Upstream eventOxidation, Uroporphyrinogen
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.
Include consideration of temporal concordance here
It has clearly been demonstrated that uroporphyrinogen oxidation is required for porphyrin accumulation. Mice fed an iron deficient diet had low levels of hepatic UROX activity and therefore did not show an accumulation of porphyrins, whereas those fed an iron sufficient diet showed increased UROX activity and porphyrin accumulation.
Uncertainties and Inconsistencies
Although porphyrinogen oxidation is identified as the cause of porphyrin accumulation in clinical porphyrias, UROX activity in human microsomes and human hepatoma cells is much lower than it is in mice (10% and 20% respectively).
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
A quantitative relationship has not been described.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
UROX leading to porphyrin accumulation has been demonstrated in, rats, mice and chicken. Human porphyria cutanea tarda is also characterized biochemically by an increase in porphyrinogen oxidation leading to accumulation of porphyrins).
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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.
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- 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.