* Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536;
Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536; and
§ Department of Microbiology and Immunology and Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky 40536
Received August 9, 2000; accepted December 4, 2000
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ABSTRACT |
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Key Words: Wy-14; 643; dibutyl phthalate; gemfibrozil; superoxide dismutase; DT-diaphorase; -tocopherol; ascorbic acid; peroxisome proliferator (PP); Sprague-Dawley rat; Syrian hamster.
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INTRODUCTION |
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The involvement of enzymes facilitating the removal of ROS in the mechanism of PP-mediated carcinogenesis has been examined in various rat and mice strains following treatment with a wide array of PPs (Ashby et al., 1994). Superoxide dismutases (SOD) are enzymes that catalyze the conversion of O2- to H2O2 and O2. In eukaryotes, 3 genes encode 3 forms of SOD, which are highly compartmentalized. Homodimeric Cu,Zn-SOD is partitioned in the cytosol, homotetrameric Mn-SOD is in the mitochondria, and homotetrameric extracellular (EC) SOD, also containing CuZn, is in the extracellular space (Mates et al., 1999
). Converting O2- to H2O2 in the absence of the equivalent activity of both catalase and selenium-dependent glutathione peroxidase (Se-GPx), both of which are able to convert H2O2 to H2O, can be more detrimental to the cell than the original ROS (de Haan et al., 1996
). Indeed, increased SOD activity leading to increased H2O2 concentrations in the presence of transition metals can result in the formation of HO- and HO via the Fenton or Haber Weiss reactions (Halliwell, 1989
; Halliwell et al., 1995
). More reactive than O2- or H2O2, HO immediately reacts with nucleophilic macromolecules resulting in cellular damage, including lipid hydroperoxides (LOO). Within cells, the lipid-soluble, antioxidant
-tocopherol can terminate LOO chain reactions (Tappel, 1980
).
Tocopherols exist as 4 forms depending on the substitution on the chromanol ring (, ß,
,
) (Brigelius-Flohe and Traber, 1999
). Additionally, the tocotrienols (
, ß,
,
) also contribute to vitamin-E activity. Of the 8 molecules collectively referred to as vitamin E,
-tocopherol is the most active antioxidant, facilitating the protection of cells from ROS-mediated lipid peroxidation and breaking the chain of radical formation (Brigelius-Flohe and Traber, 1999
; Serbinova and Packer, 1994
). The resultant
-tocopheroxyl radical can be reduced by ascorbic acid, thus regenerating
-tocopherol (Halliwell, 1989
). Furthermore, ascorbic acid has been demonstrated to "spare"
-tocopherol, leading to the conclusion that together these two molecules act synergistically in protecting cells from ROS (Halpner et al., 1998
; Wefers and Sies, 1988
). Additionally, the
-tocopherol quinone formed by chain-terminating lipid reactions can be reduced by the cytosolic flavoprotein, DT-diaphorase, resulting in the formation of the antioxidant
-tocopherol hydroquinone (Nakamura and Hayashi, 1994
; Siegel et al., 1997
). Collectively, all 3 of these antioxidant entities have been hypothesized to inhibit the carcinogenic process (Birt, 1986
; Chen et al., 1988
; Joseph et al., 1994
; McCall and Frei, 1999
; Rauth et al., 1997
).
As described earlier, PP treatment results in species-specific hepatocarcinogenesis. Although hamsters treated with PPs do not develop hepatocellular carcinomas or undergo increased cell proliferation, increased production of H2O2 does occur through increased peroxisomal ß-oxidation (Gray and de la Iglesia, 1984; Lake et al., 1993
, 2000
). Accordingly, we hypothesized that antioxidant enzymes such as SOD or DT-diaphorase, and/or the antioxidant vitamins C and E may be modulated differently in hamsters and rats following PP treatment.
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MATERIALS AND METHODS |
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Experimental design and animal treatments.
