Aop: 131

AOP Title


Aryl hydrocarbon receptor activation leading to uroporphyria

Short name:


AHR activation-uroporphyria

Graphical Representation


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Authours: Amani Farhat1, Gillian Manning, Jason OBrien2, and Sean W. Kennedy3

Environment and Climate Change Canada


Contact Information:

1) Amani_farhat@hotmail.com

2) jason.obrien@canada.ca

3) sean.kennedy.ottawa@gmail.com




Point of Contact


Amani Farhat   (email point of contact)



  • Amani Farhat
  • Jason M. O'Brien



Author status OECD status OECD project SAAOP status
Open for citation & comment TFHA/WNT Endorsed 1.7 Included in OECD Work Plan

This AOP was last modified on December 06, 2019 16:42


Revision dates for related pages

Page Revision Date/Time
Activation, AhR March 22, 2018 14:00
Oxidation, Uroporphyrinogen September 16, 2017 10:16
Inhibition, UROD May 30, 2018 12:49
Accumulation, Highly carboxylated porphyrins May 07, 2018 07:56
Uroporphyria May 07, 2018 07:53
Induction, CYP1A2/CYP1A5 May 30, 2018 14:24
Activation, AhR leads to Induction, CYP1A2/CYP1A5 May 07, 2018 08:09
Induction, CYP1A2/CYP1A5 leads to Oxidation, Uroporphyrinogen May 31, 2018 15:43
Oxidation, Uroporphyrinogen leads to Inhibition, UROD May 30, 2018 10:58
Inhibition, UROD leads to Accumulation, Highly carboxylated porphyrins May 30, 2018 12:40
Accumulation, Highly carboxylated porphyrins leads to Uroporphyria May 07, 2018 08:03
Dibenzo-p-dioxin November 29, 2016 18:42
Polychlorinated biphenyl November 29, 2016 18:42
Hexachlorobenzene November 29, 2016 18:42
Polycyclic aromatic hydrocarbons (PAHs) February 09, 2017 15:43



Hepatic uroporphyria is a disorder where the disturbance of heme biosynthesis results in accumulation and excretion of uroporphyrin, heptacarboxyl- and hexacarboxyl porphyrin: collectively referred to as highly carboxylated porphyrins (HCPs)[1][2][3]. The disorder is due to a homozygous mutation in uroporphyrinogen decarboxylase (UROD), an enzyme involved in the heme biosynthesis pathway [4], or may be chemically induced, which involves the inhibition of UROD. This adverse outcome pathway (AOP) describes the linkages leading to chemically induced porphyria through the activation of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor.  AHR activation leads to the induction of cytochrome P450 1A2, a phase I metabolizing enzyme, which in turn results in excessive oxidation of uroporphyrinogen.  This oxidation produces a UROD inhibitor, preventing the conversion of uroporphyrinogen to coprouroporphyrinogen and increasing the synthesis of the UROD inhibitor in a positive feedback loop. The accumulation of uroporphyrinogen leads to its preferential oxidation and accumulation of HCP in various organs (Uroporphyria).  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.


Background (optional)


Heme is a cyclic tetrapyrrole cofactor containing Fe2+ porphyrin-containing ferroprotein that forms various hemoproteins such as hemoglobin, cytochromes and catalases [62]. Its biosynthesis mostly occurs in the liver and involves 8 separate steps. Porphyria is a disorder in which the disturbance of any of the steps of heme biosynthesis results in accumulation and excretion of porphyrins[2]. A variety of porphyrias exist depending on which enzyme in the pathway is deficient. This AOP describes a situation in which the 5th step of heme biosynthesis, uroporphyrinogen decarboxylase (UROD), which converts uroporphyrinogen to coproporphyrinogen, is inhibited.

