The kidney is a principal target organ for numerous toxic trace metals. Current evidence suggests that porphyrinuria, an early pre-toxic manifestation of prolonged metal exposure, is predominantly of renal origin, and may, therefore, serve as a diagnostic indicator of ensuing metal toxicity in the kidney. In studies on the mechanisms by which methyl mercury (MMH) elicits renal porphyrinuria, 3 principal biochemical events which appear to underlie this process have been identified. These are: (1) metal-induced depletion of renal reduced glutathione (GSH) content, (2) consequent impairment of renal uroporphyrinogen decarboxylase (UD), and (3) a delayed increase in renal ALA synthetase activity. It is hypothesized that metal-induced depletion of renal GSH leads to deactivation and/or inhibition of UD, causing a primary block in renal porphyrin metabolism. GSH depletion also enhances heme catabolism, leading to a secondary induction of ALA synthetase with subsequent porphyrin overproduction. These changes are manifested as porphyrinuria. Studies are proposed to delineate the precise mechanisms by which each of these changes is elicited using MMH-induced porphyrinuria in rat kidney cortex as the experimental model. A highly sensitive HPLC-spectrofluorimetric assay developed in these laboratories will be used to quantitate porphyrins in tissue and assay media and to study the mechanisms of metal and GSH effects on renal porphyrin metabolism. Specific GSH depeting and repleting agents will be used to assess the interaction of GSH with renal heme and porphyrin regulation during prolonged metal exposure. The relationship of these events to lipid peroxidation and formaldehyde formation, as potential toxic sequellae of metal-induced GSH depletion in kidney cells, will also be investigated. The proposed studies will add substantially to the current understanding of the regulation of heme and porphyrin metabolism in the kidney and the role of GSH in this process. In demonstrating the mechanisms by which metals impair GSH and heme regulation during prolonged, low-level exposure, and the relationship of these events to known causes of tissue damage, these studies will provide a biochemical basis for understanding how metal toxicity is initiated in renal cells. Evidence that porphyrinuria is a magnifestation of pre-toxic biochemical events associated with trace metal exposure will lend diagnostic significance to porphyrinuria in the detection and prevention of chronic metal toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003628-03
Application #
3251118
Study Section
Toxicology Study Section (TOX)
Project Start
1986-07-01
Project End
1989-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
3
Fiscal Year
1988
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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