Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602-7389
Received February 6, 2004; accepted April 7, 2004
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ABSTRACT |
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Key Words: fumonisin B1; silymarin; tumor necrosis factor ; sphingolipid; hepatotoxicity.
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INTRODUCTION |
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Fumonisins are structurally similar to free sphingoid bases. They inhibit ceramide synthase (Merrill et al., 1993; Wang et al., 1991
), which results in the accumulation of free sphinganine and, subsequently, sphingosine, leading to a depletion of ceramide and complex sphingolipids (Merrill et al., 1993
; Riley et al., 1993
, 1997
; Wang et al., 1991
; Yoo et al., 1996
). An accumulation of free sphingoid bases promotes the formation of other sphingolipid metabolites such as sphingoid base-1-phosphates and downstream metabolites (Merrill et al., 2001
). Toxicity of FB1 is well correlated with the accumulation of free sphinganine (Riley et al., 2001
; Tsunoda et al., 1998
; Yoo et al., 1996
) and the depletion of complex sphingolipids (Tsunoda et al., 1998
; Yoo et al., 1996
).
Fumonisin B1 induces the expressions of various cytokines including tumor necrosis factor (TNF-
) in mice (Bhandari and Sharma, 2002
). It has been established that TNF-
signaling pathways modulate FB1 toxicity both in vivo and in vitro. Fumonisin B1 hepatotoxicity was reduced in mice lacking either TNF receptor (TNFR) 1 (P55) or TNFR 2 (P75) (Sharma et al., 2000a
, 2001
). Transfection of a baculovirus gene, inhibitor of apoptosis (IAP), an inhibitor of TNF-
induced cell death, protected renal cells and fibroblasts from FB1-induced apoptosis (Ciacci-Zanella and Jones, 1999
; Jones et al., 2001
). Expression of TNFR-associated protein (TRAP) 2 was induced in FB1-sensitive CV-1 cells but repressed in FB1-resistant COS cells following FB1 treatment (Zhang et al., 2001
), supporting that TNF-
signal pathways are involved in FB1 toxicity. The signaling cascade in TNF-
pathways results in apoptosis upon activation of different downstream signaling molecules after the binding of TNF-
to TNFRs (Bradham et al., 1998
).
Silymarin, an extract from seeds and fruits of Silybum marianum, is a mixture of flavonoid isomers such as silibinin, isosilibinin, silidianin, and silichristin. Silymarin suppresses the activation of caspases and nuclear factor (NF-) B in various cell types following TNF-
treatment (Manna et al., 1999
). Silymarin or silibinin, a major active component of silymarin, inhibited the production of cytokines, e.g., TNF-
, interferon (IFN)
, interleukin (IL)-2, IL-4, IL-6, and IL-8, in mouse liver in response to concanavalin Ainduced, T celldependent liver injury (Schümann et al., 2003
). Suppression of NF-
B activation by silymarin probably accounts for its inhibitory effects on cytokine production (Manna et al., 1999
; Schümann et al., 2003
). We recently reported that, in contrast to increasing TNF-
expression by itself in LLC-PK1 cells, silymarin prevented FB1-induced overexpression of this cytokine and effectively protected LLC-PK1 cells from FB1 cytotoxicity (He et al., 2002
). Silymarin has been recommended in the prevention of alcoholic liver disease (Saller et al., 2001
), and it protected against injury from various other hepatotoxicants such as carbon tetrachloride, paracetamol (Saller et al., 2001
), and concanavalin A (Schümann et al., 2003
).
In the current study, the protective effect of silymarin on FB1 hepatotoxicity was investigated in female mice. Results demonstrated that silymarin protected mice from FB1-induced liver injury, as indicated by reduced activities of circulating alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and number of apoptotic hepatocytes. Silymarin caused liver regeneration, as shown by an increased number of proliferating cells in liver. Fumonisin-induced expressions of proinflammatory cytokines were effectively prevented by pretreatment with silymarin.
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MATERIALS AND METHODS |
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Animals. Six-week-old female BALB/c mice weighing about 22 g were obtained from Harlan Laboratories (Indianapolis, IN). They were acclimated for 1 week before dosing under controlled environmental conditions at 23°C and 65% relative humidity with a 12-h light/dark cycle. Feed and water were available ad libitum. Mice were treated according to the Public Health Service Policy on Humane Care and Use of Laboratory Animals and the Institutional Animal Care and Use Committee approved treatment.
