Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|AhR activation leading to uroporphyria||KE||Strong|
Level of Biological Organization
How this Key Event works
Under normal conditions, the heme biosynthesis pathway is tightly regulated and porphyrins (other than protoporphyrin) are only present in trace amounts. However, when the regulatory process is disturbed, a variety of porphyrin precursors of heme accumulate in various organs including the liver and urinary and fecal excretion is elevated). The pattern of porphyrin accumulation in chicken and rodents is similar following exposure to a variety of chemicals, and can be used to identify which enzyme in the heme pathway is predominately affected. In the case of uroporphyrinogen decarboxylase inhibition, uroporphyrin, hepta-, and hexacarboxylic acid porphyrin (highly carboxylated porphyrins) are elevated.
How it is Measured or Detected
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?
The hepatic and urinary/fecal porphyrin patters can be determined using a high-performance liquid chromatograph equipped with a fluorescence detector. Kennedy et al. describe the method for tissue extraction and porphyrin quantification in detail, which is rapid and highly sensitive.
Evidence Supporting Taxonomic Applicability
- Marks, G. S., Powles, J., Lyon, M., McCluskey, S., Sutherland, E., and Zelt, D. (1987). Patterns of porphyrin accumulation in response to xenobiotics. Parallels between results in chick embryo and rodents. Ann. N. Y. Acad. Sci. 514, 113-127.
- Frank, J., and Poblete-Gutierrez, P. (2010) Porphyria cutanea tarda--when skin meets liver. Best. Pract. Res. Clin Gastroenterol. 24(5), 735-745.
- Kennedy, S. W., Wigfield, D. C., and Fox, G. A. (1986). Tissue porphyrin pattern determination by high-speed high-performance liquid chromatography. Anal. Biochem. 157 (1), 1-7.