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Oxidation, Uroporphyrinogen leads to Accumulation, Highly carboxylated porphyrins
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
When the normal heme biosynthesis pathway is disrupted, heme precursors are oxidized to highly stable porphyrins, which accumulate in the liver, kidneys, spleen, skin and blood; porphyrin excretion in urine and feces is also elevated. The pattern of porphyrin accumulation is indicative of which enzyme in the heme pathway is predominately affected. Chemical induced porphyria often involves the inhibition of uroporphyrinogen decarboxylase (UROD), which leads to the accumulation of uroporphyrin and hepta- and hexacarboxylic acid porphyrins (highly carboxylated porphyrins).
Evidence Supporting this KER
Each of the four acetic acid substituents of porphyrinogen is decarboxylated in sequence with the consequent formation of hepta-, hexa-, and pentacarboxylic porphyrinogens as intermediates. Oxidation of these intermediates results in their corresponding, highly stable porphyrins, which accumulate.
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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- Nakano, K., Ishizuka, M., Sakamoto, K. Q., and Fujita, S. (2009). Absolute requirement for iron in the development of chemically induced uroporphyria in mice treated with 3-methylcholanthrene and 5-aminolevulinate. Biometals 22 (2), 345-351.
- Caballes F.R., Sendi, H., and Bonkovsky, H. L. (2012). Hepatitis C, porphyria cutanea tarda and liver iron: an update. Liver Int. 32 (6), 880-893.
- Sinclair, P. R., Gorman, N., Tsyrlov, I. B., Fuhr, U., Walton, H. S., and Sinclair, J. F. (1998b). Uroporphyrinogen oxidation catalyzed by human cytochromes P450. Drug Metab Dispos. 26 (10), 1019-1025.
- 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.
- 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.