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Relationship: 865

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Oxidation, Uroporphyrinogen leads to Inhibition, UROD

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Oxidation, Uroporphyrinogen

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Inhibition, UROD

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	Allie Always (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

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	Not Specified
Adult	High
Juvenile	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

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.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

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

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

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

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

A hepatically generated UROD inhibitor has been detected in porphyric mice^[7] and rats^[6], and humans with porphyria cutanea tarda^[1]).