Dichloroacetate, sodium: 3-Month oral toxicity studies in rats and dogs

Katz, Roger M.; Tai, Chin‐Yin; Diener, Robert M.; McConnell, R.F.; Semonick, D.E.

doi:10.1016/0041-008x(81)90289-1

Cited by 70 publications

(40 citation statements)

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“…Liver weights were significantly increased in a doserelated manner beginning with the lowest dose. By comparison, the lowest effect level noted in mice is at 0.5 g/L of drinking water, which approximates 70-100 mg/kg per day, while the lowest effect level appears to be 125 mg/kg in rats (122). Thus, the hepatomegaly induced by DCA is consistently observed across species.…”

Section: Hepatocarcinogenicity Of Tnichloroacetatementioning

confidence: 80%

“…Hepatic tumors are also induced by DCA in male F344 rats (90,91). High doses of DCA given to rats produced a peripheral neuropathy (122,123) that complicated the conduct of cancer bioassays. Nevertheless, increased incidence of hyperplastic nodules and hepatocellular adenomas and carcinomas was observed at 60 weeks of treatment at 2.4 g/L ( Table 3).…”

Section: Hepatocarcinogenicity Of Tnichloroacetatementioning

confidence: 99%

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Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.

Bull

2000

Environ Health Perspect

127

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Trichloroethylene (TCE) induces liver cancer in mice but not in rats. Three metabolites of TCE may contribute-chloral hydrate (CH), dichloroacetate (DCA), and trichloroacetate (TCA). CH and TCA appear capable of only inducing liver tumors in mice, but DCA is active in rats as well. The concentrations of TCA in blood required to induce liver cancer approach the mM range. Concentrations of DCA in blood associated with carcinogenesis are in the sub-pM range. The carcinogenic activity of CH is largely dependent on its conversion to TCA and/or DCA. TCA is a peroxisome proliferator in the same dose range that induces liver cancer. Mice with targeted disruptions of the peroxisome proliferator-activated receptor alpha (PPARa) are insensitive to the liver cancer-inducing properties of other peroxisome proliferators. Human cells do not display the responses associated with PPARa that are observed in rodents. This may be attributed to lower levels of expressed PPARax in human liver. DCA treatment produces liver tumors with a different phenotype than TCA. Its tumorigenic effects are closely associated with differential effects on cell replication rates in tumors, normal hepatocytes, and suppression of apoptosis. Growth of DCA-induced tumors has been shown to arrest after cessation of treatment. The DCA and TCA adequately account for the hepatocarcinogenic responses to TCE. Low-level exposure to TCE is not likely to induce liver cancer in humans. Higher exposures to TCE could affect sensitive populations. Sensitivity could be based on different metabolic capacities for TCE or its metabolites or result from certain chronic diseases that have a genetic basis. Key words: chloral hydrate, dichloroacetate, liver tumors, mode of action, trichloroacetate, trichloroethylene. -Environ Health Perspect 108(suppl 2):241-259 (2000). http.//ehpnetl.niehs.nih.gov/docs/2000/suppl-2/24 1-259bull/abstract. html

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Section: Hepatocarcinogenicity Of Tnichloroacetatementioning

confidence: 80%

Section: Hepatocarcinogenicity Of Tnichloroacetatementioning

confidence: 99%

Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.

Bull

2000

Environ Health Perspect

127

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“…One patient who received the drug for -4 mo developed a polyneuropathy that resolved after treatment stopped (27). Chronic administration of DCA to animals in doses far exceeding those used clinically also induces a reversible peripheral neuropathy (47)(48)(49). Oxalate, an end product of DCA metabolism (39,40), is a known neurotoxin (50,51) and may be responsible for the neuropathic changes associated with DCA.…”

Section: Discussionmentioning

confidence: 99%

Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.

Stacpoole¹,

Harwood²,

Varnado³

1983

J. Clin. Invest.

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A B S T R A C T Dichloroacetate (DCA) markedly reduces circulating cholesterol levels in animals and in patients with combined hyperlipoproteinemia or homozygous familial hypercholesterolemia (FH). To investigate the mechanism of its cholesterol-lowering action, we studied the effects of DCA and its hepatic metabolites, glyoxylate and oxalate, on the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) obtained from livers of healthy, reverse light-cycled rats. Oral administration of DCA for 4 d decreased HMG CoA reductase activity 46% at a dose of 50 mg/kg per d, and 82% at a dose of 100 mg/kg per d. A 24% decrease in reductase activity was observed as early as 1 h after a single dose of 50 mg/ kg DCA. The inhibitory effect of the drug was due to a fall in both expressed enzyme activity and the total number of reductase molecules present. DCA also decreased reductase activity when added to suspensions of isolated hepatocytes. With chronic administration, DCA inhibited 3H20 incorporation into cholesterol by 38% and into triglycerides by 52%. When liver microsomes were incubated with DCA, the pattern of inhibition of reductase activity was noncompetitive for both HMG CoA (inhibition constant [Ki] 11.8 mM) and NADPH (K; 11.6 mM). Inhibition by glyoxylate was also noncompetitive for both HMG CoA (K1 1.2 mM) and NADPH (K1 2.7 mM). Oxalate inhibited enzyme activity only at nonsaturating concentrations of NADPH (K, 5.6 mM Department of Medicine, College ylene glycol, all of which can form glyoxylate, also inhibited reductase activity. Using solubilized and 60-fold purified HMG CoA reductase, we found that the inhibitory effect of glyoxylate was reversible. Furthermore, the inhibition by glyoxylate was an effect exerted on the reductase itself, rather than on its regulatory enzymes, reductase kinase and reductase phosphatase. We conclude that the cholesterol-lowering effect of DCA is mediated, at least in part, by inhibition of endogenous cholesterol synthesis. The probable mechanisms are by inhibition of expressed reductase activity by DCA per se and by conversion of DCA to an active metabolite, glyoxylate, which noncompetitively inhibits HMG CoA reductase. These studies thus identify a new class of pharmacological agents that may prove useful in regulating cholesterol synthesis and circulating cholesterol levels in man.

