API

Event: 844

Key Event Title

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Oxidation, Uroporphyrinogen

Short name

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Oxidation, Uroporphyrinogen

Key Event Component

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Process Object Action
uroporphyrinogen increased

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Aryl hydrocarbon receptor activation leading to uroporphyria KeyEvent

Stressors

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Level of Biological Organization

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Biological Organization
Cellular

Cell term

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Cell term
hepatocyte


Organ term

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Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens Strong NCBI
mouse Mus musculus Strong NCBI
rat Rattus norvegicus Strong NCBI
chicken Gallus gallus Strong NCBI

Life Stage Applicability

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Life stage Evidence
All life stages

Sex Applicability

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Term Evidence
Unspecific Strong

How This Key Event Works

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Figure 1:Oxidation of the heme precursor uroporphyrinogen III to uroporphyrin III due to inhibition of UROD. UROD: uroporphyrinogen decarboxylase. (Modified from Smith and Elder (2010) Chem. Res. Toxicol. 23 (4), 712-723.

 

Uroporphyrinogen III is the first cyclic metabolic intermediate in the biosynthesis of heme. Under normal conditions, it is converted into coproporphyrinogen III by the enzyme uroporphyrinogen decarboxylase (UROD), and subsequently processed to heme following three further steps[1]. In the event that UROD activity is reduced (due to genetic disorders or chemical inhibition) uroporphyrinogen III, and other porphyrinogen substrates of UROD, are oxidized to highly stable porphyrins, which accumulation and lead to a heme disorder known as porphyria (Figure 1)[2].


How It Is Measured or Detected

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Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

Porphyrins fluoresce red when exposed to UV light; therefore, uroporphyrinogen oxidation (UROX) can be directly measured as uropororphyrin fluorescence in a spectrophotofluorimeter. UROX has been measured spectrofluorimetrically in avian[3] and mammalian[4] species.


Evidence Supporting Taxonomic Applicability

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UROX has been measured in chicken[3], mouse[4], rat[4] and human[6] microsomes.


References

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  1. [1]"Wikipedia:Uroporphyrinogen III"
  2. Smith, A. G., and Elder, G. H. (2010). Complex gene-chemical interactions: hepatic uroporphyria as a paradigm. Chem. Res. Toxicol. 23 (4), 712-723.
  3. Sinclair, P. R., Gorman, N., Walton, H. S., Sinclair, J. F., Lee, C. A., and Rifkind, A. B. (1997). Identification of CYP1A5 as the CYP1A enzyme mainly responsible for uroporphyrinogen oxidation induced by AH receptor ligands in chicken liver and kidney. Drug Metab. Dispos. 25 (7), 779-783.
  4. Jacobs, J. M., Sinclair, P. R., Bement, W. J., Lambrecht, R. W., Sinclair, J. F., and Goldstein, J. A. (1989). Oxidation of uroporphyrinogen by methylcholanthrene-induced cytochrome P-450. Essential role of cytochrome P-450d. Biochem. J 258 (1), 247-253.
  5. Wainwright, J. S., Hopkins, K. M., Bums Jr., T.A., and Di Giulio, R. T. Investigation of potential biomarkers of exposure to bleached kraft mill effluent in North Carolina rivers. 27708-0328. 1995. Durham, NC. Ref Type: Report
  6. Sinclair, P. R., Gorman, N., Tsyrlov, I. B., Fuhr, U., Walton, H. S.,  Sinclair, A.F. (1988). Uroporphyrinogen Oxidation Catalyzed By Human Cytochromes P450. Drug Metab. Dispos. 26(10), 1019-1025.