Dichloroacetate (DCA) inhibits its own metabolism and is converted to glyoxylate by glutathione S-transferase zeta (GSTz). GSTz is identical to maleylacetoacetate isomerase, an enzyme of tyrosine catabolism that converts maleylacetoacetate (MAA) to fumarylacetoacetate and maleylacetone (MA) to fumarylacetone. MAA and MA are alkylating agents. Rats treated with DCA for up to five days had markedly decreased hepatic GSTz activity and increased urinary excretion of MA. When dialyzed cytosol obtained from human liver was incubated with DCA, GSTz activity was unaffected. In contrast, DCA incubation inhibited enzyme activity in dialyzed hepatic cytosol from rats. Incubation of either rat or human hepatic cytosol with MA led to a dose dependent inhibition of GSTz. These data indicate that humans or rodents exposed to DCA may accumulate MA and/or MAA which inhibit(s) GSTz and, consequently, DCA biotransformation. Moreover, DCA-induced inhibition of tyrosine catabolism may account for the toxicity of this xenobiotic in humans and other species.
... Glutathione transferase zeta (GSTZ1-1) catalyzes the biotransformation of a range of alpha-haloalkanoates and the cis-trans isomerization of maleylacetoacetate. ... The purpose of this study was to examine the GSTZ1-1-catalyzed bioactivation of dichloroacetic acid (DCA), including the reaction of DCA-derived glyoxylate with amino acid nucleophiles and the characterization of the structures and kinetics of adduct formation by LC/MS. The binding of (1-(14)C)DCA-derived label to bovine serum albumin required both GSTZ1-1 and GSH, whereas the binding to dialyzed rat liver cytosolic protein was increased in the presence of GSH. Studies with model peptides (antiflammin-2 and IL-8 inhibitor) indicated that glyoxylate, rather than S-(alpha-chlorocarboxymethyl)glutathione, was the reactive species that modified amino acid nucleophiles. Both addition (+74 Da) and addition-elimination (+56 Da) adducts of glyoxylic acid were observed. Addition adducts (+74 Da) could not be characterized completely by mass spectrometry, whereas addition-elimination adducts (+56 Da) were characterized as 2-carboxy-4-imidazolidinones. 2-Carboxy-4-imidazolidinones were formed by the rapid equilibrium reaction of glyoxylate with the N-terminal amino group of antiflammin-2 to give an intermediate carbinolamine (K(eq) = 0.63 mM(-1)), which slowly eliminated water to give an intermediate imine (k(2) = 0.067 hour(-1)), which rapidly cyclized to give the 2-carboxy-4-imidazolidinone. Glucose 6-phosphate dehydrogenase was inactivated partially by glyoxylate when reactants were reduced with sodium borodeuteride, which may indicate that glyoxylate reacts with selective lysine epsilon-amino groups. The results of the present study demonstrate that GSTZ1-1 catalyzes the bioactivation of DCA to the reactive metabolite glyoxylate. The reaction of glyoxylate with cellular macromolecules may be associated with the multiorgan toxicity of DCA.
Trichloroethylene (TCE) is a well-known carcinogen in rodents and concerns exist regarding its potential carcinogenicity in humans. Oxidative metabolites of TCE, such as dichloroacetic acid (DCA) and trichloroacetic acid (TCA), are thought to be hepatotoxic and carcinogenic in mice. The reactive products of glutathione conjugation, such as S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and S-(1,2-dichlorovinyl) glutathione (DCVG), are associated with renal toxicity in rats. Recently, we developed a new analytical method for simultaneous assessment of these TCE metabolites in small-volume biological samples. Since important gaps remain in our understanding of the pharmacokinetics of TCE and its metabolites, we studied a time-course of DCA, TCA, DCVG and DCVG formation and elimination after a single oral dose of 2100 mg/kg TCE in male B6C3F1 mice. Based on systemic concentration-time data, we constructed multi-compartment models to explore the kinetic properties of the formation and disposition of TCE metabolites, as well as the source of DCA formation. We conclude that TCE-oxide is the most likely source of DCA. According to the best-fit model, bioavailability of oral TCE was approximately 74%, and the half-life and clearance of each metabolite in the mouse were as follows: DCA: 0.6 hr, 0.081 mL/hr; TCA: 12 hr, 3.80 mL/hr; DCVG: 1.4 hr, 16.8 mL/hr; DCVC: 1.2 hr, 176 mL/hr. In B6C3F1 mice, oxidative metabolites are formed in much greater quantities (approximately 3600 fold difference) than glutathione-conjugative metabolites. In addition, DCA is produced to a very limited extent relative to TCA, while most of DCVG is converted into DCVC. These pharmacokinetic studies provide insight into the kinetic properties of four key biomarkers of TCE toxicity in the mouse, representing novel information that can be used in risk assessment.
