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Relationship: 865

Title

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Oxidation, Uroporphyrinogen leads to Inhibition, UROD

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Aryl hydrocarbon receptor activation leading to uroporphyria adjacent Moderate Low Amani Farhat (send email) Open for citation & comment WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
rats Rattus norvegicus High NCBI
human Homo sapiens High NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
All life stages Not Specified
Adult High
Juvenile High

Key Event Relationship Description

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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[1]. 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[2].

Phillips et al.[1] 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[8], 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 Collection Strategy

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Evidence Supporting this KER

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The WOE for this KER is moderate.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Reduced UROD enzyme activity, not protein levels, is characteristic of uroporphyria in humans and rats[3][4][5], 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[6][7]. 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)[2].

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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.[1] has been criticized by Danton and Lim[8]. 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 [9].

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[9]. 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.  

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
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Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
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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A hepatically generated UROD inhibitor has been detected in porphyric mice[7] and rats[6], and humans with porphyria cutanea tarda[1]).

References

List of the literature that was cited for this KER description. More help
  1. 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. 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.
  3. 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.
  4. 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.
  5. 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. 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. 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.
  8. 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
  9. 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(2), e89889.