Treatment. Animals were divided randomly into four groups with five mice each, and treated orally with water or silymarin by gavage once daily (750 mg/kg) at 16 h before FB1 dosing. The mice were given three daily subcutaneous injections of either phosphate-buffered saline (PBS) or 2.25 mg/kg of FB1 in PBS. The protocol had been proved to produce consistent liver damage in female mice exposed to FB1 in our laboratory.
One day after the final FB1 treatment, mice were sacrificed by decapitation. Blood was collected in heparinzed tubes, and plasma was subsequently isolated for analysis of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Livers and kidneys were collected from each animal, and aliquots were fixed immediately in neutral 10% formalin or quickly frozen in liquid nitrogen and stored at 85°C until analysis.
Analysis of liver enzymes in plasma. Activities of plasma ALT and AST were determined using a Hitachi 912 Automatic Analyzer (Roche Diagnostics, Indianapolis, IN).
Terminal deoxynucleotidyl transferase(TdT-) mediated dUTP nick-end labeling (TUNEL) assay for apoptosis. Liver tissue sections (5 mm) were prepared and subjected to dUTP nick-end labeling by TdT with a peroxidase-based, in situ Cell Death Detection kit (Roche Diagnostics), as described previously (Sharma et al., 2003a). The stained apoptotic cells were counted under a light microscope and normalized to the unit area, as described previously (Sharma et al., 1997
).
Immunohistochemistry for proliferating cellular nuclear antigen (PCNA) assay. Hepatocyte proliferation was determined by analysis of PCNA in formalin-fixed, paraffin-embedded liver tissues, as described previously (Sharma et al., 2003a,b
). The number of PCNA-positive cells were counted under a microscope and normalized to the unit area, as described previously (Sharma et al., 1997
). A few other cells beside hepatocytes, such as endothelial cells, were labeled with PCNA, but only PCNA-positive hepatocytes were counted.
Histology. Liver specimens were fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned (4 to 5 µm), and stained with hematoxylin and eosin (H&E). The tissues were examined under a microscope in a random order and without knowledge of animal or group.
Sphingolipid analysis. Free sphingosine and sphinganine of liver and kidney in base-treated lipid extracts were determined by HPLC using a modification of the extraction methods described previously (Merrill et al., 1988). Sphingoid bases were quantitated based on the recovery of a C20-sphinganine standard (D-erythro-C20-dihydro-sphingosine; Matreya Inc., Pleasant Gap, PA). The HPLC apparatus and derivation procedure were similar to those described previously (Merrill et al., 1988
), except the fluorescence detector used in this study was Luminescence Spectrometer LS30 (Perkin-Elmer Inc., Norwalk, CT).
Assay for the activity of serine palmitoyltransferase (SPT). The SPT activity in liver and kidney was analyzed using the method described by Williams et al. (1984) with minor modification. Briefly, the frozen tissues were homogenized in homogenization buffer (50 mM N-[2-hydroxyethyl]piperazine-N'- [2-ethanesulfonic acid], 5 mM DL-dithiothreitol, 10 mM ethylenediaminetetraacetic acid, and 0.25 M sucrose [pH 7.4]), and the homogenate was centrifuged at 30,000 x g for 30 min. Aliquots of 100 µg protein in the supernatant were used for analysis of SPT activity, as described previously (He et al., 2004
; Williams et al., 1984
). The protein content was determined by Bio-Rad Bradford reagent according to the manufacturer's protocol (Bio-Rad Laboratories, Hercules, CA).
RNase protection assay (RPA) for selected gene expression. Total RNA from liver tissue was extracted with TRI reagents (Molecular Research Center, Cincinnati, OH). An aliquot part of 50 mg RNA was used for RPA using RiboQuant RPA starter kit (BD Biosciences, San Diego, CA), as described previously (Sharma et al., 2003b). The relative gene expression was normalized against ribosomal protein L32.
Statistical analysis. Results are presented as mean ± standard error (SE). Data were analyzed by two-way analysis of variance (ANOVA) followed by Duncan's multiple range test, unless otherwise stated. In selected cases where unequal variances of different groups were obvious, the Wilcoxon rank sum test was employed. The level of p < 0.05 was considered significant.
