* Department of Pharmacology and Physiology and
Laboratory of Animal Medicine, University of Rochester Medical Center, 601 Elmwood Ave., Box 711, Rochester, New York 14642
Received July 23, 2002; accepted August 27, 2002
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ABSTRACT |
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Key Words: chlorofluoroacetic acid; difluoroacetic acid; dichloroacetic acid; glutathione transferase zeta; nephrotoxicity; lactic acidosis; fluoride.
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INTRODUCTION |
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DCA is biotransformed by glutathione transferase zeta (GSTZ1-1) to glyoxylate, which may be oxidized to oxalate or transaminated to glycine (James et al., 1998; Lin et al., 1993
; Tong et al., 1998a
,b
). DCA is also a mechanism-based inactivator of GSTZ1-1 that covalently modifies GSTZ1-1 and targets it for degradation (Anderson et al., 1999
; Tzeng et al., 2000
). The inactivation and lowered expression of GSTZ1-1 in different tissues of rats given DCA are associated with DCA-induced perturbations in tyrosine metabolism and with DCA-induced multiorgan toxicities (Cornett et al., 1999
; Lantum et al., 2002
).
Halogenated carboxylic acid analogues of DCA that also inhibit pyruvate dehydrogenase kinase may be alternative therapeutic agents for the treatment of congenital lactic acidosis and other lactic acidotic disorders. Chlorofluoroacetic acid (CFA) and difluoroacetic acid (DFA) also inhibit pyruvate dehydrogenase kinase (Whitehouse et al., 1974). CFA is a substrate for GSTZ1-1 and is metabolized to glyoxylate; in contrast to DCA, CFA is a poor inactivator of GSTZ1-1 (Anderson et al., 1999
; Tong et al., 1998b
; Tzeng et al., 2000
). DFA is neither a substrate nor an inactivator of GSTZ1-1 (Anderson et al., 1999
; Tong et al., 1998b
). CFA and DFA may, therefore, provide alternatives to DCA for the management of congenital and acquired lactic acidotic disorders. The toxicities of CFA and DFA have apparently not been investigated.
The objective of this study was to determine the dose- and time-dependent toxic effects of CFA in rats. The data presented indicate that the observed nephrotoxic effects of CFA are associated with its metabolism to inorganic fluoride. DFA was also nephrotoxic, although it was not metabolized to inorganic fluoride. To our knowledge, this is the first report of CFA-induced nephrotoxicity in rats.
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MATERIALS AND METHODS |
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Animals.
Male, Fischer 344 rats (200250 g; Taconic Farms, Germantown, NY) were housed individually in metabolism cages, which permitted separation of fecal waste from urine with minimal contamination from food particles, and were provided with standard rodent chow (Purina, St. Louis, MO) and double-distilled water ad libitum. The animal rooms were humidity- and temperature-controlled, and the rats were exposed to 12-h dark-light cycles. The protocol for animal use was reviewed and approved by the University Committee on Animal Resources. The rats were allowed one day to adapt to the metabolism cages prior to the start of each experiment.
Rats were given DCA, CFA, and DFA intraperitoneally. The solutions were prepared daily in 0.9% saline (Abbott Laboratories, North Chicago, IL) and were brought to pH 7.3 ± 0.2 by addition of NaOH. The solutions were filter-sterilized with 0.22-µm filter units (Sterivex-GVTM; Millipore, Bedford, MA).
Rats were divided into groups of three for each experiment and were injected once daily between 9.00 and 10.00 A.M. for 5 days with 01.2 mmol/kg DCA, CFA, or DFA dissolved in 1.5 ml saline. Urine samples were collected in plastic containers every 612 h and were centrifuged at 3000 rpm to remove food particles. The 24-h samples from individual rats were pooled and stored at 20°C prior to urinalysis.
After 5 or 6 days of treatment, animals were anesthetized with ether and sacrificed by decapitation. Blood was collected in nonheparinized polypropylene tubes and centrifuged at 5000 rpm to obtain serum that was stored at 80°C until analyzed.
