The Dichloroacetate Dilemma: Environmental Hazard versus Therapeutic Goldmine—Both or Neither?
نویسنده
چکیده
BACKGROUND Dichloroacetate (DCA) is known to environmental scientists as a by-product of water chlorination and as a metabolite of industrial solvents, including Superfund chemicals. In contrast, DCA is studied by clinical investigators for its therapeutic potential in several life-threatening conditions, including genetic mitochondrial diseases, pulmonary arterial hypertension, and cancer. Thus, DCA holds an almost unique position at the interface between environmental science and allopathic medicine. OBJECTIVE I critically reviewed laboratory and clinical pharmacological research on DCA to address questions about the current and future status of DCA in relation to human health. DISCUSSION Recent information on the clinical toxicogenetics of DCA is interpreted particularly in light of its use as an investigational drug. Adverse effects from chronic DCA exposure have been identified in several target organs in animals. However, in humans, toxicity has so far been limited to reversible effects on the nervous system and liver. DCA is primarily biotransformed to glyoxylate by the bifunctional enzyme glutathione transferase zeta1 and maleylacetoacetate isomerase (GSTz1/MAAI), which also catalyzes the penultimate step in the phenylalanine and tyrosine catabolic pathway. DCA is a suicide inhibitor of GSTz1/MAAI, which can result in delayed plasma clearance of DCA and the accumulation of potentially toxic tyrosine intermediates. Age and GSTz1/MAAI haplotype can markedly affect the toxicokinetics of DCA in humans and rodents. CONCLUSIONS I have defined new potential avenues of research that focus on discrete human populations that may be at increased health risk or that may receive increased health benefit from chronic exposure to DCA at both environmentally and clinically relevant concentrations.
منابع مشابه
The Dichloroacetate Dilemma : Environmental Hazard vs . Therapeutic Goldmine – Both or Neither ?
متن کامل
Clinical pharmacology and toxicology of dichloroacetate.
Dichloroacetate (DCA) is a xenobiotic of interest to both environmental toxicologists and clinicians. The chemical is a product of water chlorination and of the metabolism of various drugs and industrial chemicals. Its accumulation in groundwater and at certain Superfund sites is considered a potential health hazard. However, concern about DCA toxicity is predicated mainly on data obtained in i...
متن کاملTreat now or later: the dilemma of postoperative radiotherapy.
The management of adverse pathology following radical prostatectomy (RP) is a difficult treatment dilemma. The debate centers on three treatment paradigms: additional systemic therapy, additional local therapy, or close observation. For the individual patient, the decision focuses on risk of systemic disease and risk of local recurrence. The excellent review article by Stephenson et al. [1] con...
متن کاملAssessment of Salinity Hazard of Irrigation Water Quality in Monsoon Season of Batiaghata Upazila, Khulna District, Bangladesh and adaptation strategies
Batiaghata Upazila, Khulna District in south-west coastal region of Bangladesh is the mostly saline affected area, where agriculture activities are mainly dependent on rainfall. 23 water samples from surface water and shallow tube well (STW) were collected in the monsoon season and analyzed for physico-chemical properties to classify them according to salinity hazard. Electrical Conductivity (E...
متن کاملContact lens-induced edema in vitro. Pharmacology and metabolic considerations.
The effects of physiologic and pharmacologic manipulations on contact lens-induced edema were studied. In isolated superfused rabbit corneas bathed in Ringer's solution and covered with large-diameter polymethylmethacrylate (PMMA) lenses, corneal swelling rates of 17-26 microns/hr (versus -5-5 microns/hr in paired controls) were observed. Neither the calcium antagonist diltiazem (10(-4) M), the...
متن کامل