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RESULTS |
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The effect of 3-day FB1 treatment on mouse liver was limited to the presence of scattered apoptotic hepatocytes, characterized by the presence of small round to ovoid cells and occasional mitotic figures. No swollen cells indicative of oncotic changes were observed. The cells undergoing apoptosis were usually present as single cells with no leukocytic infiltration and were surrounded by normal cells. The architecture of liver tissue was not influenced by either treatment, and treatment with silymarin provided no distinguishable differences from livers of control animals. Figure 2 shows both an H&E-stained and a TUNEL-stained liver section from an FB1-treated mouse. The extent of damage was corroborated with ALT and AST activities and enumeration of apoptotic cells in tissue sections by TUNEL assay.
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Silymarin Prevented FB1-Induced Activation of SPT in Liver
As the overall content of free sphingoid bases was much higher in silymarin-pretreated mice in response to FB1, we measured the activity of SPT, the first enzyme in the pathway of de novo biosynthesis of sphingolipid (Hannun et al., 2001). Compared to the controls, a significant increase in the activity of hepatic SPT was observed in FB1 alonetreated mice (Table 2). Silymarin significantly decreased the activity of liver SPT to a similar extent as in mice treated with either silymarin or silymarin + FB1.
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The Effects of Silymarin on the Expressions of Selected Genes in Response to FB1 Treatment
FB1 treatment increased the expressions of hepatic genes for selected TNF- superfamily, namely TNF-
, TNFR1, TNF receptorassociated apoptosis-inducing ligand (TRAIL), and lymphotoxin (LT) ß (Fig. 4). Silymarin moderately increased the expression of TNF-
in liver; however, it completely prevented FB1-induced increases of these genes (Fig. 4).
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DISCUSSION |
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The FB1-induced alterations in mouse liver were similar to those reported previously employing similar protocols (Sharma et al., 1997, 2003a
,b
). The only difference in treatments was the duration (3 vs. 5 days in former reports) and gender (females in the current experiments). Exposure of mice to FB1 caused the appearance of apoptotic cells in liver with no other noticeable alterations. The PCNA-positive cells were also increased in FB1-treated mice. In the group treated with both silymarin and FB1, the number of apoptotic (TUNEL-positive) cells was decreased and the number of proliferating (PCNA-positive) cells was increased. These changes suggested that silymarin both decreased the cellular damage and increased the regeneration of liver when coadministered with FB1.
Silymarin has been reported to stimulate enzymatic activity of DNA-dependent RNA polymerase 1 and subsequent biosynthesis of RNA and protein, resulting in DNA biosynthesis and cell proliferation (Sonnenbichler and Zetl, 1986). The stimulatory effect of silymarin on liver regeneration was observed only in damaged livers (Sonnenbichler and Zetl, 1986
). These findings indicate that silymarin increases regeneration potency of damaged liver tissues. Consistent with these studies, we demonstrated that silymarin increased proliferating hepatocytes in response to FB1-induced cell death without modulation of cell proliferation in normal livers (Table 1). The capability of silymarin to stimulate regeneration activity of liver tissue in FB1 intoxication could partly account for the observed hepatoprotective actions.
Silymarin has clinical applications in the treatment of cirrhosis, ischemic injury, and toxic hepatitis induced by various toxins such as ethanol, carbon tetrachloride, acetaminophen, organic solvents, and toxic mushroom (Saller et al., 2001). The pharmacological properties of silymarin involve the regulation of cell membrane permeability and integrity, inhibition of leukotriene, reactive oxygen species scavenging, suppression of NF-
B activity, depression of protein kinases, and collagen production (Saller et al., 2001
). Silymarin is able to reduce the cellular uptake of xenobiotics including mushroom poisons (Saller et al., 2001
); it has been recently shown that silymarin can potentiate doxorubicin cytotoxicity by inhibiting P-glycoproteinmediated drug efflux (Zhang and Morris, 2003
).
