* Department of Comparative Biosciences and the Molecular and Environmental Toxicology Center; and Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706
Received February 20, 2004; accepted April 2, 2004
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ABSTRACT |
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Key Words: 1,3-butadiene; 3-butene-1,2-diol; rat-sensitive; hepatotoxicity; hypoglycemia; glutathione-depletion.
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INTRODUCTION |
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BD is metabolized in mouse, rat, and human microsomes to butadiene monoxide (BMO; Csanady et al., 1992; Duescher and Elfarra, 1994
). In human microsomes, BMO is readily hydrolyzed via cytosolic or microsomal epoxide hydrolase to 3-butene-1,2-diol (BDD; Kemper and Elfarra, 1996
; Krause et al., 1997
). BDD has also been shown to represent a significant fraction of the total metabolites recovered in mouse and rat urine after BD treatment (Nauhaus, et al., 1996
). However, few in vivo toxicity studies have been conducted on BDD. Nonetheless, BDD has been suggested to be a detoxification product of BMO (Bechtold et al., 1994
).
Previous studies in our laboratory have shown that BDD can be bioactivated by cytochrome P450s or alcohol dehydrogenase (ADH) to yield hydroxymethylvinylketone (HMVK), a reactive Michael acceptor that could deplete cellular GSH levels and alkylate cellular macromolecules (Kemper and Elfarra, 1996; Krause et al., 2001
; Powley et al., 2003
). Recently, our laboratory identified propionic acid, crotonic acid, and 2-ketobutyric acid as in vivo urinary metabolites of BDD in rats and mice. While the amounts of carboxylic acids excreted were similar, a male rat-sensitive inhibition of hippuric acid formation was observed after BDD treatment (125 and 200 mg/kg; Sprague and Elfarra, 2003
). Treatment of male mice with BDD (125 and 250 mg/kg) had no effect on hippuric acid formation. The decreased hippuric acid formation in rats was thought to be a result of BDD-derived carboxylic acids conjugating coenzyme A (CoA) and thus inhibiting the conjugation of benzoic acid (present in rodent feed) with CoA, which is the first step in hippuric acid formation (Gatley and Sherratt, 1977
). When compared to mice, rats were thought to be more sensitive to inhibition of hippuric acid formation, because they have a lower capacity to form CoA conjugates (Seymour et al., 1987
). Significant concentrations of short-chain carboxylic acids can interfere with essential mitochondrial functions such as conversion of pyruvate to oxaloacetate, which could then disrupt gluconeogenesis or ureogenesis (Brass, 1986
; Sherratt, 1985
). Therefore HMVK and carboxylic acid formations after BDD treatment are potential bioactivation pathways of BDD metabolism.
BDD, an allylic alcohol, is a structural analogue to crotyl alcohol and allyl alcohol (Atzori et al., 1989). Administration of allyl alcohol caused hepatotoxicity in both mice and rats (Jaeschke et al., 1987
; Reid, 1972
) and hemolysis of mouse erythrocytes 2 h after exposure (Ferrali et al., 1990
). The rapid uptake of allyl alcohol and the zonal distribution of alcohol dehydrogenase (ADH; oxidizes allyl alcohol to the Michael acceptor acrolein) are believed responsible for the allyl alcohol-induced periportal necrosis within the liver lobule (Reid, 1972
). Similar to allyl alcohol, the cytotoxicity of crotyl alcohol in isolated hepatocytes seemed dependent upon ADH-mediated oxidation of crotyl alcohol to the Michael acceptor crotonaldehyde (Fontaine et al., 2002
), a known hepatotoxin (Chung et al., 1986
). Collectively, allylic alcohols may represent a toxic group of compounds, and characterizing the toxicity of BDD in mice and rats will provide additional information about the in vivo toxicity of allylic alcohols.