Dichloroacetate (DCA) is a potential environmental hazard and an investigational drug. Repeated doses of DCA result in reduced drug clearance, probably through inhibition of glutathione transferase zeta1 (GSTZ1), a cytosolic enzyme that converts DCA to glyoxylate. DCA is known to be taken up by mitochondria, where it inhibits pyruvate dehydrogenase kinase, its major pharmacodynamic target. We tested the hypothesis that the mitochondrion was also a site of DCA biotransformation. Immunoreactive GSTZ1 was detected in liver mitochondria from humans and rats, and its identity was confirmed by liquid chromatography/tandem mass spectrometry analysis of the tryptic peptides. Study of rat submitochondrial fractions revealed GSTZ1 to be localized in the mitochondrial matrix. The specific activity of GSTZ1-catalyzed dechlorination of DCA was 2.5- to 3-fold higher in cytosol than in whole mitochondria and was directly proportional to GSTZ1 protein expression in the two compartments. Rat mitochondrial GSTZ1 had a 2.5-fold higher (App)K(m) for glutathione than cytosolic GSTZ1, whereas the (App)K(m) values for DCA were identical. Rats administered DCA at a dose of 500 mg/kg/day for 8 weeks showed reduced hepatic GSTZ1 activity and expression of approximately 10% of control levels in both cytosol and mitochondria. We conclude that the mitochondrion is a novel site of DCA biotransformation catalyzed by GSTZ1, an enzyme colocalized in cytosol and mitochondrial matrix. /Dichloroacetate/
Dichloroacetic acid is metabolized in the liver by oxidative dechlorination to yield glyoxylate, which can enter intermediary metabolism and either be oxidized to oxalate and excreted, converted to carbon dioxide, and/or incorporated into amino acids or other cellular molecules. (L2086)
IDENTIFICATION AND USE: Dichloroacetic acid (DCA) is a colorless liquid. Dichloroacetic acid, particularly in the form of its esters, is an intermediate in organic synthesis, used in the production of glyoxylic acid, dialkoxy and diaroxy acids, and sulfonamides and in the preparation of iron chelates in the agricultural sector. It is also used as an analytical reagent in fiber manufacture (polyethylene terephthalate) and as a medicinal disinfectant (substitute for formalin). DCA is a cauterizing agent and is used in medical practice as dichloroacetate on calluses, hard and soft corns, xanthoma palpebrarum, seborrhoeic keratoses, in-grown nails, cysts and benign erosion of the cervix. DCA is a nonproprietary drug used for treatment of inherited mitochondrial diseases. It was discovered in 2007 that dichloroacetate sodium (the sodium salt of DCA) promotes human cancer cell death by a novel mechanism. Soon after this discovery, physicians began using it off-label for cancer treatment. Dichloroacetate inhibits pyruvate dehydrogenase kinase, an enzyme that promotes pyruvate entry into mitochondria. HUMAN STUDIES: Drowsiness is a fairly frequent side effect of DCA and has been observed in healthy volunteers, adults with type I diabetes and patients with lactic acidosis. A patient with homozygous familial hypercholesterolemia who received single doses of 50 mg/kg bw DCA daily for four months developed reversible peripheral neuropathy characterized by loss of reflexes and muscle weakness. The effect subsided several weeks after cessation of administration of DCA. Preclinical evidence suggests that dichloroacetate can reverse the "Warburg effect" and inhibit growth in cancer models. The "Warburg effect," also termed aerobic glycolysis, describes the increased reliance of cancer cells on glycolysis for ATP production, even in the presence of oxygen. Consequently, there is continued interest in inhibitors of glycolysis as cancer therapeutics. One example is dichloroacetate, a pyruvate mimetic that stimulates oxidative phosphorylation through inhibition of pyruvate dehydrogenase kinase. ANIMAL STUDIES: DCA induced severe injury when applied to eyes of rabbits. Exposure of male and female rats to DCA at target doses of 10-600 mg/kg body weight per day in the drinking water for 14 days resulted in reduced weight gain only in the group given the highest dose. Treatment also increased urinary excretion of ammonia and changed the activities of enzymes of ammoniagenesis, indicating renal compensation for an acid