Upstream eventOxidation, Uroporphyrinogen
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Aryl hydrocarbon receptor activation leading to uroporphyria||adjacent||Moderate||Low|
Life Stage Applicability
|All life stages||Not Specified|
Key Event Relationship Description
One of the oxidation products of uroporphyrinogen is believed to be a competitive inhibitor of uroporphyrinogen decarboxylase (UROD). This inhibitor binds to the active site of UROD preventing the normal synthesis of heme, allowing uroporphyrinogen oxidation to dominate and increasing accumulation of hepatic porphyrins. The formation of this inhibitor is increased by iron, a well-known oxidant, by activity of cytochrome P-4501A2, by alcohol excess and by estrogen therapy.
Phillips et al. identified this inhibitor as being uroporphomethene using a murine model for porphyria; however, their interpretation of the mass spectroscopy results has been criticized as inaccurate, leaving the exact characterization of the UROD inhibitor unresolved.
A negative-feedback loop exists in which the end-product (heme) represses the enzyme ALA synthase 1 and prevents excess formation of heme. When UROD activity is low, the regulatory heme pool is potentially depleted, causing a repression of the negative feedback loop, thereby increasing levels of precursors and furthering the accumulation of porphyrins.
Evidence Supporting this KER
The WOE for this KER is moderate.
Reduced UROD enzyme activity, not protein levels, is characteristic of uroporphyria in humans and rats, indicating that disrupted decarboxylation is due to an enzyme inhibitor rather that a reduction in protein synthesis. Early reports confirmed the presence of a UROD inhibitor in porphyric animal models that was not present in animals resistant to chemical-porphyria under the same conditions. The identity of this UROD inhibitor is not yet agreed upon, but there is a general consensus among the scientific community that it is an oxidation product of uroporphyrinogen or hydroxymethylbilane (the tetrapyrrole precursor of uroporphyrinogen).
Include consideration of temporal concordance here
Phillips et al. identified uroporphomethene, a compound in which one bridge carbon in the uroporphyrinogen macrocycle is oxidized, as a potent UROD inhibitor derived from the liver of porphyric mice.
Uncertainties and Inconsistencies
The precise mechanism of UROD inhibition has yet to be identified. It could be a direct or indirect inhibition via an oxidized uroporphyrinogen generated by CYP1A2 or reactive oxygen species derived from iron overload, or other induced pathways.
The characterization of the inhibitor isolated by Phillips et al. has been criticized by Danton and Lim. Namely, they claim that the high-performance liquid chromatography/electrospray ionization tandem mass spectrometry results were interpreted incorrectly. They analyzed the fragmentation pattern themselves, and concluded that the compound is not a tetrapyrrole or an uroporphyrinogen or uroporphyrin related molecule, but rather a poly(ethylene glycol) structure. The expected chemical instability of the inhibitor – a partially oxidized porphyrinogens that bear unsubstituted methylene group(s) at the meso position –might play an important role in the difficulty to characterize it .
Porphodimethene inhibitor 16 (PI-16), a synthetic inhibitor of UROD, was developed based on its similarity to coproporphyrinogen, uroporphyrinogen, and the previously suggested endogenous inhibitor. This molecule directly interacts with UROD to specifically and effectively inhibit its activity. PI-16 structural similarity to an oxidized uroporphyrinogen including the suggested endogenous inhibitor supports the hypothesis of an oxidized uroporphyrinogen as endogenous UROD inhibitor.
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?
This linkage has not been quantitatively characterized.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
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
- ↑ 1.0 1.1 1.2 1.3 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.
- ↑ 2.0 2.1 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.
- ↑ Elder, G. H., and Sheppard, D. M. (1982) Immunoreactive uroporphyrinogen decarboxylase is unchanged in porphyria caused by TCDD and hexachlorobenzene. Biochem. Biophys. Res. Commun. 109 (1), 113-120.
- ↑ Elder, G. H., Urquhart, A. J., De Salamanca, R. E., Munoz, J. J., and Bonkovsky, H. L. (1985) Immunoreactive uroporphyrinogen decarboxylase in the liver in porphyria cutanea tarda. Lancet 2 (8449), 229-233.
- ↑ 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.
- ↑ 6.0 6.1 Rios de Molina, M. C., Wainstok de, C. R., and San Martin de Viale LC (1980). Investigations on the presence of porphyrinogen carboxy-lyase inhibitor in the liver of rats intoxicated with hexachlorobenzene. Int. J Biochem. 12 (5-6), 1027-1032.
- ↑ 7.0 7.1 Smith, A. G., and Francis, J. E. (1987). Chemically-induced formation of an inhibitor of hepatic uroporphyrinogen decarboxylase in inbred mice with iron overload. Biochem. J 246 (1), 221-226.
- ↑ Danton, M., and Lim, C. K. (2007). Porphomethene inhibitor of uroporphyrinogen decarboxylase: analysis by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry. Biomed. Chromatogr. 21 (7), 661-663
- Yip, K. W., Zhang, Z., Sakemura-Nakatsugawa, N., Huang, J. W., Vu, N. M., Chiang, Y. K., To, T. (2014). A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase. PloS one, 9 (2), e89889.