The National Toxicology Program, Research Triangle Park, NC, performed all animal treatments. Male, Sprague-Dawley rats (46 weeks old, Harlan Sprague-Dawley Inc., Indianapolis, IN) and male, Syrian hamsters (46 weeks old, Frederick Cancer Research and Development Center, Frederick, MD) were treated with PPs in an NTP-2000 unrefined diet (Ziegler Brothers, Inc., Gardners, PA). Animals (n = 5) were administered a control diet or the following amounts of PPs: Wy-14,643 at 50 and 500 ppm, DBP at 5000 and 20,000 ppm in both rats and hamsters, and gemfibrozil at 1000 and 16,000 ppm in rats, 6000 and 24,000 ppm in hamsters. Gemfibrozil was used at higher concentrations in hamsters, due to its predominate urinary excretion in this species; thus using the same dose in both animals may result in hamsters receiving a lesser biological dose (Dix et al., 1999). Animals were treated for 6, 34, or 90 days and euthanized by carbon dioxide overexposure. Livers were then frozen in liquid nitrogen with subsequent storage at 80°C.
Preparation of whole liver homogenates (WLH).
WLH for enzyme assays were prepared by homogenizing samples, using a Tekmar TR-10 tissue homogenizer (Tekmarr, Cincinnati, OH) in 1.15% KCl, 0.1 mM EDTA, pH 7.4. Protein concentrations (mg/ml) of WLH were determined using the Bicinchoninic Acid (BCA) method (Pierce Chemical Co., Rockford, IL), using IgG as the standard.
Cytochrome C SOD assay.
SOD was measured in sonicated WLH using xanthine and xanthine oxidase to generate O2- and measuring the inhibition of cytochrome C reduction according to the method of Crapo et al. (1978) with modifications described by Spitz and Oberley (1989). Briefly, a 3-ml reaction containing 0.1 mM xanthine, 10 µM cytochrome C (derived from horse heart), 50 µM NaCN, 50 mM K2HPO4, pH 7.8, and 0.1 mM EDTA was assembled. To this reaction, xanthine oxidase (XO) was added and the change in absorbance at 550 nm was measured. The amount of XO added was adjusted until a linear curve with a slope of change in absorbance of 0.025 per min was achieved. The same reaction was reassembled with the addition of sample until a linear, 50% inhibition in the rate of cytochrome C reduction was achieved. One unit of SOD was considered that which inhibits 50% of the O2- reduction of cytochrome C. The number of units of SOD was normalized to mg protein.
SOD activity gels.
SOD activity gels were conducted using the method of Beauchamp and Fridovich (1971) as modified by St. Clair et al. (1991). Sonicated samples used in the cytochrome C assay were pooled (n = 5, 20 µg each) to a total of 100 µg and diluted in sample buffer with a final concentration of 10% glycerol, 62.4 mM Tris-Cl, pH 6.8, and 0.01% bromophenol blue. Samples and standards (1 unit Mn-SOD, E. coli-derived, and 1 unit Cu,Zn-SOD, Bovine erythrocyte derived) were kept on ice at all times and loaded onto a nondenaturing, 5% polyacrylamide stacking gel (0.125 M Tris-Cl, pH 6.8) and 10% polyacrylamide separating gel (0.75 M Tris-Cl, pH 8.8) assembled and cooled at 4°C. Electrophoresis proceeded at 100 volts, overnight (16 h), 4°C, in running buffer (25 mM Tris base, 192 mM glycine, pH 8.8). Following electrophoresis, gels were overlaid with 2.5 mM nitro blue tetrazolium (NBT) and incubated for 15 min at room temperature (RT). This solution was decanted and 0.028 mM riboflavin, 30 mM TEMED, 50 mM K2HPO4, pH 7.8 was overlaid onto the gel. Incubation was continued, in the dark, for 15 min at RT. Immediately following incubation, gels were washed repeatedly with deionized H2O and exposed to fluorescent light. Areas that did not develop blue color were considered to be due to SOD inhibition of NBT reduction by O2-. Following exposure, gels were scanned using an HP computer scanner, and vacuum dried. Scanned gels were converted to black and white and the colors were inverted using PhotoShop 5.0 Software to facilitate reading.
DT-diaphorase assay.
