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Amani Farhat and Gillian Manning
Sean W. Kennedy
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Hepatic uroporphyria is a disorder where the disturbance of heme biosynthesis results in accumulation and excretion of uroporphyrin, heptacarboxylic acid and hexacarboxylic acid: collectively referred to as highly carboxylated porphyrins (HCPs). The disorder can be genetically acquired, due to a dysfunction in any of the 7 enzymes involved in the heme biosynthesis pathway , or may be chemically induced, which involves the inhibition of uroporphyrinogen decarboxylase (UROD). This adverse outcome pathway (AOP) describes the linkages leading to chemically induced porphyria through the activation of the aryl hydrocarbon receptor (AHR), a transcription factor that plays important endogenous roles in reproduction, liver and heart development, cardiovascular function, immune function and cell cycle regulation . This AOP was developed in accordance with OECD guidelines and demonstrates a high degree of confidence as a qualitative AOP. The quantitative understanding of this AOP however is not yet complete, preventing the accurate prediction of uroporphyria from lower level key events.
Summary of the AOP
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Molecular Initiating Event
|Molecular Initiating Event||Support for Essentiality|
|Event||Support for Essentiality|
|Highly carboxylated porphyrins, Accumulation||Strong|
Relationships Among Key Events and the Adverse Outcome
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Life Stage Applicability
|herring gull||Larus argentatus||Strong||NCBI|
|Japanese quail||Coturnix japonica||Strong||NCBI|
Overall Assessment of the AOP
Domain of Applicability
Life Stage Applicability,
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.
Life Stage Applicability: Uroporphyria occurs following chemical exposure in juvenile or adult individuals. Fetal exposure to dioxin-like compounds causes developmental abnormalities and embryolethality rather than HCP accumulation. Turkish children under the age of two that were exposed to HCB through breastmilk passed away from a condition called "pink sore”.
Taxonomic Applicability: Although the AHR is highly conserved in evolution, chemical-induced uroporphyria has only been detected in birds and mammals , including an accidental outbreak in humans due to hexachlorobenzen-contaminated grain in the 1950s. Fish are less susceptible to chemical-induced uroporphyria, but elevated levels of HCP have been documented in highly contaminated environments.
Sex Applicability: Although this AOP applies broadly to both males and females, sexual dimorphism for uroporphyria has been observed in rats exposed to hexachlorobenzene (HCB). Hepatic uroporphyrin III was markedly increased in female rats exposed to HCB whereas exposed males showed levels of hepatic porphyrins similar to controls.
Essentiality of the Key Events
Molecular Initiating Event Summary,
Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.
Every Key event in this AOP is absolutely essential for downstream events to occur. A summary of evidence for essrntiality of each key event is given below.
Molecular Initiating Event: AHR activation (Essentiality=strong)
- Mice with a high-affinity Ahr allele (C57BL/6J ) are much more sensitive to uroporphyria than mice with low-affinity Ahr allele (DBA/2);
- The Ah locus influences the susceptibility of C57BL/6J mice to HCB-induced porphyria;
- Ahr knockout mice (C57BL/6) are resistant to development of porphyria, even in the presence of iron loading;
- Primary hepatocytes of avian species indicate that species that are highly sensitive to AHR activation are more sensitive to uroporphyrin accumulation than species with lower sensitivity to AHR activation.
Key Event 1: CYP1A2/Cyp1A5 induction (Essentiality=strong)
- CYP1A2 knockout in mice prevents chemical-induced uroporphyria;
- CYP1A2 knockout prevents porphyria in genetically predisposed mice (Hfe-/-, Urod-/+) that normally develop porphyria in absence of external stimuli;
- CYP1A2 levels are correlated with the extent of urophorphyrin accumulation in mice;
- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and non-ortho substituted PCBs that are potent inducers of CYP1A4/5 cause accumulation of only HCPs in chicken embryonic hepatocytes cultures, whereas PCBs that do not induce CYP1A4/5 cause a porphyrin pattern that is not consistent with inhibition of UROD;
- Common tern (Sterna hirundo) embryonic hepatocyte cultures, which are ~50 to > 1600 times less sensitive than chicken embryonic hepatocyte cultures to CYP1A5 induction by TCDD and PCBs, do not accumulate HCPs upon chemical exposure.