The purpose of this study was to test the hypothesis that BDD may have hepatotoxic potential. This hypothesis was investigated in male Sprague-Dawley rats and B6C3F1 mice. These two species were used because of their known differences in metabolism of BD (Richardson et al., 1999), BMO (Krause and Elfarra, 1997
, Sharer et al., 1992
), and BDD (Sprague and Elfarra, 2003
). Initially, four rats were given 250 mg/kg BDD and were to be sacrificed after 24 h. Since two of the rats in this study died, additional studies were conducted to investigate the possible cause of death and identify possible species differences between mice and rats. These studies in mice and rats characterized the toxicity by noting the presence of lesions in tissues, alterations in blood cell profile and clinical chemistry, and changes in the hepatic, erythrocyte, and plasma GSH levels. Although the BDD doses used in this study are unlikely to occur given the current BD exposure limits (1 ppm, 8 h time weighted average; OSHA, 1996
), characterization of the acute toxicity of BDD will provide additional insight into the toxicity of allylic alcohols and will be useful when conducting chronic BDD toxicity studies at lower doses more relevant to BD exposure concentrations.
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MATERIALS AND METHODS |
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Animals. Male B6C3F1 mice (2429 g) were purchased from The Jackson Laboratory (Bar Harbor, ME) and male Sprague-Dawley rats (220300 g) were purchased from Sasco (Omaha, NE). Mice were administered BDD (250 mg/kg) in saline, ip, and housed together (3 per group) in polycarbonate metabolism cages (Nalgene, Rochester, NY). Rats were dosed with BDD (125250 mg/kg), ip, and housed individually in metabolism cages (Doses of BDD were chosen based on a previous study investigating the formation of carboxylic acid metabolites in mice and rats (Sprague and Elfarra, 2003). Mice and rats were maintained on a 12-h light/dark cycle and water and feed were provided ad libitum. Animals were euthanized with CO2. All experiments were carried out in accordance with the guides for the care and use of laboratory animals as recommended by the U.S. National Institutes of Health and the University of Wisconsin-Madison's Animal Care Committee.
Tissue pathology. After blood samples were collected, tissue samples were removed from each rat or mouse. These tissues included the liver, heart, kidney, small intestine, bladder, lung, spleen, pancreas, sternum, and brain. Tissue samples were fixed in 10% neutral buffered formalin and later stained with hematoxylin and eosin for histological analysis. Samples were then analyzed (blindly, without knowledge of treated or control animals) for indicators of toxicity, including necrosis, hemorrhage, or inflammation. Regions of cellular necrosis were determined by the consistent presence of the disruption of cellular adhesions and tissue architecture, cellular swelling, or an increase in eosinophilia. Hemorrhage was identified by the presence of pooled erythrocytes. Acute inflammation was characterized by the presence of neutrophils.
Clinical pathology. Blood samples (collected by cardiac puncture) from mice and rats dosed with BDD were processed with the Advia 120 Hematology Analyzer (Bayer Corporation, Tarrytown, NY) and serum and EDTA plasma samples were analyzed with the Hitachi 912 (Roche Diagnostics Corporation, Indianapolis, IN) in the Clinical Pathology Laboratory of the Veterinary Medicine Teaching Hospital at the University of Wisconsin-Madison School of Veterinary Medicine. Whole mouse and rat blood samples stored in EDTA tubes were analyzed for red blood cell (RBC), white blood cell (WBC), and platelet counts, hemoglobin (Hgb) concentration, erythrocyte indices, including mean cell volume (MCV), mean cell Hgb (MCH), and mean cell hemoglobin concentration (MCHC), mean platelet volume (MPV), WBC differential counts, and morphology of RBC. Serum and plasma samples were collected from rats given 200 (sacrificed 1, 4, or 24 h after treatment) or 250 mg/kg BDD (sacrificed 15 min, 1, 2, 3, or 4 h after treatment). Plasma samples were analyzed for ammonia levels and serum samples for concentrations of sodium, potassium, and chloride ions, enzymatic CO2, glucose, blood urea nitrogen (BUN), total calcium, and aspartate aminotransferase (AST), alanine aminotransferase (ALT), -glutamyl transpeptidase (GGT), and creatine kinase (CK) activities. Serum samples obtained 24 h after rats were treated with 125 mg/kg BDD were analyzed for BUN levels and ALT and AST activities.