Dicumarol-sensitive DT-diaphorase was measured using 2,6-dichlorophenolindophenol (DCPIP) as substrate, according to the method of Lind et al. (1990) with consideration of the findings of Hodnick and Sartorelli (1997). Briefly, WLH was added to a reaction containing 50 mM Tris-Cl, pH 7.5, 0.08% Triton X-100, 40 µM DCPIP, and 0.05 mM NADH. The rate of DCPIP reduction was measured at 600 nm. Dicumarol was added to the reaction at a final concentration of 10 µM and the rate of DCPIP reduction was measured at 600 nm. DT-diaphorase activity was calculated by subtracting the dicumarol-inhibited rate from the uninhibited rate and using 21 mM1 cm1 for the coefficient of DCPIP at 600 nm. Results were normalized to mg protein.
Vitamin assays.
Ascorbic acid was measured in acid-precipitated WLH homogenates according to the method of Omaye et al. (1979). The concentration of ascorbic acid in unknowns was determined from a standard curve and normalized per g liver. -Tocopherol was extracted from WLH using hexane, essentially as described by Desai (1984) and was analyzed by HPLC using the method of Buttriss and Diplock (1984). For HLPC analysis, a Shimadzu HPLC (computer controller model SCL-10A, pump model LC-10AS, autoinjector model SIL-10A, fluorimetric detector model RF-551) was fitted with a 15-cm C18 column containing a 100% methanol mobile phase flowing at a rate of 1.0 ml per min. Fluorimetric detection was set with an excitation at 205 nm and emission at 360 nm. Standards of
-tocopherol from Lancaster Chemical Co. (Windham, NH) were used to create a standard curve for analysis of unknowns.
-Tocopherol was normalized per mg protein.
Statistical analysis.
All statistical analyses were conducted using SYSTAT V.8 (SPSS, Inc.) software. Results were analyzed for statistical significance using one-way ANOVA; individual differences between means were examined using the Bonferroni post hoc test; p-values of < 0.05 were considered significant. The number of samples used for analyses is denoted in the corresponding figure legend or table note.
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RESULTS |
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DISCUSSION |
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PPs can induce the activity of cytochrome P450s 4A1 and 4A6 and increased P450 activity has been hypothesized to increase intracellular O2-. and H2O2 (Bondy and Naderi, 1994; Kappus, 1987
; Makowska et al., 1992
; Starke et al., 1997
). Increased O2-. not removed by the action of SOD may result in damage to cellular macromolecules directly, or can interact with H2O2 in the Haber-Weiss reaction, producing the most reactive ROS, HO (Kappus, 1987
; Michiels et al., 1994
). In this study, short-term (6 days) treatment with DBP increased SOD activity in both species. On the other hand, SOD was decreased in both species by Wy-14,643 at all time points and in rats treated with DBP for 90 days. Decreased hepatic or plasma SOD activity following treatment with other PPs has been previously reported in both rats and mice (Cai et al., 1995
; Dhaunsi et al., 1994
; Rivero et al., 1994
). Opposing these results, increased SOD following PP treatment has also been reported (Arnaiz et al., 1995
; Becuwe et al., 1999
; Glauert et al., 1992
). Combining both the cytochrome C assays with NBT activity gels, it can be concluded that the decreased activity observed following PP treatment herein was due in part to decreases in Cu,Zn-SOD activity. This decreased SOD activity may be due to decreased protein as has been reported following ciprofibrate treatment (Dhaunsi et al., 1994
). The role of PPAR
in mediating these events is unknown, but it should be mentioned that a PPRE has been identified in the rat Cu,Zn-SOD gene and transient transfection experiments have demonstrated induction of this element with arachidonic acid (Yoo et al., 1999
). Additionally, a positive correlation between Cu,Zn-SOD and PPAR
mRNA has been observed (Inoue et al., 1998
). Furthermore, there is evidence that Cu2+ metabolism is altered in PP-treated rats, affecting ceruloplasmin oxidase activity and the mRNA for ceruloplasmin (Eagon et al., 1999
). How these observations correlate with the decreased SOD activity observed herein is unknown.
