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Perturbation of the tyrosine degrada...

Lantum, Hoffman Biminyuy Moka.

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Perturbation of the tyrosine degradation pathway by dichloroacetic acid (DCA): A mechanism for DCA-induced multiorgan toxicity and hepatocarcinogenesis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Perturbation of the tyrosine degradation pathway by dichloroacetic acid (DCA): A mechanism for DCA-induced multiorgan toxicity and hepatocarcinogenesis./
Author:	Lantum, Hoffman Biminyuy Moka.
Description:	277 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0156.
Contained By:	Dissertation Abstracts International64-01B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3078414
ISBN:	0493989382

Perturbation of the tyrosine degradation pathway by dichloroacetic acid (DCA): A mechanism for DCA-induced multiorgan toxicity and hepatocarcinogenesis.
Lantum, Hoffman Biminyuy Moka.

Perturbation of the tyrosine degradation pathway by dichloroacetic acid (DCA): A mechanism for DCA-induced multiorgan toxicity and hepatocarcinogenesis. - 277 p.

Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0156.

Thesis (Ph.D.)--The University of Rochester, 2003.

Dichloroacetic acid (DCA) is a disinfection by-product (DBP) present in many municipal water supplies. DCA, as a noncompetitive inhibitor of pyruvate dehydrogenase kinase, is an investigational therapeutic compound for clinical management of lactic acidosis. Environmental and therapeutic exposure to DCA is a concern; multiorgan toxicities in rodents, dogs, and humans and liver tumors in rodents are observed after prolonged exposure to DCA. The mechanisms of toxicity and hepatocarcinogenesis of DCA are poorly understood.

ISBN: 0493989382Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Perturbation of the tyrosine degradation pathway by dichloroacetic acid (DCA): A mechanism for DCA-induced multiorgan toxicity and hepatocarcinogenesis.
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100 1 $a Lantum, Hoffman Biminyuy Moka. $3 1948366
245 1 0 $a Perturbation of the tyrosine degradation pathway by dichloroacetic acid (DCA): A mechanism for DCA-induced multiorgan toxicity and hepatocarcinogenesis.
300 $a 277 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0156.
500 $a Supervisor: M. W. Anders.
502 $a Thesis (Ph.D.)--The University of Rochester, 2003.
520 $a Dichloroacetic acid (DCA) is a disinfection by-product (DBP) present in many municipal water supplies. DCA, as a noncompetitive inhibitor of pyruvate dehydrogenase kinase, is an investigational therapeutic compound for clinical management of lactic acidosis. Environmental and therapeutic exposure to DCA is a concern; multiorgan toxicities in rodents, dogs, and humans and liver tumors in rodents are observed after prolonged exposure to DCA. The mechanisms of toxicity and hepatocarcinogenesis of DCA are poorly understood.
520 $a DCA is a substrate and mechanism-based inactivator of glutathione transferase zeta (GSTZ1-1), which catalyzes the isomerization of maleylacetoacetic acid (MAA) to fumarylacetoacetate (FAA), the penultimate step of the tyrosine degradation pathway. We hypothesized that toxic and carcinogenic effects of DCA may be associated with inactivation of GSTZ1-1 and perturbation of MAA-metabolism. The general objective of this thesis was to determine the effects of DCA-induced inactivation of GSTZ1-1 on MAA-metabolism.
520 $a Steady-state kinetic analyses with recombinant hGSTZ1-1 showed that the DCA-inactivated enzyme lacks isomerase activity. The loss of isomerase activity was confirmed in rats treated with DCA for 5 days, wherein, immunohistochemical, immunoblotting and activity analyses showed loss of GSTZ1-1 expression and activities in most tissues tested. DCA-treated rats excreted MAA-derived maleylacetone (MA). Though MA was toxic to hepatocytes in vitro (EC50 &sim;350 muM after 6 hr), little toxicity was observed in liver of rats given DCA for 5 days. During the kinetic analysis, we observed that MA covalently modified GSTZ1-1 by Michael-addition reactions with solvent-accessible thiol moieties. These data support the concept that MA-dependent alkylation of proteins underlies toxic effects of DCA. MA-formation has significant implications for assessing the safety of other GSTZ1-1-inactivating alpha-haloacids---the National Toxicology Program has classified some alpha-haloacids as 'high priority agents of public health concern.'
520 $a Given the therapeutic potential of alpha-haloacids, the toxicity of chlorofluoroacetic acid (CFA) and difluoroacetic acid (DFA), which inhibit pyruvate dehydrogenase kinase but do not inactivate GSTZ1-1, was determined. CFA and DFA were acutely nephrotoxic in rats given ≥0.6 mmol/kg/day for 5 days. These compounds are thus unsuitable alternatives for treatment of lactic acidotic disorders.
590 $a School code: 0188.
650 4 $a Health Sciences, Pharmacology. $3 1017717
650 4 $a Health Sciences, Toxicology. $3 1017752
650 4 $a Chemistry, Biochemistry. $3 1017722
690 $a 0419
690 $a 0383
690 $a 0487
710 2 0 $a The University of Rochester. $3 1249304
773 0 $t Dissertation Abstracts International $g 64-01B.
790 1 0 $a Anders, M. W., $e advisor
790 $a 0188
791 $a Ph.D.
792 $a 2003
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3078414