To assess liver and kidney toxicity 4 h after mice were given 250 mg/kg BDD, we analyzed serum samples for BUN and glucose levels and ALT and AST activities.
Quantitation of GSH and GSSG. The methods for measuring the levels of plasma, erythrocytic, and hepatic GSH and GSSG were based on methods used by Tietze (1969), Wild and Mulcahy (1999)
, and Gunnarsdottir et al. (2002)
. In preparation for analysis of GSSG and GSH, plasma from treated animals was diluted with 50% SSA for a resulting SSA concentration of 5%. RBCs were diluted with 2 volumes of double deionized H2O and subsequently diluted with 50% SSA to 5% SSA. Insufficient quantities of mouse blood were obtained for RBC GSH and GSSG and total plasma GSH analysis. Liver samples from each treated mouse or rat were homogenized in 6.67% SSA (2 volume/1 g). Samples were then stored at 80°C until the time of analysis or up to one week. For rat total GSH levels, plasma, RBC, and liver samples were diluted 1:1, 1:20, and 1:63, respectively, with 5% SSA. Mouse liver samples were diluted 1:200 with 5% SSA for total GSH levels. After making the dilutions, 10 µl of each solution were added to a 96-well microtiter plate and analyzed on a Molecular Devices Versamax Microplate reader (Molecular Devices Corporation, Sunnyvale, CA) as described previously (Gunnarsdottir et al., 2002
). GSSG levels were quantified as described above after GSH was derivatized with 2-vinylpyridine (Griffith, 1980
). Rat erythrocyte and liver samples were diluted to a ratio of 1:10 and 1:4, respectively, in 5% SSA. Insufficient volumes of rat or mouse plasma were obtained for the GSSG analysis. Mouse liver samples were diluted 1:10 with 5% SSA. Aliquots of 2-vinylpyridine (2 µl) and triethanolamine (6 µl) were added to 100 µl of each diluted sample. These samples were derivatized for 1 h in complete darkness and were processed as described above. The reduced GSH and GSSG levels were calculated in nmol/g tissue as described previously (Gunnarsdottir et al., 2002
).
Plasma BDD analysis. BDD was extracted from heparinized plasma and derivatized with BSTFA (with 10% TMCS) as described previously (Kemper et al., 1998). Briefly, aliquots of plasma (50 µl) and 2-butene-1,4-diol (50 µl; internal standard) were placed on the solid-phase Extrelut packing material inside a glass column (1 g). After 5 min, 2 x 3-ml aliquots of ethyl acetate were added to each column. The combined ethyl acetate extracts were concentrated to 100200 µl under nitrogen, derivatized with BSTFA with 10% TMCS, and analyzed by GC/MS as described below.
GC/MS conditions. Plasma BDD analysis was performed on a Hewlett Packard series 6890 gas chromatograph with a mass selective detector by using a modified method described by Kemper et al. (1998). The gas chromatograph was fitted with a 30 m x 0.32 mm ID x 3.0 µm film thickness J&W Scientific DB-1 column (Folsom, CA). The injection port temperature was 175°C with a pressure of 2.55 psi. Injections (3 µl) were made in splitless mode at a column-head pressure of 2.55 psi. The initial oven temperature was set to 90°C. The temperature then increased at a rate of 30°C/min to 270°C, where it was held for 15 min. Under these conditions the retention times for BDD and 2-butene-1,4-diol were 7.38 and 8.11 min, respectively. The concentrations of BDD were determined as described previously (Kemper et al., 1998
).
