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AOP 131: Aryl Hydrocarbon Receptor Activation Leading to Uroporphyria

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AOP 131: Aryl Hydrocarbon Receptor Activation Leading to Uroporphyria Organisation for Economic Co-operation and Development DOCUMENT CODE For Official Use English - Or. English 1 January 1990 AOP 131: Aryl hydrocarbon receptor activation leading to uroporphyria Short Title: AHR activation-uroporphyria This document was approved by the Extended Advisory Group on Molecular Screening and Toxicogenomics in June 2018. The Working Group of the National Coordinators of the Test Guidelines Programme and the Working Party on Hazard Assessment are invited to review and endorse the AOP by 29 March 2019. Magdalini Sachana, Administrator, Hazard Assessment, [email protected], +(33- 1) 85 55 64 23 Nathalie Delrue, Administrator, Test Guidelines, [email protected], +(33-1) 45 24 98 44 This document, as well as any data and map included herein, are without prejudice to the status of or sovereignty over any territory, to the delimitation of international frontiers and boundaries and to the name of any territory, city or area. 2 │ Foreword This Adverse Outcome Pathway (AOP) on Aryl hydrocarbon receptor activation leading to uroporphyria, has been developed under the auspices of the OECD AOP Development Programme, overseen by the Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST), which is an advisory group under the Working Group of the National Coordinators for the Test Guidelines Programme (WNT). The AOP has been reviewed internally by the EAGMST, externally by experts nominated by the WNT, and has been endorsed by the WNT and the Working Party on Hazard Assessment (WPHA) in xxxxx. Through endorsement of this AOP, the WNT and the WPHA express confidence in the scientific review process that the AOP has undergone and accept the recommendation of the EAGMST that the AOP be disseminated publicly. Endorsement does not necessarily indicate that the AOP is now considered a tool for direct regulatory application. The Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology agreed to declassification of this AOP on xxxx. This document is being published under the responsibility of the Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology. The outcome of the internal and external reviews are publicly available respectively in the AOP Wiki and the eAOP Portal of the AOP Knowledge Base at the following links: [internal review] [external review]. │ 3 Table of contents Foreword ................................................................................................................................................ 2 Adverse Outcome Pathway on Aryl hydrocarbon receptor activation leading to uroporphyria Short Title: AHR activation-uroporphyria ......................................................................................... 5 Short Title: AHR activation-uroporphyria ........................................................................................... 5 Authours: .......................................................................................................................................... 5 Abstract .................................................................................................................................................. 6 Background ............................................................................................................................................ 7 Graphical Representation ..................................................................................................................... 8 Summary of the AOP ............................................................................................................................ 9 Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO) ............................... 9 Key Event Relationships ...................................................................................................................... 9 Stressors ............................................................................................................................................... 9 Dibenzo-p-dioxin ........................................................................................................................... 10 Polychlorinated biphenyl ................................................................................................................ 10 Hexachlorobenzene ........................................................................................................................ 10 Overall Assessment of the AOP .......................................................................................................... 12 Domain of Applicability .................................................................................................................... 12 Life Stage Applicability ................................................................................................................. 12 Taxonomic Applicability ................................................................................................................ 12 Sex Applicability ............................................................................................................................ 12 Essentiality of the Key Events ........................................................................................................... 13 Weight of Evidence Summary ........................................................................................................... 14 Quantitative Consideration ................................................................................................................ 18 Considerations for Potential Applications of the AOP (optional) ................................................... 19 References ............................................................................................................................................ 19 Appendix 1 ........................................................................................................................................... 24 List of MIEs in this AOP ................................................................................................................... 24 Event: 18: Activation, AhR ............................................................................................................ 24 List of Key Events in the AOP .......................................................................................................... 40 Event: 850: Induction, CYP1A2/CYP1A5 ..................................................................................... 40 Event: 844: Oxidation, Uroporphyrinogen ..................................................................................... 45 Event: 845: Inhibition, UROD ....................................................................................................... 47 Event: 846: Accumulation, Highly carboxylated porphyrins ......................................................... 50 List of Adverse Outcomes in this AOP .............................................................................................. 52 Event: 369: Uroporphyria ............................................................................................................... 52 Appendix 2: List of Key Event Relationships in the AOP ............................................................... 57 List of Adjacent Key Event Relationships ......................................................................................... 57 Relationship: 869: Activation, AhR leads to Induction, CYP1A2/CYP1A5 ................................. 57 Relationship: 868: Induction, CYP1A2/CYP1A5 leads to Oxidation, Uroporphyrinogen ............ 60 4 │ Relationship: 865: Oxidation, Uroporphyrinogen leads to Inhibition, UROD............................... 65 Relationship: 1070: Inhibition, UROD leads to Accumulation, Highly carboxylated porphyrins . 68 Relationship: 866: Accumulation, Highly carboxylated porphyrins leads to Uroporphyria .......... 71 │ 5 Adverse Outcome Pathway on Aryl hydrocarbon receptor activation leading to uroporphyria Short Title: AHR activation-uroporphyria Short Title: AHR activation-uroporphyria Authours: Amani Farhat1, Gillian Manning, and Jason OBrien2 Contact Information: 1) [email protected] 2) [email protected] 6 │ Abstract 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
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