Biochemical analysis of urine and serum.
Urine and serum samples were analyzed by the Veterinary Laboratory of Rochester (Rochester, NY) and by the Strong Memorial Hospital Clinical Laboratories (University of Rochester, Rochester, NY). The urine samples were analyzed according to standard laboratory automated protocols for protein, creatinine, glucose, potassium, sodium, and chloride concentrations, pH, and specific gravity. Sera from nonhemolyzed blood samples were analyzed for chloride, carbon dioxide, potassium, sodium, urea nitrogen, creatinine, glucose, and calcium, albumin, total protein, and total bilirubin concentrations and for alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) activities.
Fluoride analysis.
Inorganic fluoride concentrations in urine and serum were measured with a pH/ISE meter 920A (ThermoOrion; ATI Orion, Boston, MA) equipped with fluoride-selective and reference electrodes (9001, 9409, and 9609, ThermoOrion) and with the low-level total ion strength adjustor buffer (TISAB), according to the manufacturers instructions. The fluoride concentrations determined in 100-µl urine samples were adjusted for 24-h urine volumes for each rat, to determine the daily excretion of inorganic fluoride, which was reported as µmol fluoride/24 h.
Morphological analysis.
Rats were anesthetized with ether and then sacrificed by decapitation. The kidneys, liver, testes, brain, and heart were excised. For light microscopic studies, sections of each tissue were immersed immediately in 250 ml of neutralized 10% (v/v) formalin (JT Baker, Phillipsburg, NJ). The tissues were kept in the fixative for 12 h, dehydrated with serial ethanol cycles, and then embedded in paraffin. The paraffin-embedded tissue was cut into 5-µm sections and mounted on Superfrost-plus slides (VWR Scientific Products, West Chester, PA). The tissue sections were deparaffinized and stained with Mayer hematoxylin and eosin stains for light microscopic analysis. The slides were coded before submission to the pathologist for analysis.
For electron microscopic studies, 2 x 2-mm sections of excised tissue were immersion-fixed for 24 h in phosphate-buffered saline (pH 7.4) containing 4.0% paraformaldehyde and 1.0% glutaraldehyde. The tissue was then rinsed in phosphate-buffered saline, postfixed in phosphate-buffered 1.0% osmium tetroxide, dehydrated in a graded series of ethanol-containing solutions, and subsequently immersed into 100% propylene oxide. The tissue samples were infiltrated with Epon resin (Electron Microscopy Sciences, Fort Washington, PA), embedded in molds, and polymerized overnight at 65°C. One- or two-micron sections were cut and stained with toluidine blue to determine the area of interest, which was then thin-sectioned with a diamond knife. The thin sections were mounted on copper grids and stained with aqueous 2.0% uranyl acetate and lead citrate. The sections were examined and photographed with a Hitachi H-7100 electron microscope. A renal pathologist analyzed the coded electron micrographs.
Hepatic and renal GSTZ1-1 activities with chlorofluoroacetic acid as substrate.
Samples of liver and kidney were obtained at sacrifice and were rinsed in isotonic ice-cold homogenization buffer containing 20 mM potassium phosphate buffer (pH 7.4), 2 mM EDTA, 2 mM DTT, 100 µM phenylmethylsulfonyl fluoride (Sigma-Aldrich), and 1.15% KCl. The tissues (3 g wet weight) were placed in 15 ml of homogenization buffer and were homogenized with a power-driven Dounce-type Teflon pestle homogenizer; the homogenates were centrifuged at 700g for 15 min. The supernatant fractions were dialyzed overnight in 30 volumes of the homogenization buffer that lacked KCl and were stored at 80°C until used. GSTZ1-1 activities were determined in samples (150500 µg protein) of the 700 g supernatant fractions with 2 mM CFA as substrate, as previously described (Lantum et al., 2002).
Statistical analyses.
The data were analyzed by analysis of variance with Bonferronis Multiple Comparison Test (GraphPad Prism®, GraphPad Software Inc., San Diego, CA). A level of p < 0.05 was chosen for acceptance or rejection of the null hypothesis.
