API

Relationship: 1070

Title

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Inhibition, UROD leads to Accumulation, Highly carboxylated porphyrins

Upstream event

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Inhibition, UROD

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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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Aryl hydrocarbon receptor activation leading to uroporphyria adjacent Moderate Moderate

Taxonomic Applicability

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

Sex Applicability

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Sex Evidence
Unspecific Not Specified

Life Stage Applicability

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Term Evidence
Adult High

Key Event Relationship Description

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Through the normal heme biosynthesis pathway, uroporphyrinogen is converted to coproporphyrinogen by uroporphyrinogen decarboxylase (UROD)[1]. In the event that UROD activity is reduced (due to genetic disorders or chemical inhibition) uroporphyrinogen, and other porphyrinogen substrates of UROD, are preferentially oxidized to highly stable porphyrins by the phase one metabolizing enzyme CYP1A2 (in mammals;CYP1A5 in birds)[2][3][4] . Uroporphyrin and hepta- and hexa-carboxylic acid porphyrins (highly carboxylated porphyrins)[5] accumulate in the liver, kidneys, spleen, skin and blood leading to a heme disorder known as porphyria [6][7].

Evidence Supporting this KER

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The WOE for this KER is strong in mammals and Moderate in birds.

Biological Plausibility

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Hepatic uroporphyrinogen accumulation versus inhibition of uroporphyrinogen decarboxylase activity from individual mice treated with iron and HCB. Control: ○, Treated: ∆. (Source: Lambrecht, R.W. et al. (1988) Biochem. J. 253 (1), 131-138.)

 

It is well established that porphyrin accumulation, which is a result of uroporphyrin oxidation (UROX), and UROD inhibition go hand in hand[8]. Because CYP1A2/5 binds a broad range of substrates, significant UROX only occurs when there is an excess of uroporphyrinogen, which occurs when UROD is inhibited. 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[9]. Oxidation of these intermediates results in their corresponding, highly stable porphyrins.

Empirical Evidence

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Include consideration of temporal concordance here

A number of studies have demonstrated that increased UROD inhibition results in higher hepatic porphyrin accumulation[10][11][12].

Uncertainties and Inconsistencies

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Uroporphyrin accumulation in avian models is less consistently accompanied by decreased UROD activity, and when it does occur, it is less marked than in mammals[13][14]. Although numerous studies show both a decrease in UROD activity and porphyrin accumulation in avian species, Lambrecht et al.[14] reported the accumulation of porphyrins in chicken embryo hepatocytes and Japanese quail liver without a decrease in UROD activity. They also note that the modest reduction in UROD activity (often less than 50%) is not enough to explain the extent of porphyrin accumulation observed and suggests there may be another mechanism at play. Alternatively, the difference between avian and mammals in regard to UROD inhibition may lie in the time-course of the response rather than its mechanism[19].

 

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 reduction in UROD activity of at least 70% is required to achieve a makeable increase in hepatic porphyrins, in mammals.[15][16][17]

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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Induction of CYP1A2 increases its availability and consequently its ability to compete with UROD to oxidize uroporphyrinogen. At least one of these oxidation products is believed to be a competitive inhibitor of UROD. Therefore, UROD inhibition potentiates the oxidation of uroporphyrinogens by CYP1A2 to porphyrins leading to increased porphyrin accumulation and in turn UROD inhibition.

Domain of Applicability

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Chemical induces porphyrin accumulation has been demonstrated in, rats, mice and chicken[18][4][2]. Human porphyria cutanea tarda is also characterized biochemically by an increase in porphyrinogen oxidation leading to accumulation of porphyrins[15]. The correlation between reduced UROD activity and HCP accumulation in mammals is well defined[15][16][17] but is less consistent in avian models[14].

References

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  1. Smith, A. G., Clothier, B., Carthew, P., Childs, N. L., Sinclair, P. R., Nebert, D. W., and Dalton, T. P. (2001) Protection of the Cyp1a2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 173 (2), 89-98.
  2. 2.0 2.1 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.
  3. Lambrecht, R. W., Sinclair, P. R., Gorman, N., and Sinclair, J. F. (1992). Uroporphyrinogen oxidation catalyzed by reconstituted cytochrome P450IA2. Arch. Biochem. Biophys. 294 (2), 504-510.
  4. 4.0 4.1 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.
  5. 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.
  6. Frank, J., and Poblete-Gutierrez, P. (2010) Porphyria cutanea tarda--when skin meets liver. Best. Pract. Res. Clin Gastroenterol. 24(5), 735-745.
  7. 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.
  8. Smith, A. G., and Elder, G. H. (2010) Complex gene-chemical interactions: hepatic uroporphyria as a paradigm. Chem. Res. Toxicol. 23 (4), 712-723.
  9. Elder, G. H., and Roberts, A. G. (1995). Uroporphyrinogen decarboxylase. J Bioenerg. Biomembr. 27 (2), 207-214.
  10. Phillips, J. D., Bergonia, H. A., Reilly, C. A., Franklin, M. R., and Kushner, J. P. (2007) A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc. Natl. Acad. Sci. U. S. A 104 (12), 5079-5084.
  11. Sano, S., Kawanishi, S., and Seki, Y. (1985) Toxicity of polychlorinated biphenyl with special reference to porphyrin metabolism. Environ. Health Perspect. 59, 137-143.
  12. Sinclair, P. R., Gorman, N., Trask, H. W., Bement, W. J., Szakacs, J. G., Elder, G. H., Balestra, D., Sinclair, J. F., and Gerhard, G. S. (2003). Uroporphyria caused by ethanol in Hfe(-/-) mice as a model for porphyria cutanea tarda. Hepatology 37 (2), 351-358.
  13. James, C. A., and Marks, G. S. (1989). Inhibition of chick embryo hepatic uroporphyrinogen decarboxylase by components of xenobiotic-treated chick embryo hepatocytes in culture. Can. J Physiol Pharmacol. 67 (3), 246-249.
  14. 14.0 14.1 14.2 Lambrecht, R. W., Sinclair, P. R., Bement, W. J., Sinclair, J. F., Carpenter, H. M., Buhler, D. R., Urquhart, A. J., and Elder, G. H. (1988) Hepatic uroporphyrin accumulation and uroporphyrinogen decarboxylase activity in cultured chick-embryo hepatocytes and in Japanese quail (Coturnix coturnix japonica) and mice treated with polyhalogenated aromatic compounds. Biochem. J. 253 (1), 131-138.
  15. 15.0 15.1 15.2 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.
  16. 16.0 16.1 Mylchreest, E., and Charbonneau, M. (1997) Studies on the mechanism of uroporphyrinogen decarboxylase inhibition in hexachlorobenzene-induced porphyria in the female rat. Toxicol. Appl. Pharmacol. 145 (1), 23-33.
  17. 17.0 17.1 Seki, Y., Kawanishi, S., and Sano, S. (1987). Mechanism of PCB-induced porphyria and yusho disease. Ann. N. Y. Acad. Sci. 514, 222-234.
  18. 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.
  19. Lambrecht, R. W., Jacobs, J. M., Sinclair, P. R., & Sinclair, J. F. (1990). Inhibition of uroporphyrinogen decarboxylase activity. The role of cytochrome P-450-mediated uroporphyrinogen oxidation. Biochemical Journal269(2), 437-441.