load. Ocular toxicity was observed in beagle dogs that were treated for 13 weeks with an approximate dose of 1100 mg/kg body weight DCA in the drinking water. No similar organ specific effect has been seen in other studies or in other species. Induction of peroxisome proliferation has been repeatedly associated with the chronic toxicity and carcinogenicity of DCA to the liver. It can induce peroxisome proliferation in the livers of both mice and rats, as indicated by increased activities of palmitoyl coenzyme A oxidase and carnitine acetyl transferase, the appearance of a peroxisome proliferation associated protein and increased volume-density of peroxisomes after exposure to DCA for 14 days. In eight studies, DCA salt administered in the drinking water to male and/or female mice increased the incidences of hepatocellular adenomas and/or carcinomas. Following oral administration of DCA in the drinking-water to male rats, an increased incidence of hepatocellular carcinomas was found at a dose that decreased body weight and an increase in the combined incidence of adenomas and carcinomas was found at a lower dose. When administered in the drinking-water, DCA promoted hepatocellular carcinomas in carcinogen-initiated male and female mice in three studies. DCA and its metabolites accumulate in rat fetuses after treatment of the dam. Maternal doses of 140-2400 mg/kg bw per day on days 6-15 of gestation altered development of the heart and major vessels and less frequently, the kidneys and the orbits of the eyes, as reported in some studies. DNA strand breaks were not induced in mammalian cells in vitro in the absence of an exogenous metabolic activation system, but contradictory results were obtained in vivo. No effect was seen in either mouse or rat hepatic cells after single or repeated dosing, and no effects were observed in epithelial cells from spleen, stomach or duodenum after a single dose. Dichloroacetic acid did not induce differential toxicity in DNA repair-deficient strains of Salmonella typhimurium but did induce prophage in Escherichia coli in one study. It was mutagenic to Salmonella typhimurium TA100 and TA98 in single studies. Most of the mutations in 400 revertants of DCA-treated Salmonella typhimurium TA100 cultures were GA AT transitions. ECOTOXICITY STUDIES: DCA is a common contaminant of aquatic ecosystems. A study to investigate potential phytotoxic effects was conducted on rooted and floating macrophytes (Myriophyllum spicatum, M. sibiricum, and Lemna gibba). The most sensitive plant endpoints were wet mass and plant length.
The dichloroacetate ion stimulates the activity of the enzyme pyruvate dehydrogenase by inhibiting the enzyme pyruvate dehydrogenase kinase. Thus, it decreases lactate production by shifting the metabolism of pyruvate from fermentation towards oxidation in the mitochondria. (Wikipedia)
There is inadequate evidence in humans for the carcinogenicity of dichloroacetic acid. There is sufficient evidence in experimental animals for the carcinogenicity of dichloroacetic acid. Overall evaluation: Dichloroacetic acid is possibly carcinogenic to humans (Group 2B).
EPA finds there are no data on humans indicating that DCA is a carcinogen. However, there is sufficient evidence to conclude that DCA is carcinogenic in at least two species of experimental animals. A statistically significant and dose-related incidence of hepatocellular adenomas and carcinomas occur in male and female mice, and male rats. Large foci of cellular alteration (LFCA, formerly called hyperplastic nodules), which are expected to progress into hepatocellular adenomas and carcinomas, increased in rats and mice. Additional support is provided by: (1) the number of independent studies reporting consistently positive results and at roughly comparable doses, (2) site concordance for tumor formation between two species, (3) clear evidence of a dose-response relationship for tumor incidence and multiplicity, and (4) apparent development of tumors from more than one hepatic cell line and no clear data supporting a cohesive mode of action. Therefore, EPA believes that DCA is likely to be a carcinogen in humans.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
A3；已确认对动物有致癌性，但对人类的相关性未知。
A3; Confirmed animal carcinogen with unknown relevance to humans.
