The broad objective of this application is to extend past and ongoing research aimed at defining the basic mechanisms which underlie the porphyrinogenic and tissue damaging properties of trace metals in biological tissues. The research will focus on the mechanisms by which trace metals cause porphyrin accumulation (porphyria) and cell injury (nephrotoxicity) in mammalian kidney, a principal target organ of numerous metals of toxicologic importance. The principal hypothesis to be tested is that renal porphyria and nephrotoxicity have a common mechanistic etiology in the formation of reactive oxidants (peroxides, free radicals) and depletion of cellular glutathione (GSH) which occur during prolonged metal exposures. These events promote oxidation of reduced porphyrins and peroxidation of cellular constituents, leading progressively to porphyria and cell injury, respectively. Studies are proposed to define the precise mechanisms by which metals (1) deplete cellular GSH and (2) elicit the formation of reactive oxidants, and to identify how these events interact to (3) promote porphyria nd (4) cause cell injury. A prolonged-exposure model of methyl mercury-induced porphyria and cell injury in Sprague-Dawley rat kidney developed in this laboratory for study of these mechanisms will be used as the principal experimental model. Highly sensitive HPLC-spectrofluorometric assay procedures will be used to measure porphyrinogenic events in kidney fractions and to quantitate metal effects on GSH metabolism. Reactive oxidant formation by renal cells will be measured by established spectrophotometric procedures. Ultrastructural/morphometric and enzymatic microdetermination techniques will be employed to determine if lipid peroxidation of cell constituents resulting from GSH depletion and reactive oxidant formation is a cause of renal cell injury during metal exposure. The proposed research will add substantially to current understanding of the mechanisms by which toxic trace metals alter the regulation of GSH metabolism and promote reactive oxidant formation i biological tissues, and the role of these events in metal-induced porphyria and nephrotoxicity. Identification of a common mechanistic etiology of the porphyrinogenic and tissue damaging properties of metals will establish the biological and potential diagnostic significance of renal porphyria as a pre-toxic manifestation of biochemical events associated with the initiation of metal toxicity in kidney cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003628-08
Application #
2153369
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1986-07-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1995-06-30
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Battelle Centers/Pub Health Research & Evaluatn
Department
Type
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43201
Heyer, Nicholas J; Bittner, Alvah C; Echeverria, Diana et al. (2007) Reply to the Letter to the Editor: Response to comment on: "" A cascade analysis of the interaction of mercury and coproporphyrinogen oxidase (CPOX) polymorphism on the heme biosynthetic pathway and porphyrin production"" by Heyer et al. [Toxicol. Lett. 1 Toxicol Lett 169:93-94
Akins, J M; Hooper, M J; Miller, H et al. (1993) Porphyrin profiles in the nestling European starling (Sturnus vulgaris): a potential biomarker of field contaminant exposure. J Toxicol Environ Health 40:47-59
Miller, D M; Woods, J S (1993) Redox activities of mercury-thiol complexes: implications for mercury-induced porphyria and toxicity. Chem Biol Interact 88:23-35
Miller, D M; Woods, J S (1993) Urinary porphyrins as biological indicators of oxidative stress in the kidney. Interaction of mercury and cephaloridine. Biochem Pharmacol 46:2235-41
Woods, J S; Miller, H D (1993) Quantitative measurement of porphyrins in biological tissues and evaluation of tissue porphyrins during toxicant exposures. Fundam Appl Toxicol 21:291-7
Woods, J S; Martin, M D; Naleway, C A et al. (1993) Urinary porphyrin profiles as a biomarker of mercury exposure: studies on dentists with occupational exposure to mercury vapor. J Toxicol Environ Health 40:235-46
Lund, B O; Miller, D M; Woods, J S (1993) Studies on Hg(II)-induced H2O2 formation and oxidative stress in vivo and in vitro in rat kidney mitochondria. Biochem Pharmacol 45:2017-24
Bowers, M A; Luckhurst, C L; Davis, H A et al. (1992) Investigation of factors influencing urinary porphyrin excretion in rats: strain, gender, and age. Fundam Appl Toxicol 19:538-44
Woods, J S; Davis, H A; Baer, R P (1992) Enhancement of gamma-glutamylcysteine synthetase mRNA in rat kidney by methyl mercury. Arch Biochem Biophys 296:350-3
Bowers, M A; Aicher, L D; Davis, H A et al. (1992) Quantitative determination of porphyrins in rat and human urine and evaluation of urinary porphyrin profiles during mercury and lead exposures. J Lab Clin Med 120:272-81

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