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“…These effects range from cardiac malformations in rats to hepatocellular carcinomas in rats and mice (Bhat et al, 1991;DeAngelo et al, 1991DeAngelo et al, , 1996Daniel et al, 1992). In addition, DCA is spermatotoxic in rats (Bhat et al, 1991;Linder et al, 1997); causes central and peripheral nervous system disorders in humans (Stacpoole et al, 1998), dogs (Katz et al, 1981;Cicmanec et al, 1991), and rats (Moser et al, 1999); causes diffuse degeneration of the tubular epithelium and glomerular cells in rats (Mather et al, 1990); and causes bronchial toxicity and prostatic glandular atrophy in dogs (Cicmanec et al, 1991). A time-and dose-dependent decrease in plasma insulin concentrations are observed in B6C3F1 mice given DCA, and this effect has been associated with DCA-induced inactivation of GSTZ1-1 (Lingohr et al, 2001).…”

Section: Fig 9 Immunohistochemical Detection Of Gstz1-1 In Rat Adrementioning

confidence: 99%

“…DCA-induced toxicities, including peripheral neuropathies, testicular atrophy (Katz et al, 1981;Toth et al, 1992;Linder et al, 1994), and hepatocellular carcinomas Nelson et al, 1990;DeAngelo et al, 1991;Carter et al, 1995), are observed in rats, mice, and dogs. Rats are more susceptible than mice to DCA-induced hepatocellular carcinomas, and male rats are more susceptible than female rats (Richmond et al, 1995;DeAngelo et al, 1996;Pereira, 1996).…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical Localization and Activity of Glutathione Transferase Zeta (GSTZ1–1) in Rat Tissues

Lantum

Baggs²,

Krenitsky³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Glutathione transferase zeta (GSTZ1-1) catalyzes the biotransformation of a range of ␣-haloacids, including dichloroacetic acid (DCA), and the penultimate step in the tyrosine degradation pathway. DCA is a rodent carcinogen and a common drinking water contaminant. DCA also causes multiorgan toxicity in rodents and dogs. The objective of this study was to determine the expression and activities of GSTZ1-1 in rat tissues with maleylacetone and chlorofluoroacetic acid as substrates. GSTZ1-1 protein was detected in most tissues by immunoblot analysis after immunoprecipitation of GSTZ1-1 and by immunohistochemical analysis; intense staining was observed in the liver, testis, and prostate; moderate staining was observed in the brain, heart, pancreatic islets, adrenal medulla, and the epithelial lining of the gastrointestinal tract, airways, and bladder; and sparse staining was observed in the renal juxtaglomerular regions, skeletal muscle, and peripheral nerve tissue. These patterns of expression corresponded to GSTZ1-1 activities in the different tissues with maleylacetone and chlorofluoroacetic acid as substrates. Specific activities ranged from 258 ؎ 17 (liver) to 1.1 ؎ 0.4 (muscle) nmol/min/mg of protein with maleylacetone as substrate and from 4.6 ؎ 0.89 (liver) to 0.09 ؎ 0.01 (kidney) nmol/min/mg of protein with chlorofluoroacetic acid as substrate. Rats given DCA had reduced amounts of immunoreactive GSTZ1-1 protein and activities of GSTZ1-1 in most tissues, especially in the liver. These findings indicate that the DCA-induced inactivation of GSTZ1-1 in different tissues may result in multiorgan disorders that may be associated with perturbed tyrosine metabolism.Glutathione transferases (GST 1 ) are a multigene family of phase II drug-metabolizing enzymes that catalyze the conjugation of glutathione with a range of endogenous and exogenous substrates (Armstrong, 1997;Salinas and Wong, 1999). Soluble and membrane-bound GSTs are expressed in many tissues, and soluble GSTs constitute 1 to 5% of total cytosolic protein (Morgenstern et al., 1984;Sundberg et al., 1993;Rowe et al., 1997). Activities with model substrates and the subcellular localization of GSTA, GSTM, GSTP, GSTT, and GSTO class GSTs and of microsomal GST1 have been previously characterized (Meyer et al., 1991;Hiratsuka et al., 1994;Mannervik and Widersten, 1995;Armstrong, 1997;Otieno et al., 1997;Yin et al., 2001).The expression of GSTs is regulated pre-and post-translationally in a tissue-specific manner resulting in protein products that differ quantitatively in different tissues (Tu et al., 1983;Rozell et al., 1993;Rowe et al., 1997). Testes express the highest amount of total GST protein per milligram cytosolic protein followed by the liver, brain, pancreas, adrenals, heart, and lung (DePierre and Morgenstern, 1983;Listowsky et al., 1998). Major GST-expressing tissues are the principal sites for drug and chemical metabolism indicative of the role of GSTs in the biotransformation of xenobiotics (Pabst et al., 1973;Armstrong, 1997). Studies...

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Dichloroacetate, sodium: 3-Month oral toxicity studies in rats and dogs

Cited by 70 publications

References 10 publications

Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.

Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.

Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.

Immunohistochemical Localization and Activity of Glutathione Transferase Zeta (GSTZ1–1) in Rat Tissues

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