In response to FB1, mice cotreated with silymarin had a greater accumulation of free sphingoid bases in both liver and kidney than those exposed only to FB1 (Fig. 3). It has been suggested that the hydrophilic FB1 entered cells in an LLC-PK1 cell model through passive diffusion (Enongene et al., 2002). Moreover, we previously reported that mice lacking p-glycoprotein genes exhibited a similar response to FB1 hepato- and nephrotoxicity as their wild-type counterparts, suggesting little role of multidrug transport system in FB1 toxicity (Sharma et al., 2000b
). Therefore, the effect of silymarin on P-glycoprotein would not account for its protection against FB1 toxicity. The mechanisms by which silymarin potentiates FB1-induced accumulation of free sphingoid bases are currently unknown. The activity of SPT was not increased in response to silymarin or silymarin + FB1, suggesting that silymarin potentiation of FB1-induced free sphingoid bases accumulation in liver and kidney tissues is not due to increased de novo biosynthesis. Sphingosine kinase is responsible for the conversion of free sphingoid bases to their 1-phosphate metabolites (Hannun et al., 2001
). It is unclear whether or not silymarin affects the activity of sphingosine kinase or efflux of intracellular free sphingoid bases from cells. Silymarin is able to stabilize cellular membrane (Saller et al., 2001
). The higher levels of free sphinganine and sphingosine in silymarin + FB1treated mouse livers and kidneys might result from reduced efflux of intracellular free sphingoid bases as a consequence of inhibiting cellular membrane damage.
Free sphingoid bases are proapoptotic and cell growth inhibitory (Merrill et al., 2001). The disruption of sphingolipid metabolism resulting from the inhibition of ceramide synthase by FB1 is believed responsible for FB1 toxicity. The accumulation of free sphinganine and depletion of complex sphingolipid correlated with FB1 toxicity in vitro and in vivo (Riley et al., 2001
; Tsunoda et al., 1998
; Yoo et al., 1996
). The inhibition of SPT prevented the accumulation of free sphinganine and reversed FB1 cytotoxicity in various cell types (He et al., 2002
; Schmelz et al., 1998
; Tolleson et al., 1999
; Yoo et al., 1996
). In the present study, the FB1-induced elevations of serum ALT and AST and apoptotic hepatocytes were dramatically decreased by silymarin, though greater accumulation of hepatic free sphingoid bases was observed in cotreatment with silymarin and FB1. These results suggest that silymarin protects FB1 toxicity through blocking the actions of free sphingoid bases. The ability of silymarin to preserve the integrity of cellular and mitochodrial membrane could in part explain its protective effects on FB1 hepatotoxicity.
Fumonisin has been shown to increase the expressions of many cytokines and apoptotic signaling factors (Bhandari and Sharma, 2002). Silymarin has been shown to protect liver from hepatotoxin injury by inhibiting the production of TNF-
, IFN
, IL-2, and IL-4 as a consequence of blocking hepatic NF-
B activation (Schümann et al., 2003
). Consistent with these findings, we observed in the present study that silymarin reversed FB1 induction of TNF-
, TNFR1, TRAIL, LT ß, and IFN
(Figs. 4 and 5). Silymarin also has been shown to repress TNF-
induced activation of NF-
B and apoptosis in various cell types (Manna et al., 1999
). Either TNFR1 or TNFR2 knockout mice exhibited less sensitivity to FB1 liver injury compared to their wild-type counterparts (Sharma et al., 2000a
, 2001
). It has been shown that transfection of a baculovirus gene, an important inhibitor of apoptosis (IAP) in TNF-
induced apoptosis pathway, protected CV-1 cells from FB1-induced activation of caspase 8 and apoptosis (Ciacci-Zanella and Jones, 1999
; Jones et al., 2001
). These studies supported the idea that the signal pathways of TNF-
play an important role in the pathogenesis of FB1. Lacking IFN
has also been shown to be less responsive to FB1 treatment (Sharma et al., 2003a
). Silymarin-reversed FB1 overexpressions of signal factors in TNF-
superfamily and IFN
could in part account for its protective role in FB1 hepatotoxicity.
In conclusion, we have clearly demonstrated that silymarin plays a protective role in FB1 hepatotoxicity in a mouse model. These findings suggest a therapeutic potential of silymarin in fumonisin liver injury in humans or animals exposed to fumonisin-producing, fungus-contaminated feeds. The efficacy of silymarin in the protection from liver damage after long-term exposure to the mycotoxin still needs to be studied.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389. Fax: (706) 542-3015. E-mail: rpsharma{at}vet.uga.edu.
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