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RESULTS |
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In rats given 0.6 and 1.2 mmol/kg CFA, a significant, dose-dependent increase in urine volumes for the first 4 days of treatment was observed (Fig. 1A; the 24-h urine volume of one of the rats given 1.2 mmol/kg was less than that of controls beyond the second day, indicating oligouria, which accounts for the large error bars in that group.) The specific gravity was also significantly reduced in rats that received 0.6 and 1.2 mmol/kg CFA (Fig. 1B
). Urine glucose excretion was significantly elevated for the first 2 days of treatment in rats given 1.2 mmol/kg CFA (Fig. 1C
), but returned to control values on days 35 of treatment. After treatment of rats for 5 days with CFA, serum glucose concentrations were not significantly different from control (data not shown). No significant changes in protein excretion were observed (data not shown). Urine sodium, potassium, and chloride concentrations were not significantly different from control values in CFA-treated rats; the pH of the urine samples of the CFA-treated rats was similar to that of control animals (pH = 7.5 ± 0.5).
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Rats given DCA for 5 days and then a single dose of CFA also showed renal damage, which was more pronounced than that seen in rats that were given saline and then a single dose of CFA. The characteristics of the proximal tubule damage, although enhanced, were similar to those described for rats given daily doses of CFA alone for 5 days (see Fig. 2).
Renal and hepatic biotransformation of CFA.
The renal and hepatic biotransformation of CFA to glyoxylate was determined in homogenates of kidney and liver from rats given saline, DCA, or CFA for 5 days. The biotransformation of CFA to glyoxylate was increased in kidney homogenates from rats given CFA compared with those from rats given saline alone or DCA (Fig. 6A). Hence, these data indicate that treatment of rats with CFA for 5 days enhanced the renal biotransformation of CFA to glyoxylate.
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Systemic effects of CFA.
Serum analysis did not show any significant dose-dependent differences in blood urea nitrogen, electrolytes, total bilirubin, and total protein concentrations. Aminotransferases (ALT, AST) and alkaline phosphatase activities were within normal values. Morphological analysis of liver, brain, heart, and testis of rats given CFA did not reveal any significant changes. These data indicated that the effects of CFA were limited to the kidneys after a 5-day treatment regimen.
Comparison of the nephrotoxicity of DCA, CFA, and DFA.
The effects of five daily doses of 1.2 mmol/kg CFA, 1.2 mmol/kg DFA, and 1.2 mmol/kg DCA were compared with those of saline-treated rats. In rats given DCA, urine volume, glucose excretion, urine specific gravity, and renal morphology were not significantly different from saline-treated rats (data not shown).
DFA was, however, nephrotoxic, although the characteristics of DFA-induced renal damage differed from those induced by CFA. The 24-h urine volumes and inorganic fluoride excretion in rats given DFA were not significantly different from saline- or DCA-treated rats, whereas CFA caused polyuria and elevated fluoride excretion (Figs. 7A and 7B). Light microscopic analysis of kidneys from rats given 1.2 mmol/kg DFA for 5 days showed limited morphological changes, which were more prominent in the distal tubule than the proximal tubule when compared with saline- and DCA-treated rats (data not shown). CFA-induced damage was more severe than DFA-induced damage and was predominant in the proximal tubules (data not shown).
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DISCUSSION |
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The dose-response curve for CFA was apparently steep, with a threshold for anuria and lethality lying between 1.21.5 mmol/kg. The effect of CFA was most prominent after the initial dose. The regenerative lesions observed and the transient changes in urine volume and glucose excretion indicated a rapid repair process. The steep dose-response effects, the transient nature of the biochemical changes, and the rapid repair process may underlie some of the variability that was observed in rats given 1.2 mmol/kg CFA.
