API

Relationship: 864

Title

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Oxidation, Uroporphyrinogen leads to Accumulation, Highly carboxylated porphyrins

Upstream event

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Oxidation, Uroporphyrinogen

Downstream event

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Accumulation, Highly carboxylated porphyrins

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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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[1][2]. 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)[3].

Evidence Supporting this KER

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Biological Plausibility

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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[4]. Oxidation of these intermediates results in their corresponding, highly stable porphyrins, which accumulate.

Empirical Evidence

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Include consideration of temporal concordance here

It has clearly been demonstrated that uroporphyrinogen oxidation is required for porphyrin accumulation[5]. 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

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Although porphyrinogen oxidation is identified as the cause of porphyrin accumulation in clinical porphyrias[6], UROX activity in human microsomes and human hepatoma cells is much lower than it is in mice (10% and 20% respectively)[7].

Quantitative Understanding of the Linkage

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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.

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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UROX leading to porphyrin accumulation has been demonstrated in, rats, mice and chicken[5][8][9]. Human porphyria cutanea tarda is also characterized biochemically by an increase in porphyrinogen oxidation leading to accumulation of porphyrins[6]).

References

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  1. Frank, J., and Poblete-Gutierrez, P. (2010) Porphyria cutanea tarda--when skin meets liver. Best. Pract. Res. Clin Gastroenterol. 24(5), 735-745.
  2. Doss, M., Schermuly, E., and Koss, G. (1976). Hexachlorobenzene porphyria in rats as a model for human chronic hepatic porphyrias. Ann. Clin Res. 8 Suppl 17, 171-181.
  3. 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.
  4. Elder, G. H., and Roberts, A. G. (1995). Uroporphyrinogen decarboxylase. J Bioenerg. Biomembr. 27 (2), 207-214.
  5. 5.0 5.1 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.
  6. 6.0 6.1 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.
  7. 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.
  8. 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.
  9. 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.