Life Sci. 59, 12371246.[ISI][Medline]
Dong, W., Simeonova, P. P., Gallucci, R., Matheson, J., Flood, L., Wang, S., Hubbs, A., and Luster, M. I. (1998). Toxic metals stimulate inflammatory cytokines in hepatocytes through oxidative stress mechanisms. Toxicol. Appl. Pharmacol. 151, 359366.[ISI][Medline]
Dudley, R. E., and Klaassen, C. D. (1984). Changes in hepatic glutathione concentration modify cadmium-induced hepatotoxicity. Toxicol. Appl. Pharmacol. 72, 530538.[ISI][Medline]
Dudley, R. E., Svoboda, D. J., and Klaassen, C. D. (1982). Acute exposure to cadmium causes severe liver injury in rats. Toxicol. Appl. Pharmacol. 65, 302313.[ISI][Medline]
Dudley, R. E., Svoboda, D. J., and Klaassen, C. D. (1984). Time course of cadmium-induced ultrastructural changes in rat liver. Toxicol. Appl. Pharmacol. 76, 150160.[ISI][Medline]
Eaton, D. L., and Toal, B. F. (1982). Evaluation of the Cd/hemoglobin affinity assay for the rapid determination of metallothionein in biological tissues. Toxicol. Appl. Pharmacol. 66, 134142.[ISI][Medline]
Ellman, G. L. (1959). Tissue sulfhydryl groups. Arch. Biochem. Biophys. 82, 7077.[ISI][Medline]
Goering, P. L., and Klaassen, C. D. (1983). Altered subcellular distribution of cadmium following cadmium pretreatment: Possible mechanism of tolerance to cadmium-induced lethality. Toxicol. Appl. Pharmacol. 70, 195203.[ISI][Medline]
Goering, P. L., and Klaassen, C. D. (1984a). Tolerance to cadmium-induced hepatotoxicity following cadmium pretreatment. Toxicol. Appl. Pharmacol. 74, 308313.[ISI][Medline]
Goering, P. L., and Klaassen, C. D. (1984b). Zinc-induced tolerance to cadmium hepatotoxicity. Toxicol. Appl. Pharmacol. 74, 299307.[ISI][Medline]
Gupta, S., Rogers, L. K., and Smith, C. V. (1994). Biliary excretion of lysosomal enzymes, iron, and oxidized protein in Fischer-344 and Sprague-Dawley rats and the effects of diquat and acetaminophen. Toxicol. Appl. Pharmacol. 125, 4250.[ISI][Medline]
Habeebu, S. S., Liu, J., and Klaassen, C. D. (1998). Cadmium-induced apoptosis in mouse liver. Toxicol. Appl. Pharmacol. 149, 203209.[ISI][Medline]
Harvey, M. J., and Klaassen, C. D. (1983). Interaction of metals and carbon tetrachloride on lipid peroxidation and hepatotoxicity. Toxicol. Appl. Pharmacol. 71, 316322.[ISI][Medline]
Hoffmann, E. O., Cook, J. A., di Luzio, N. R., and Coover, J. A. (1975). The effects of acute cadmium administration in the liver and kidney of the rat. Light and electron microscopic studies. Lab. Invest. 32, 655664.[ISI][Medline]
Hoglen, N. C., Regan, S. P., Hensel, J. L., Younis, H. S., Sauer, J. M., Steup, D. R., Miller, M. J., Waterman, S. J., Twerdok, L. E., and Sipes, I. G. (1998). Alteration of Kupffer cell function and morphology by low melt point paraffin wax in female Fischer-344 but not Sprague-Dawley rats. Toxicol. Sci. 46, 176184.[Abstract]
Horiguchi, H., Mukaida, N., Okamoto, S., Teranishi, H., Kasuya, M., and Matsushima, K. (1993). Cadmium induces interleukin-8 production in human peripheral blood mononuclear cells with the concomitant generation of superoxide radicals. Lymphokine Cytokine Res. 12, 421428.[ISI][Medline]
Kapoor, N. K., Agarwala, S. C., and Kasuya, M. (1961). The distribution and retention of cadmium in subcellular fractions of rat liver. Ann. Biochem. Exp. Med. 21, 5154.[ISI][Medline]
Kayama, F., Yoshida, T., Elwell, M. R., and Luster, M. I. (1995). Role of tumor necrosis factor-alpha in cadmium-induced hepatotoxicity. Toxicol. Appl. Pharmacol. 131, 224234.[ISI][Medline]
Kershaw, W. C., and Klaassen, C. D. (1991). Cadmium-induced elevation of hepatic isometallothionein concentrations in inbred strains of mice. Chem. Biol. Interact. 78, 269282.[ISI][Medline]
Keuster, R. K., Waalkes, M. P., Goering, P. L., Li, G., Fisher, B., Younis, H. S., and Sipes, I. G. (1999). Differential induction of metallothionein and heat shock protein 72 by cadmium in the liver of male Fischer-344 and Sprague-Dawley rats. Toxicologist 48, 1673 (Abstract).