It should be noted that a recent study by Davies et al. found that both C57BL/6J mice (susceptible to chemical-induced porphyria) and DBA/2 mice (resistant to porphyria due to polymorphism in AHR gene) showed increased expression of CYP1A2 when exposed to TCDD, even though the DBA/2 strain did not develop porphyria. Furthermore AHR-/- mice showed a mild uroporphyric response in the presence of iron loading and 5-aminolevulinic acid (a heme precursor). These findings suggest that the induction of CYP1A2 is not crucial for chemical-induced porphyria, but a basal level of expression is absolutely essential.
Key Event 2: Uroporphyrinogen oxidation (UROX) (Essentiality=strong)
- Uroporphyria is characterized biochemically by increased formation of HCPs derived by oxidation of the porphyrinogen substrates of uroporphyrinogen decarboxylase (UROD); secondary to decreased activity of this enzyme in the liver;
- Uroporphomethane, derived from oxidizing a single carbon bridge in uroporphyrinogen, has been identified as the UROD inhibitor that leads to chemically- and genetically-induced uroporphyria in mice;
- UROX activity is positively correlated with uroporphyrin levels in mice.
Key Event 3: Uroporphyrinogen decarboxylase (UROD) inhibition (Essentiality=strong)
- Mutations in the UROD gene that reduce or eliminate UROD activity lead to porphyria in mammals; a decrease in hepatic UROD activity of at least 70% is necessary to observe symptoms from overproduction of porphyrins;
- A marked progressive decrease in UROD enzyme activity is a common feature in animal models of chemical-induced porphyria;
- Liver cytosol UROD activity in female rats exposed to HCB was decreased more than 70% and correlated with elevated hepatic uroporphyrin levels, whereas male rats, which did not develop porphyria, showed UROD activity similar to controls;
- UROD activity is inversely proportional to uroporphyrin levels in mice;
- In chicken hepatocytes, the strongest inducers of porphyrin accumulation were also the strongest inhibitors of UROD activity;
- Reduced UROD enzyme activity, not protein levels, is characteristic of uroporphyria in humans and rats.
Key Event 4: Highly carboxylated porphyrin (HCP) accumulation (Essentiality=strong)
- Under normal heme biosynthesis, porphyrins are only present in trace amounts in the liver; however, in the absence of UROD activity, the oxidation of Uroporphorynogen to uroporphyrins dominates, leading to an accumulation of HCPs;
- Porphyrins are strongly fluorescent compounds resulting in a characteristic red fluorescence of hepatic tissue under UV light that is proportional to the level of porphyrins. Increased urinary excretion of porphyrins is also indicative of their accumulation and can lead to dark red/brown urine. HCPs also accumulate in the skin causing solar hypersensitivity and increased skin fragility;
- HCP accumulation was observed in avian embryo hepatocyte cultures following exposure potent AHR agonists (dioxin-like compounds) and in the livers of Japanese quails and chickens exposed to PCBs;
- HCP accumulation was evident in mice treated with polyhalogenated aromatic compounds and TCDD-treated rats.
Weight of Evidence Summary
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.
Table 1 demonstrates that upstream KEs (monooxygenase activity/quantity) are significantly affected at lower doses than downstream KEs (porphyrin levels). After a 6 month recovery period, CYP450 and hepatic porphyrin levels were dramatically reduced, however, they did not return to normal. Furthermore, urinary porphyrin excretion remained maximally elevated
Table 2 demonstrates that upstream KEs (CYP1A2 expression and UROD inhibition) are significantly affected at earlier time-points than downstream KEs (porphyrin levels). These studies also show that upstream KEs are more sensitive to change than downstream KEs; ddY mice showed a 44% reduction in UROD activity but did not develop uroporphyria.
Key Events Relationships
Table 3 shows a sampling of the literature that demonstrates changes in KEs at multiple levels of organization leading to uroporphyria. The use of animal models resistant to porphyria (low AHR affinity or AHR/CYP1A2 knockout) illustrates the essentiality of these KEs in for downstream effects.
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.
The overall quantitative understanding of this AOP is poor. Quantitative models have been developed that predict the AHR transactivation potential of various compounds , but the extent of AHR activation necessary to produce porphyria is not known. It has been established that a reduction in UROD activity of at least 70% is required to lead to overt uroporphyrin in mammals. Additionally, numerous in vitro systems have been developed to study porphyrin accumulation and UROD inhibition simultaneously; therefore, this KER provides the most feasible target for a predictive, quantitative model. However, care must be taken when reading across to other species; UROD inhibition is not always observed in avian models of porphyria, and when it is, it is less pronounced.
Considerations for Potential Applications of the AOP (optional)
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