API

Relationship: 867

Title

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Inhibition, UROD leads to Oxidation, Uroporphyrinogen

Upstream event

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Inhibition, UROD

Downstream event

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Oxidation, Uroporphyrinogen

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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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 oxidized to highly stable porphyrins, which accumulation and lead to a heme disorder known as porphyria[2].

Evidence Supporting this KER

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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[2]. Because CYP1A2/5 binds a broad range of substrates, significant UROX only occurs when there is an excess of uroporphorynogen, which occurs when UROD is inhibited.

Empirical Evidence

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Include consideration of temporal concordance here

Although there is no record in the literature of the simultaneous measurement of UROD and UROX activities, a number of studies show that in increase in UROD inhibition results in higher hepatic porphyrin accumulation, which is an indication of increased UROX activity.[3][4][5]

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[6][7]. Although numerous studies show both a decrease in UROD activity and porphyrin accumulation in avian species, Lambrecht et al.[7] 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.

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, and therefore UROX, in mammals.[8][9][10]

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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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 Smith, A. G., and Elder, G. H. (2010) Complex gene-chemical interactions: hepatic uroporphyria as a paradigm. Chem. Res. Toxicol. 23 (4), 712-723.
  3. 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.
  4. Sano, S., Kawanishi, S., and Seki, Y. (1985) Toxicity of polychlorinated biphenyl with special reference to porphyrin metabolism. Environ. Health Perspect. 59, 137-143.
  5. 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.
  6. 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.
  7. 7.0 7.1 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.
  8. 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.
  9. 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.
  10. Seki, Y., Kawanishi, S., and Sano, S. (1987). Mechanism of PCB-induced porphyria and yusho disease. Ann. N. Y. Acad. Sci. 514, 222-234.