Upstream eventAccumulation, Highly carboxylated porphyrins
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Directness||Weight of Evidence||Quantitative Understanding|
|Aryl hydrocarbon receptor activation leading to uroporphyria||directly leads to||Strong||Strong|
|herring gull||Larus argentatus||Strong||NCBI|
Life Stage Applicability
How Does This Key Event Relationship Work
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.
Weight of Evidence
The WOE for tyhis KER is strong.
Empirical Support for Linkage
Include consideration of temporal concordance here
Uroporphyria is defined as the accumulation and excretion of uroporphyrin, heptacarboxylic acid and hexacarboxylic acid: collectively referred to as highly carboxylated porphyrins (HCPs). It is the animal model equivalent to the human disorder, porphyria cutanea tarda.
Uncertainties or Inconsistencies
No current inconsistencies to report.
Quantitative Understanding of the Linkage
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?
According to the U.S. National Library of Medicine, red blood cell porphyrin levels in healthy individuals should lie within the following ranges:
- Total porphyrin levels: 16 to 60 mcg/dL
- Coproporphyrin level: < 2 mcg/dL
- Protoporphyrin level: 16 to 60 mcg/dL
- Uroporphyrin level: < 2 mcg/dL
The European Porphyria Network details the minimum laboratory requirements necessary for diagnosing each type of porphyria .
Studies in mice show trace amount of hepatic and urinary porphyrins in normal individuals (total porphyrins <1 nmol/g liver and < 1 µM, respectively)[8,9,10]. Healthy rats were shown to have total hepatic porphyrin levels ranging from 0.78-1.22 nmol/g liver, and urinary excretion of uroporphyrin < 5 µg a day.
Excessive accumulation of porphyrins can lead to the neuropsychiatric symptoms of hereditary hepatic porphyrias; Andrade et al. demonstrate that a linear combination of urinary prophyrin levels in rats exposed to heavy metals can predict the magnitude of the resulting neurotoxicity.
Fox and colleagues (1988) screened for highly carboxylated porphyrins (HCPs) in 8 wild bird species in relatively uncontaminated areas, and found that healthy individuals should contain no more than 25 pmol HCPs/g liver. The livers of puffins, chickens, quail, doves and finches and herring gulls contained 4 to 24 pmol HCPs/g and fulmars and murres contained a maximum of 12 pmol HPCs/g liver.
Evidence Supporting Taxonomic 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 "
- ↑ Andrade, V., Mateus, M. L., Batoreu, M. C., Aschner, M., and Marreilha dos Santos, A. P. (2014). Changes in rat urinary porphyrin profiles predict the magnitude of the neurotoxic effects induced by a mixture of lead, arsenic and manganese. Neurotoxicology 45, 168-177.
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.