Klaassen, C. D. (1978). Effect of metallothionein on hepatic disposition of metals. Am. J. Physiol 234, E47E53.[ISI][Medline]
Klaassen, C. D., Liu, J., and Choudhuri, S. (1999). Metallothionein: An intracellular protein to protect against cadmium toxicity. Annu. Rev. Pharmacol. Toxicol. 39, 267294.[ISI][Medline]
Liu, J., Kershaw, W. C., Liu, Y. P., and Klaassen, C. D. (1992). Cadmium-induced hepatic endothelial cell injury in inbred strains of mice. Toxicology 75, 5162.[ISI][Medline]
Liu, J., Liu, Y., Habeebu, S. S., and Klaassen, C. D. (1999). Metallothionein-null mice are highly susceptible to the hematotoxic and immunotoxic effects of chronic CdCl2 exposure. Toxicol. Appl. Pharmacol. 159, 98108.[ISI][Medline]
Liu, J., Liu, Y., Michalska, A. E., Choo, K. H., and Klaassen, C. D. (1996). Metallothionein plays less of a protective role in cadmium-metallothionein-induced nephrotoxicity than in cadmium chloride-induced hepatotoxicity. J. Pharmacol. Exp. Ther. 276, 12161223.[Abstract]
Marth, E., Barth, S., and Jelovcan, S. (2000). Influence of cadmium on the immune system. Description of stimulating reactions. Cent. Eur. J. Public Health 8, 4044.
Miccadei, S., and Floridi, A. (1993). Sites of inhibition of mitochondrial electron transport by cadmium. Chem. Biol. Interact. 89, 159167.[ISI][Medline]
Muller, L. (1986). Consequences of cadmium toxicity in rat hepatocytes: Mitochondrial dysfunction and lipid peroxidation. Toxicology 40, 285295.[ISI][Medline]
Muller, L., and Ohnesorge, F. K. (1984). Cadmium-induced alteration of the energy level in isolated hepatocytes. Toxicology 31, 297306.[ISI][Medline]
Nolan, C. V., and Shaikh, Z. A. (1986). An evaluation of tissue metallothionein and genetic resistance to cadmium toxicity in mice. Toxicol. Appl. Pharmacol. 85, 135144.[ISI][Medline]
Quaife, C., Durnam, D., and Mottet, N. K. (1984). Cadmium hypersusceptibility in the C3H mouse liver: Cell specificity and possible role of metallothionein. Toxicol. Appl. Pharmacol. 76, 917.[ISI][Medline]
Rikans, L. E., and Yamano, T. (2000). Mechanisms of cadmium-mediated acute hepatotoxicity. J. Biochem. Mol. Toxicol. 14, 110117.[ISI][Medline]
Sauer, J. M., Waalkes, M. P., Hooser, S. B., Kuester, R. K., McQueen, C. A., and Sipes, I. G. (1997). Suppression of Kupffer cell function prevents cadmium induced hepatocellular necrosis in the male Sprague-Dawley rat. Toxicology 121, 155164.[ISI][Medline]
Shaikh, Z. A., Vu, T. T., and Zaman, K. (1999). Oxidative stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants. Toxicol. Appl. Pharmacol. 154, 256263.[ISI][Medline]
Singhal, R. K., Anderson, M. E., and Meister, A. (1987). Glutathione, a first line of defense against cadmium toxicity. FASEB J. 1, 220223.
Stacey, N. H., Jr., Cantilena, L. R., and Klaassen, C. D. (1980). Cadmium toxicity and lipid peroxidation in isolated rat hepatocytes. Toxicol. Appl. Pharmacol. 53, 470480.[ISI][Medline]
Steup, D. R., Wiersma, D., McMillan, D. A., and Sipes, I. G. (1991). Pretreatment with drinking water solutions containing trichloroethylene or chloroform enhances the hepatotoxicity of carbon tetrachloriode in Fischer 344 rats. Fundam. Appl. Toxicol. 16, 798809.[ISI][Medline]
Stine, E. R., Gunawardhana, L., and Sipes, I. G. (1991). The acute hepatotoxicity of the isomers of dichlorobenzene in Fischer-344 and Sprague-Dawley rats: Isomer-specific and strain-specific differential toxicity. Toxicol. Appl. Pharmacol. 109, 472481.[ISI][Medline]
Szuster-Ciesielska, A., Lokaj, I., and Kandefer-Szerszen, M. (2000). The influence of cadmium and zinc ions on the interferon and tumor necrosis factor production in bovine aorta endothelial cells. Toxicology 145, 135145.[ISI][Medline]
Yamano, T., DeCicco, L. A., and Rikans, L. E. (2000). Attenuation of cadmium-induced liver injury in senescent male fischer 344 rats: Role of Kupffer cells and inflammatory cytokines. Toxicol. Appl. Pharmacol. 162, 6875.[ISI][Medline]
Yamano, T., Shimizu, M., and Noda, T. (1998). Age-related change in cadmium-induced hepatotoxicity in Wistar rats: Role of Kupffer cells and neutrophils. Toxicol. Appl. Pharmacol. 151, 915.[ISI][Medline]