Plasma BDD half-life and clearance calculations. Mouse plasma BDD values 15 min, 1, 2, 3, or 4 h after 250 mg/kg BDD treatment were obtained from Kemper et al. (1998). Rat plasma BDD levels were measured in the current study at the same time points, after 250 mg/kg BDD administration. To determine the half-life of BDD in the plasma of mice and rats, the plasma BDD concentrations were first log-transformed and plotted versus time. The resulting slope of each line was multiplied by 2.3 to obtain the rate of elimination (kel). The half-life was then calculated for mice and rats by dividing 0.693 by the kel value. Plasma BDD clearance was calculated by dividing the dose BDD (ip) by the area under the curve (calculated using Sigmaplot software, SPSS Inc., Chicago, IL.).
Statistical analyses. All results were analyzed using Sigmastat software (SPSS Inc., Chicago, IL.). A paired t-test and Mann-Whitney rank sum test were used to determine significance between two groups.
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RESULTS |
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Mice given 250 mg/kg BDD and sacrificed 1, 4, or 24 h after treatment remained alert and did not exhibit any obvious adverse reaction to BDD treatment.
Effect of BDD Treatment on Tissue Pathology
Three out of five rats dosed with 250 mg/kg BDD and sacrificed after 1 h had periportal and midzonal hepatic necrosis, and two out of five rats in the same treatment group had periportal and midzonal liver hemorrhage (Fig. 1). There was no indication of inflammation in the livers of rats treated with 250 mg/kg and then sacrificed after 1 h. However, all six rats given 250 mg/kg BDD and sacrificed 4 h later had periportal and midzonal necrosis and hemorrhage, and five of the six had periportal and midzonal inflammation in the liver (Fig. 1). The pericentral region of the liver lobule in rats was largely unaffected by the 250-mg/kg dose (Fig. 1). Two out of five rats given 250 mg/kg BDD and sacrificed after 1 h had mild interstitial pancreatic edema. All six rats given 250 mg/kg and sacrificed 4 h later had mild pancreatic interstitial edema, and five out of six had mild pancreatic hemorrhage. However, because the mild nature of the pancreatic lesions, and because one out of three rats given saline and then sacrificed after 4 h had mild hemorrhage in the pancreas, the contribution of the pancreatic lesions to BDD hypoglycemia toxicity is unclear. All five rats treated with 200 mg/kg BDD and sacrificed 4 h after exposure had necrosis localized in the periportal and midzonal regions of the liver lobule (Fig. 2), four rats had periportal and midzonal hemorrhage, and three rats had periportal and midzonal inflammation after BDD treatment. Similar to rats given the 250-mg/kg dose, the pericentral region was unaffected by 200-mg/kg BDD treatment (Fig. 2). All five of the rats sacrificed 24 h after treatment with 200 mg/kg BDD showed indications of necrosis, inflammation, and hemorrhage localized in the mid-zonal region of the liver, with some lesions in the periportal region (Fig. 2), and also had mild interstitial edema and hemorrhage in the pancreas (data not shown). Other tissues (spleen, heart, kidney, lungs, small intestine, bladder, sternum, and brain) removed 1, 4, or 24 h after treatment with BDD (200 or 250 mg/kg) did not indicate consistent lesions. Also, there were no lesions observed in the liver or kidneys 24 h after rats were given 125 mg/kg BDD. There were no lesions present in similar tissues removed from control animals dosed with saline.
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Effect of BDD Treatment on Blood Profile
Rats treated with 250 mg/kg BDD and sacrificed after both 1 or 4 h had significantly lower (p < 0.01) platelet counts when compared to controls given saline (Table 2). Also, 1 and 4 h after rats were given 250 mg/kg BDD, MPVs were significantly increased (p < 0.05) relative to controls (Table 2).
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Treatment of mice with 250 mg/kg BDD did not alter the RBC, WBC, or platelet counts or MCV, MCH, MCHC, and Hgb concentrations, RBC morphology, or MPV 1 at 4 h after BDD treatment (Table 2).