Hepatic uroporphyria is viewed somewhat differently by clinicians and toxicologists. For the former it is mostly a sporadic disease (porphyria cutanea tarda; PCT) occurring sometimes in patients exposed to a variety of insults such as alcohol, estrogens, hepatitis viruses, HIV and on dialysis. Importantly, very early on it was found that lowering body iron stores by bleeding or now chelators causes remission [61]. In some northern European and US patients, carrying the hemochromatosis mutation is a risk factor but in other patients other iron susceptibility genes may contribute. Carrying a UROD mutation (lowering activity) is also a risk factor but still dependent on other susceptibility factors to see porphyria. To reproduce these findings experimentally has proved challenging but now possible. For toxicologists hepatic uroporphyria has mostly been seen as a toxic, but unique and curious endpoint of polychlorinated ligands of the AHR.  Experimentally, TCDD in mice is the most potent agent consistent with AHR mode of action but is more difficult in rats and other organisms. Hexachlorobenzene (HCB) has been greatly studied for its porphyria-inducing abilities and a large incident of porphyria in some young people in Turkey 60 years ago was ascribed to susceptible individuals who had consumed HCB. It is controversial whether HCB is a weak AHR ligand. Evidence of porphyria in people exposed accidentally or occupationally to accepted AHR ligands such as TCDD and PCBs is thin. Importantly, iron status can profoundly modify experimental uroporphyria induced by these chemicals especially in mice. In fact iron overload alone of mice will eventually produce a strong hepatic uroporphyria which is markedly genetically determined and toxicity can be ameliorated by chelators resembling PCT. Thus hepatic porphyria could alternatively be viewed as an iron AOP. At an overall level hepatic uroporphyria in animals and patients is the outcome of complex genetic traits and external stimuli in which in some traditional toxicological circumstances binding of a chemical to the AHR may have a major contribution[67] but in others may not.

Summary of the AOP


Events: Molecular Initiating Events (MIE)


Key Events (KE)


Adverse Outcomes (AO)


Sequence Type Event ID Title Short name
1 MIE 18 Activation, AhR Activation, AhR
2 KE 850 Induction, CYP1A2/CYP1A5 Induction, CYP1A2/CYP1A5
3 KE 844 Oxidation, Uroporphyrinogen Oxidation, Uroporphyrinogen
4 KE 845 Inhibition, UROD Inhibition, UROD
5 KE 846 Accumulation, Highly carboxylated porphyrins Accumulation, Highly carboxylated porphyrins
6 AO 369 Uroporphyria Uroporphyria

Relationships Between Two Key Events
(Including MIEs and AOs)


Title Adjacency Evidence Quantitative Understanding
Activation, AhR leads to Induction, CYP1A2/CYP1A5 adjacent High High
Induction, CYP1A2/CYP1A5 leads to Oxidation, Uroporphyrinogen adjacent Moderate Low
Oxidation, Uroporphyrinogen leads to Inhibition, UROD adjacent Moderate Low
Inhibition, UROD leads to Accumulation, Highly carboxylated porphyrins adjacent Moderate Moderate
Accumulation, Highly carboxylated porphyrins leads to Uroporphyria adjacent High High

Network View





Life Stage Applicability


Life stage Evidence
Adult High
Juvenile High

Taxonomic Applicability


Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
human Homo sapiens High NCBI
chicken Gallus gallus Moderate NCBI
herring gull Larus argentatus Moderate NCBI
Japanese quail Coturnix japonica Low NCBI
Common Starling Common Starling Moderate NCBI

Sex Applicability


Sex Evidence
Unspecific High

Overall Assessment of the AOP


Overall, this AOP can most accurately be applied to mammalian species past the embryonic and infant stage of development.  It is also representative of a solid toxicity pathway in avian species, however the contribution of the defining key event (UROD inhibition) is not as well understood; it is not as dramatically and consistently inhibited as it is with mammals.  There is minimal evidence supporting the applicability of this AOP in fish, and none in alternate species.  Details and supporting evidences are summarized below.

Domain of Applicability


Life Stage Applicability, Taxonomic Applicability, Sex 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[15][16][17][18][19]. Turkish children under the age of two that were exposed to HCB through breastmilk passed away from a condition called "pink sore”[20].

Taxonomic Applicability: Although the AHR is highly conserved in evolution[21], chemical-induced uroporphyria has only been detected in birds[1][2][3] and mammals[22] , including an accidental outbreak in humans due to hexachlorobenzen-contaminated grain in the 1950s[20]. Fish are less susceptible to chemical-induced uroporphyria, but elevated levels of HCP have been documented in highly contaminated environments[23].

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[24].

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 essentiality 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)[25][26][27][28][29];
  • The Ah locus influences the susceptibility of C57BL/6J mice to HCB-induced porphyria[30];
  • Ahr knockout mice (C57BL/6) are resistant to development of porphyria, even in the presence of iron loading[25];
  • 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[31].

