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Accumulation, Highly carboxylated porphyrins leads to Uroporphyria
Key Event Relationship Overview
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||High||High||Amani Farhat (send email)||Open for citation & comment||TFHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
Accumulation of porphyrins causes both physical and chemical damage to tissues, resulting in what is generally termed porphyria. The ability of porphyrins to absorb light of 400–410 nm (the Soret band) is the key factor in producing the photocutaneous lesions observed on sun exposed areas in affected individuals. The porphyrins absorb this light and enter a high energy state, which is then transferred to molecular oxygen resulting in reactive oxygen species (ROS). These ROS cause phototoxic damage and further catalyze the oxidation of porphyrinogens to porphyrins. Some porphyrins, mainly uroporphyrin and heptacarboxyl porphyrin, form needle-shaped crystals resulting in hydrophilic cytoplasmic inclusions. Porphyrins demonstrate a range of water solubilities, and therefore show unique tissue and cellular distributions, resulting in different patterns of phototoxic damage histologically and cytologically.
Evidence Supporting this KER
The WOE for tyhis KER is strong.
Uncertainties and Inconsistencies
No current inconsistencies to report.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- ↑ 1.0 1.1 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.
- ↑ 2.0 2.1 Sarkany, R. P. (2008). Making sense of the porphyrias. Photodermatol. Photoimmunol. Photomed. 24 (2), 102-108.
- ↑ 3.0 3.1 Kennedy, S. W., and Fox, G. A. (1990) Highly carboxylated porphyrins as a biomarker of polyhalogenated aromatic hydrocarbon exposure in wildlife: Confirmation of their presence in Great Lakes herring gull chicks in the early 1970s and important methodological details. Chemosphere 21 (3), 407-415.
- ↑ 4.0 4.1 Smith, A. G., and Elder, G. H. (2010) Complex gene-chemical interactions: hepatic uroporphyria as a paradigm. Chem. Res. Toxicol. 23 (4), 712-723.
- ↑ [ https://www.nlm.nih.gov/medlineplus/ency/article/003372.htm]"Diagnostic blood test for porphyria "
- ↑ [ http://porphyria.eu/en/content/laboratory-diagnosis]"Diagnosis of Porphyrias "
- Phillips, J. D., Jackson, L. K., Bunting, M., Franklin, M. R., Thomas, K. R., Levy, J. E., Andrews, N. C., and Kushner, J. P. (2001). A mouse model of familial porphyria cutanea tarda. Proc. Natl. Acad. Sci. U. S. A 98(1), 259-264.
Gorman, N., Ross, K. L., Walton, H. S., Bement, W. J., Szakacs, J. G., Gerhard, G. S., Dalton, T. P., Nebert, D. W., Eisenstein, R. S., Sinclair, J. F., and Sinclair, P. R. (2002). Uroporphyria in mice: thresholds for hepatic CYP1A2 and iron. Hepatology 35(4), 912-921.
Smith, A. G., Clothier, B., Carthew, P., Childs, N. L., Sinclair, P. R., Nebert, D. W., and Dalton, T. P. (2001). Protection of the Cyp1a2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 173(2), 89-98.
Bohrer, H., Schmidt, H., Martin, E., Lux, R., Bolsen, K., and Goerz, G. (1995). Testing the porphyrinogenicity of propofol in a primed rat model. Br. J. Anaesth. 75(3), 334-338.
Goldstein, J. A., Linko, P., and Bergman, H. (1982). Induction of porphyria in the rat by chronic versus acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem. Pharmacol. 31(8), 1607-1613.
Fox, G.A., Kennedy, S.W. and Nordstrom, R.J. (1988) Porphyria In Herring Gulls: A Biochemical Response To Chemical Contamination Of Great Lakes Food Chains. Env. Tox. Chem. 7, 831-9.