Effect of BDD Administration on Clinical Chemistry
Rats given 250 mg/kg BDD and then sacrificed 4 h later had a six-fold increase (p < 0.01) in ALT and AST activities, and lower serum concentrations of glucose (p < 0.01) compared to controls (Table 1). The two rats that experienced seizures during the 4-h time period had serum glucose concentrations of 4 and 12 mg/deciliter (dl). Also, plasma ammonia levels of rats 4 h after treatment with 250 mg/kg BDD were significantly elevated (220 ± 33 µmol/l; p < 0.01) relative to controls (160 ± 17 µmol/l). After 4 h, the levels of serum BUN (Table 1) and CK activities (data not shown) were similar between rats given 250 mg/kg BDD and controls dosed with saline. The rats treated with 250 mg/kg BDD and sacrificed 1 h later had similar levels of CK, ALT, and AST activities and similar BUN, glucose, and ammonia concentrations relative to controls (data not shown). Rats given 200 mg/kg BDD and then sacrificed 4 h later had similar levels of BUN and glucose and ALT and AST activities as compared to control rats (Table 1). However, 24 h after rats were given 200 mg/kg BDD, serum activities of ALT (1365 ± 1571 Units/l) and AST (1580 ± 2075 Units/l, respectively) were significantly higher (p < 0.05) than control ALT (43.3 ± 12.5 Units/l) and AST activities (70.0 ± 10.3 Units/l), whereas the BUN concentrations were similar to controls (data not shown). Rats treated with 200 or 250 mg/kg BDD had serum concentrations of sodium, potassium, and chloride ions, enzymatic CO2, and total calcium, and GGT activity similar to controls (data not shown). Twenty-four h after treatment, rats given 125 mg/kg BDD had serum BUN concentrations and ALT and AST activities similar to control rats (data not shown).
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In order to investigate the sequence of events involved in BDD-induced hepatotoxicity in rats, additional experiments were conducted to determine serum glucose concentrations, ALT and AST activities, and plasma ammonia levels at different time points (15 min, 1, 2, 3, and 4 h) after rats were given 250 mg/kg BDD (Fig. 3). Serum glucose was initially elevated (Fig. 3; most likely in response to ip injection). Glucose concentrations at 3 and 4 h after treatment were significantly lower (p < 0.05) than values obtained at 15 min and 1 h after treatment (Fig. 3). Glucose levels 4 h after treatment were significantly lower (p < 0.05) relative to values obtained from controls given saline. However, plasma ammonia levels were significantly higher (p < 0.05) 4 h after treatment relative to control rats given saline and sacrificed 4 h later. Serum ALT and AST activity was significantly higher (p < 0.01) 3 and 4 h after treatment relative to ALT and AST activities 15 min and 1 h after treatment (Fig. 3). Rats treated with 250 mg/kg BDD had significantly elevated (p < 0.01) ALT and AST activities 4 h after BDD treatment relative to control animals given saline. Serum glucose and ALT and AST activities and plasma ammonia levels were similar between rats given 250 mg/kg BDD and sacrificed after 1 h compared to control rats administered saline and sacrificed after 1 h.
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Differences Between Mouse and Rat Plasma BDD Concentrations and Half-Lives
The plasma BDD concentrations at different time points after 250 mg/kg BDD administration are shown in Figure 5. The plasma BDD concentration at 15 min after treatment was significantly higher (p < 0.01) in mice than in rats. However, the plasma BDD concentrations 3 and 4 h after treatment were significantly higher (p < 0.01) in rats than in mice. The plasma BDD concentrations were similar in mice and rats 1 and 2 h after treatment. The half-life of BDD in mice and rats given 250 mg/kg BDD was 0.44 and 2.12 h, respectively. Mice and rats had similar rates of plasma BDD clearance (data not shown).