Key Event 1: CYP1A2/Cyp1A5 induction (Essentiality=strong)

  • CYP1A2 knockout in mice prevents chemical-induced uroporphyria[32][33][34];
  • CYP1A2 knockout prevents porphyria in genetically predisposed mice (Hfe-/-, Urod-/+) that normally develop porphyria in absence of external stimuli[35];
  • CYP1A2 levels are correlated with the extent of urophorphyrin accumulation in mice[36];
  • 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[37];
  • 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[31].

It should be noted that a recent study by Davies et al.[25] 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[22];
  • 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[38];
  • UROX activity is positively correlated with uroporphyrin levels in mice[36].

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[22];
  • A marked progressive decrease in UROD enzyme activity is a common feature in animal models of chemical-induced porphyria[22][34][39][40][41];
  • 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[24];
  • UROD activity is inversely proportional to uroporphyrin levels in mice[36];
  • In chicken hepatocytes, the strongest inducers of porphyrin accumulation were also the strongest inhibitors of UROD activity[41];
  • Reduced UROD enzyme activity, not protein levels, is characteristic of uroporphyria in humans and rats[24][42][43].

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[44][45]. Increased urinary excretion of porphyrins is also indicative of their accumulation and can lead to dark red/brown urine[22]. HCPs also accumulate in the skin causing solar hypersensitivity and increased skin fragility[46];
  • HCP accumulation was observed in avian embryo hepatocyte cultures following exposure potent AHR agonists (dioxin-like compounds)[37][47][48][49] and in the livers of Japanese quails and chickens exposed to PCBs[50][51][52];
  • HCP accumulation was evident in mice treated with polyhalogenated aromatic compounds[36] or TCDD[25].

Evidence Assessment


Summary Table

Dose concordance

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[53]

Uroporphyria Table 1 TCDD recovery.png

Temporal Concordance

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[25][54].

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.

Uroporphyria Table 3 KER Summary.png


CYPs other than CYP1A2 are able of catalyzing uroporphyrinogen oxidation, raising doubts on the essentiality of CYP1A2 for this pathway. For instance, Phillips et al.[35] were able to generate mild uroporphyria in a Cyp1A2-/- mouse model that is genetically predisposed (Hfe-/-, Urod-/+) to develop porphyria.

The essentiality of CYP1A2 induction in human porphyria cutanea tarda is unclear. UROX activity in human liver microsomes was not correlated with CYP1A2 content[66]. Furthermore, there is contradictory evidence regarding the association between CYP1A2 polymorphism and susceptibility to porphyria cutanea tarda [63-64]. It may be possible that in patients with a genetic variation in UROD causing an inherent reduction in activity, the activity of CYP1A2 is less important.

UROD inhibition is not always observed and/or is less pronounced in avian models of porphyria, mainly in quail [47]. It is suggested that a mechanism other than UROD inhibition explain the extent of porphyrin accumulation in birds. Therefore, the applicability of this AOP to avian remains uncertain.

The characterization of the UROD inhibitor isolated by Phillips [38] has been criticized by Danton[66]. Therefore, UROD inhibitor has yet to be identified.

AhR binding stressors under certain conditions do not lead to adverse effect in particular mammalian strains[25].

Quantitative Understanding


Summary Table
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 moderate for mammals and poor for alternate species. Quantitative models have been developed that predict the AHR transactivation potential of various compounds [55][56][57], 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[58][24][54]. 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[59][60][47].

Considerations for Potential Applications of the AOP (optional)


This AOP was developed with the intended purpose of chemical screening as well as ecological risk assessment.  There are numerous in vitro assays for each key event up to the level of UROD activity.  There is sufficient evidence that a 70% inhibition of UROD activity significantly increases the risk of developing uroporphyria in mammals, making it a promising target assay in the battery of chemical screening tools.   Furthermore, there has recently been significant advances in the understanding of differences in avian sensitivity to AHR agonists, and a similar effort is underway for fish.  Sequencing the AHR ligand binding domain of any bird species (and potentially fish species) allows for its classification as low, medium or high sensitivity, which aids in the chemical risk assessment of DLCs and other AHR agonists.  There is also potential use for this AOP in risk management, as minimum allowable environmental levels can be customized to the sensitivity of the native species in the area under consideration.



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