We characterized the pharmacokinetics and dynamics of dichloroacetate (DCA), an investigational drug for mitochondrial diseases, pulmonary arterial hypertension, and cancer. Adult Beagle dogs were orally administered 6.25 mg/kg q12h DCA for 4 weeks. Plasma kinetics was determined after 1, 14, and 28 days. The activity and expression of glutathione transferase zeta 1 (GSTZ1), which biotransforms DCA to glyoxylate, were determined from liver biopsies at baseline and after 27 days. Dogs demonstrate much slower clearance and greater inhibition of DCA metabolism and GSTZ1 activity and expression than rodents and most humans. Indeed, the plasma kinetics of DCA in dogs is similar to humans with GSTZ1 polymorphisms that confer exceptionally slow plasma clearance. Dogs may be a useful model to further investigate the toxicokinetics and therapeutic potential of DCA. /Dichloroacetate/
... The kinetics and biotransformation of dichloroacetate (DCA) and its effects on tyrosine metabolism /were measured/ in nine patients treated for 6 months with 25 mg/kg/day and in rats treated for 5 days with 50 mg/kg/day. ... The activity and expression of hepatic GSTz1/MAAI /was also measured/. Chronic administration of DCA causes a striking age-dependent decrease in its plasma clearance and an increase in its plasma half-life in patients and rats. Urinary excretion of unchanged DCA in rats increases with age, whereas oxalate, an end product of DCA metabolism, shows the opposite trend. Low concentrations of monochloroacetate (MCA), which is known to be neurotoxic, increase as a function of age in the urine of dosed rats. MCA was detectable in plasma only of older animals. Hepatic GSTz1/MAAI-specific activity was inhibited equally by DCA treatment among all age groups, whereas plasma and urinary levels of maleylacetone, a natural substrate for this enzyme, increased with age. We conclude that age is an important variable in the in vivo metabolism and elimination of DCA and that it may account, in part, for the neurotoxicity of this compound in humans and other species. /Dichloroacetate/
... Seven subjects with cirrhosis and six healthy volunteers received a 5-hour primed constant infusion of 6,6-2H2-glucose. After a 2-hour basal period, subjects received intravenous dichloroacetate, 35 mg/kg, over 30 minutes. Dichloroacetate pharmacokinetics were compared by the mixed-effects population-based technique. Glucose production was calculated by means of isotope dilution. ... Peak plasma dichloroacetate concentration in subjects with cirrhosis did not differ from that in control subjects, but typical dichloroacetate clearance was only 36% of that in control subjects (P <0 .001). Dichloroacetate decreased plasma lactate concentration by approximately 50% (P < 0.001), glucose production by 7% to 9% (P < 0.05), and plasma glucose concentration by 9% to 14% (P < 0.05) in both subjects with cirrhosis and control subjects. Dichloroacetate-induced decreases in plasma lactate and glucose concentrations and in glucose production in subjects with cirrhosis did not differ from those in control subjects. ... Plasma dichloroacetate clearance is markedly decreased in patients with cirrhosis, likely because of compromised hepatic function. Subjects with cirrhosis exhibit neither exaggerated inhibition of glucose production nor increased risk of hypoglycemia as a result of acute dichloroacetate-induced hypolactatemia. /Dichloroacetate/
The disposition of dichloroacetic acid (DCA) was investigated in Fischer 344 rats over the 48 hr after oral gavage of 282 mg/kg of 1- or 2-(14)C-DCA (1-DCA or 2-DCA) and 28.2 mg/kg of 2-DCA. DCA was absorbed quickly, and the major route of disposition was through exhalation of carbon dioxide and elimination in the urine. The dispositions of 1- and 2-DCA at 282 mg/kg were similar. With 2-DCA, the disposition differed with dose in that the percentage of the dose expired as carbon dioxide decreased from 34.4% (28.2 mg/kg) to 25.0% (282 mg/kg), while the percentage of the radioactivity excreted in the urine increased from 12.7 to 35.2%. This percentage increase in the urinary excretion was mostly attributable to the presence of unmetabolized DCA, which comprised more than 20% at the higher dose and less than 1% at the lower dose. The major urinary metabolites were glycolic acid, glyoxylic acid, and oxalic acid. DCA and its metabolites accumulated in the tissues and were eliminated slowly. After 48 hr, 36.4%, 26.2%, and 20.8% of the dose was retained in the tissues of rats administered 28.2 and 282 mg/kg of 2-DCA and 282 mg/kg of 1-DCA, respectively. Of the organs examined, the liver (4.9-7.9% of dose) and muscle (4.5-9.9%) contained the most radioactivity, followed by skin (3.3-4.5%), blood (1.4-2.6%), and intestines (1.0-1.7%). ...