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DISCUSSION |
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Comparison of the hepatic GSH and GSSG levels (Fig. 4) after rats were given 200 or 250 mg/kg BDD and after mice were given 250 mg/kg BDD shows species differences in the response to BDD treatment and provides insight into the mechanism of BDD-induced toxicity. Hepatic GSH and GSSG levels were rapidly depleted 1 h after mice and rats were given 250 mg/kg BDD and 1 h after rats were administered 200 mg/kg BDD. Hepatic GSH and GSSG levels only remained significantly lower 4 h after rats were administered 250 mg/kg BDD. The hepatic GSH and GSSG levels 4 h after rats were given 200 mg/kg BDD or mice were given 250 mg/kg BDD were able to recover from the initial BDD-induced GSH depletion. Because the levels of hepatic GSSG were not elevated, as is typical with oxidative stress, the continued depletion of hepatic GSH and GSSG suggests the formation of reactive metabolites that are depleting hepatic GSH and GSSG pools and may also alkylate macromolecules and disrupt cellular function.
Noting differences in the levels of BDD in the plasma of mice (data from Kemper et al., 1998) and rats (data from the present study) illustrate species differences in the half-life of BDD that may help explain the rat-sensitive BDD-induced toxicity. The half-life of BDD in the plasma of rats was over four times longer than that of mice. Although mice had higher plasma BDD concentrations 15 min after treatment, rats were exposed to BDD for a longer period of time. This could explain the sustained depletion of hepatic GSH and GSSG experienced by rats 4 h after BDD treatment. As a result of the longer half-life, the rat may also be exposed to GSH-depleting metabolite(s) of BDD for longer periods of time as compared to the mouse.
The rat clinical chemistry data illustrated events that occurred after the initial 250 mg/kg BDD-induced hepatic GSH and GSSG depletion. Serum glucose was only significantly depleted (Fig. 3) 3 and 4 h after treatment (relative to 15 min and 1 h time points). Similar to serum glucose, ALT and AST activities (Fig. 3) were only significantly higher 3 and 4 h after treatment relative to 15 min and 1 h after treatment. The data show that liver integrity and function (serum glucose and ALT and AST activities) was not impaired until 3 h after treatment. Therefore, the depletion of hepatic GSH and GSSG occurred about 2 h before the other signs of hepatotoxicity. Also, the impaired liver function of rats (hypoglycemia) was observed only with the sustained depletion of hepatic GSH and GSSG concentrations. Therefore, the continued depletion of hepatic GSH is likely contributing to the observed species differences of susceptibility to BDD-induced hepatotoxicity.
Similar to BDD, there is evidence suggesting rats are more sensitive to allyl alcohol-induced hepatotoxicity than are mice (Eigenberg et al., 1986). Oral administration of allyl alcohol (0.86 and 1.29 mmol/kg) resulted in a 10- and 30-fold increase, respectively, in rat serum ALT activity as compared to increases of 2- and 2.5-fold, respectively, in mouse serum. In the current study, BDD (250 mg/kg, i.e., 2.84 mmol/kg BDD) resulted in a similar rat-sensitive increase in serum ALT activity. Allyl alcohol may be toxic to rats at lower doses than BDD, but mice appear to be less sensitive to BDD- or allyl alcohol-induced hepatotoxicity. The periportal and midzonal distribution of BDD-induced lesions provides further evidence that ADH (Gebhardt, 1992
) likely contributes to the bioactivation of allylic alcohols (Fontaine et al., 2002
; Reid, 1972
) to their corresponding Michael acceptors (Fig. 6). Also, the observed BDD-induced hepatotoxicity in rats combined with the known hepatotoxicity of allyl alcohol and crotyl alcohol further shows allylic alcohols possess the capacity to be hepatotoxic, and as a result, should be handled with caution.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at 3154 School of Veterinary Medicine, 2015 Linden Drive, Madison, WI 53706. Fax: (608) 262-3926. E-mail: elfarra{at}svm.vetmed.wisc.edu.
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