CFA induced dose-dependent nephrotoxicity that was most prominent in proximal tubular epithelial cells and was characterized by transient polyuria and glycosuria. Electron microscopic studies of kidneys of CFA-treated rats showed the presence of apoptotic cells, indicating a role for apoptosis in CFA-induced nephrotoxicity. DFA was also nephrotoxic, but DCA was not. The nephrotoxic potencies of the three -dihaloacetic acids were: CFA > DFA > DCA.
Mechanism of CFA-induced nephrotoxicity.
GSTZ1-1 is expressed in renal proximal tubules (Lantum et al., 2002) and catalyzes the biotransformation of CFA to glyoxylate with a concomitant release of fluoride (Tong et al., 1998b
). The observations that urine fluoride concentrations were elevated in rats given CFA and that CFA caused a dose-dependent transient polyuria and glycosuria indicate a role for fluoride in CFA-induced nephrotoxicity. The data also showed that treatment with DCA for 5 days enhanced the renal biotransformation of CFA to glyoxylate, fluoride excretion, and CFA-induced renal damage. These data support a role for GSTZ1-1-catalyzed biotransformation of CFA to inorganic fluoride in CFA-induced nephrotoxicity.
Methoxyflurane-induced nephrotoxicity is attributed to its metabolism to inorganic fluoride (Kharasch et al., 1995; Mazze et al., 1972
), and methoxyflurane-induced nephrotoxicity is characterized by transient polyuria, transient glycosuria, lowered urine specific gravity, and proximal tubular damage (Kharasch et al., 1995
; Mazze et al., 1972
). The nephrotoxic effects of methoxyflurane are similar to those seen in rats given CFA and in acute fluoride-induced nephrotoxicity (Taylor et al., 1961
). The mechanism of fluoride-induced nephrotoxicity is not fully understood, but it is associated with impaired uptake of sodium and impaired reabsorption of water in different segments of the nephron (Lochhead et al., 1997
; Zager and Iwat, 1997). Some of these effects are associated with mitochondrial dysfunction and inhibition of Na+-K+-ATPase pump activity in the kidney (Cittanova et al., 1996
) or impaired cAMP-dependent signaling (Rush and Willis, 1982
).
CFA is metabolized to glyoxylate, which may also play a role in CFA-induced nephrotoxicity. CFA-derived glyoxylate may be oxidized to oxalate, reduced to glycolate, or transaminated to glycine (James et al., 1998). Glyoxylate is cytotoxic to isolated mouse proximal tubular cells at concentrations >2.5 mg/ml, and the in vivo metabolism of glyoxylate to oxalate may result in obstructive crystalluria (Poldelski et al., 2001
). Glycine is not nephrotoxic (Heyman et al., 1992
) and, on the contrary, blocks the effects of several nephrotoxic agents (Chen et al., 2001
). It is, however, unlikely that glyoxylate and its metabolites are associated with the acute CFA-induced nephrotoxicity, because DCA, which is also metabolized to glyoxylate, oxalate, and glycine (James et al., 1998
; Lipscomb et al., 1995
; Tong et al., 1998a
,b
), was not nephrotoxic in the present study. Hence, the mechanism of CFA-induced nephrotoxicity appears to be associated with its renal biotransformation to inorganic fluoride.
Dose-dependent fluoride excretion.
Rats given 0.3, 0.6, or 1.2 mmol/kg CFA excreted 11 ± 1 µmol fluoride/24 h (0.2 mg fluoride/24 h), 20 ± 3 µmol fluoride/24 h (
0.4 mg fluoride/24 h), and 38 ± 8 µmol fluoride/24 h (
0.7 mg fluoride/24 h), respectively, after the initial dose of CFA. These daily fluoride excretion rates in rats after a single ip dose of 0.31.2 mmol/kg CFA are of the same magnitude as those measured in rats given single oral doses of 520% of the LD50 of NaF (11.3 mmol/kg; 471.7 mg NaF/kg rat body weight); rats given 0.62.3 mmol/kg NaF excrete
0.10.8 mg/24 h inorganic fluoride (Usuda et al., 1999
). The dose-dependent fluoride excretion in CFA-treated rats was therefore very similar to that of NaF, lending further support to the hypothesis that inorganic fluoride release underlies CFA nephrotoxicity. Fluoride release may be a good marker of CFA exposure and therefore a good predictor of CFA toxicity.