Heterocyclic amide compounds and pharmaceutical use of the same
申请人：The Green Cross Corporation
公开号：US05948785A1
公开（公告）日：1999-09-07
Heterocyclic amide compounds of the formula (I) ##STR1## wherein each symbol is as defined in the specification, pharmacologically acceptable salts thereof, pharmaceutical compositions thereof and pharmaceutical use thereof. The heterocyclic amide compounds and pharmacologically acceptable salts thereof of the present invention have superior inhibitory activity against chymase groups in mammals inclusive of human, and can be administered orally or parenterally. Therefore, they are useful as chymase inhibitors and can be effective for the prophylaxis and treatment of various diseases caused by chymase, such as those caused by angiotensin II.
[EN] TRPV4 ANTAGONISTS<br/>[FR] ANTAGONISTES DE TRPV4
申请人：GLAXOSMITHKLINE LLC
公开号：WO2013012500A1
公开（公告）日：2013-01-24
The present invention relates to spirocarbamate compounds of Formula (I) in which R1, (R2)Y, R3, R4, X and A have the meanings given in the specification. The invention further provides pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof and relates to their use of these compounds as TRPV4 antagonists in treating or preventing conditions associated with TRPV4 imbalance.
Salts of zinc and aliphatic haloid carboxylic acids for therapy of skin neoplasms and visible mucous coats
申请人：Tsyb, Anatoly Fyodorovich
公开号：EP1746082A1
公开（公告）日：2007-01-24
The invention relates to medicine, and more particularly to dermatology, namely to new salts of zinc and aliphatic haloid carboxylic acids which can be used to treat benign skin lesions and visible mucous coats.
The following chemical formula of salts of zinc and aliphatic haloid carboxylic acids is proposed
wherein in formulae Fluorine (F), Chlorine (Cl), Bromine (Br) or Iodine (J) can be a halogen atom.
The obtained technical result is the creation of a unique preparation to treat benign skin lesions and visible mucous coats. The preparation is low-toxic, fast acting with a pronounced therapeutic effect and a good tolerance. It causes no complications during therapy, and ensures healing without scar tissue formation. The created preparation allows to extend the assortment of drugs for therapy of similar diseases.
Olefin cyclisations of hindered α-acyliminium ions
作者：B.P. Wijnberg、W.N. Speckamp、A.R.C. Oostveen
DOI：10.1016/0040-4020(82)85067-9
日期：1982.1
imides 2 and 4. HCOOH-Cyclisation of the hydroxylactams affords polycyclic piperidines through stereoselective α-acyliminium ring closure. Concomitant synchronous and stepwise cyclisation pathways are operative in the anti-periplanar addition of tertiary α-acyliminiumions to Me substituted olefins 8c and 11c.
An Efficient and Practical System for the Catalytic Oxidation of Alcohols, Aldehydes, and α,β-Unsaturated Carboxylic Acids
作者：Joseph M. Grill、James W. Ogle、Stephen A. Miller
DOI：10.1021/jo0612574
日期：2006.12.1
Upon exposure to commercial bleach (∼5% aqueous sodium hypochlorite), nickel(II) chloride or nickel(II) acetate is transformed quantitatively into an insoluble nickel species, nickel oxide hydroxide. This material consists of high surface area nanoparticles (ca. 4 nm) and is a useful heterogeneous catalyst for the oxidation of many organic compounds. The oxidation of primary alcohols to carboxylic