Numerous recent studies have speculated about the involvement of DT-diaphorase in carcinogenesis and oxidative stress (Rauth et al., 1997). The endogenous role of this mainly cytosolic enzyme may involve vitamin-K metabolism, although recent data have clearly demonstrated its role in reducing
-tocopherol quinone to
-tocopherol hydroquinone (Nakamura and Hayashi, 1994
; Siegel et al., 1997
) and maintaining reduced coenzyme Q (Beyer et al., 1997
). Basal DT-diaphorase activity is approximately 2.4-fold higher in the hamster than the rat, which agrees with and furthers previously published data that DT-diaphorase activity varies with sex, strain, and species (Horie, 1990
). Rats had decreased DT-diaphorase activity following Wy-14,643 treatment across all time points examined, indicating that they may have a decreased ability to defend against lipid peroxidation or quinone redox cycling. Only short-term (6-day) treatment of hamsters with Wy-14,643 resulted in significant decreases in DT-diaphorase activity. Decreased DT-diaphorase activity has been reported previously in PP-treated rats and opposing effects (increased DT-diaphorase) have been reported in PP-treated mice (Cai et al., 1995
; Glauert et al., 1992
; Sohlenius et al., 1992
, 1993
). Interestingly, gemfibrozil treatment increased DT-diaphorase activity in rats at the 2 earlier time points, indicating the effect on this enzyme may be compound-specific. Although the role of DT-diaphorase in vitamin K metabolism is still undetermined, it is interesting that survival of Wy-14,643-treated rats was increased to control levels by supplementing the diet with vitamin K (Hurtt et al., 1997
). These data suggest more experimentation is needed to determine if these 2 observations are related, and how important a role DT-diaphorase has in both survival and carcinogenesis with regard to PPs.
-Tocopherol and ascorbic acid are known to combat ROS in a synergistic manner (Halpner et al., 1998
). Although no conclusive significant changes were observed with ascorbic acid, depletion of
-tocopherol was apparent following PP treatment. Moreover, this depletion was neither compound-specific nor species-specific. The data herein agree with previous reports concerning the depletion of
-tocopherol by PPs (Conway et al., 1989
; Glauert et al., 1992
; Lake et al., 1989
). The underlying mechanism may be related to one or more circumstances. As has been proposed by Arnaiz et al. (Lores Arnaiz et al., 1997
), hypolipidemic drugs obviously affect lipoprotein transport and this would affect the uptake of tocopherols that are transported the same as fatty acids (Drevon, 1991
). Although
-tocopherol is clearly reduced whereas ascorbic acid content is not, in these animals, this may not be indicative of the situation that occurs in humans since they, unlike these rodents, are unable to synthesize ascorbic acid (Johnson, 1979
). Nonetheless, ascorbic acid inhibits the loss of
-tocopherol by restoring it to its reduced form following interaction with peroxide radicals (Halpner et al., 1998
). In addition, ascorbic acid serves to spare
-tocopherol by interacting with peroxyl radicals as well as its ability to inhibit DNA adduction due to ROS (Barja et al., 1994
; Halpner et al., 1998
). However, in the rodent model, increased ascorbic acid with decreased
-tocopherol may render cells susceptible to the "pro-oxidant" effects of ascorbic acid (Bogaards et al., 1992
; Foliot and Beaune, 1994
).
In summary, these results only partially support the hypothesis that these antioxidants or antioxidant enzymes are differentially modified in rats and hamsters. DT-diaphorase is clearly altered differentially: hamsters have a much higher basal level of this enzyme, and it is lowered in rats but not in hamsters by Wy-14,643, the most efficacious of these peroxisome proliferators at inducing hepatocellular carcinomas in rats and mice. For SOD, ascorbic acid, and -tocopherol, there are minor species differences after peroxisome-proliferator administration, but the overall effects appear to be similar. Accordingly, although DT-diaphorase is modified differentially, other mechanisms additionally must be considered, such as modification of genes containing peroxisome-proliferator response elements (PPREs) (Corton et al., 2000
), changes in DNA synthesis and apoptosis (Roberts et al., 2000
), and changes in cell to cell communication (Isenberg et al., 2000
), among others.
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ACKNOWLEDGMENTS |
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NOTES |
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2 Present address: U.S. Food and Drug Administration/CFSAN/OPA/DPP, 200 "C" St. SW, HFS-207, Washington, DC 20204.
3 To whom correspondence should be addressed at Microbiology and Immunology, MS433A Medical Science Building, 800 Rose Street, Lexington, KY 405360298. Fax: (859) 257-8994. E-mail: bspear{at}pop.uky.edu.
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