Bioactivation of CFA.
GSTZ1-1 catalyzes the biotransformation of CFA and other dihaloacetic acids to glyoxylate (Anderson et al., 1999; Tong et al., 1998b
). Evidence implicating another enzyme in the biotransformation of another dihaloacetic acid, bromochloroacetic acid, has been presented, but the enzyme has not been identified (Sylvester et al., 2002
). Experiments designed to determine the effects of DCA-induced inactivation of GSTZ1-1 showed that rats given DCA for 5 days before a single dose of CFA had normal 24-h urine volumes and normal urine protein and glucose concentrations (data not shown), indicating that DCA blocked some of the nephrotoxic effects of CFA. DCA treatment did not, however, prevent the increased fluoride excretion and morphological damage induced by CFA. The reason for these contradictory outcomes is not known but may indicate that some of the toxic effects of CFA may be attributed to CFA itself or to an enzyme in addition to GSTZ1-1 that catalyzes the renal metabolism of CFA to fluoride or another nephrotoxic metabolite. It is also possible that the residual, GSTZ1-1-catalyzed biotransformation of CFA in DCA-treated rats plays a role in CFA-induced nephrotoxicity.
The cytochromes P450 and glutathione transferases play major roles in the hepatic biotransformation of halogenated hydrocarbons in rats and mice (Anders 1980; Madelian and Warren, 1977
; Van Dyke, 1966
). Less is known, however, about the renal biotransformation of halogenated hydrocarbons. The hepatic biotransformation of methoxyflurane to inorganic fluoride, for example, is catalyzed by CYPs 2E1, 2A6, and 3A in humans (Kharasch and Thummel, 1993
). The role of these enzymes and other renal enzymes, in addition to GSTZ1-1, in the metabolism of CFA and DFA has not been well studied and merits investigation.
DFA toxicity.
DFA is neither a substrate nor an inactivator of GSTZ1-1 (Anderson et al., 1999; Tong et al., 1998b
), and its nephrotoxicity was not associated with increased fluoride excretion. This indicates that the observed nephrotoxicity of DFA may be associated with the parent molecule or with alternative bioactivation reactions. Mechanisms of the bioactivation of DFA merit investigation.
Human exposure to CFA and DFA.
Humans may be exposed to CFA from a variety of sources. Human exposure to CFA and DFA may occur as a consequence of the metabolism of chlorotrifluoroethylene and tetrafluoroethylene by the cysteine conjugate ß-lyase pathway (Anders and Dekant, 1998; Dekant et al., 1987
; Hargus et al., 1991
; Lock and Ishmael, 1998
). The cytochrome P450-dependent metabolism of 1,2-dichloro-1-fluoroethane (HCFC-141) and 1,1,2-trichloro-2-fluoroethane (HCFC-131) leads to the formation of CFA as a metabolite (Yin et al., 1996
). The toxicities of CFA and DFA described in this study may have implications regarding the safety of a variety of hydrofluorocarbons or hydrochlorofluorocarbons that yield CFA and DFA as metabolites (Anders, 1991
).
Conclusions.
CFA and DFA are nephrotoxic -haloalkanoic acids. The available evidence supports the concept that the mechanism of CFA-induced nephrotoxicity is associated with its biotransformation to inorganic fluoride. Indeed, CFA-induced nephrotoxicity bears strong resemblance to methoxyfluorane- and inorganic fluoride-induced nephrotoxicity: all are characterized by transient polyuria, glycosuria, decreased urine specific gravity, and proximal tubular damage. In contrast, the data about DFA-induced nephrotoxicity do not implicate a mechanism involving inorganic fluoride, although the mechanism of DFA-induced nephrotoxicity is not understood.
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ACKNOWLEDGMENTS |
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NOTES |
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