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Relationship: 868
Title
Induction, CYP1A2/CYP1A5 leads to Oxidation, Uroporphyrinogen
Upstream event
Downstream event
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 | Moderate | Low | Allie Always (send email) | Open for citation & comment | WPHA/WNT Endorsed |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Unspecific | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| Adults | High |
| Juvenile | High |
The oxidation of uroporphyrinogen to its corresponding porphyrin (UROX) is preferentially catalyzed by the phase one metabolizing enzyme, CYP1A2, in mammals[1][2] and CYP1A5 in birds[3]. Uroporphyrinogen, an intermediate in heme biosynthesis, is normally converted to coproporphyrinogen by uroporphyrinogen decarboxylase (UROD)[4]; induction of CYP1A2 expression translates to increased protein levels and therefore an increased incidence of binding, and oxidation of uroporphyrinogen, preventing its normally dominant conversion to coproporphyrinogen.
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
It is worth noting that Cyp1a2(-/-) knockout mice have up to 40% of the UROX activity of Cyp1a2(+/+) mice[7], suggesting that some UROX activity is CYP1A2-independent. Likewise, transfection of human Cyp1a1, Cyp3a4, Cyp3a5, or Cyp2e1 in insect cells resulted in UROX activity[10], suggesting that UROX can be catalyzed by other CYPs than CYP1A2 both in mouse and human. Additionally, iron overload or other induced pathways can potentially induce UROX [13]. However, it was shown in mice that only CYP1A2-dependent UROX activity is associated with UROD inhibition[7]. No such experiment was conducted in human, therefore, uncertainties remain for that species.
In mice, TCDD can elicit AhR-dependent, CYP1A1/A2-independent mitochondrial ROS production suggesting that general oxidative stress induced independently of CYP1A2 induction may contribute to the resulting overall UROX by TCDD [14].
Phillips et al.[11] were able to generate uroporphyria in a Cyp1A2-/- mouse model that is genetically predisposed (Hfe-/-, Urod-/+, which translates into intrinsic iron-overload and reduced UROD activity) to develop porphyria in the absence of external stimuli; CYP1A2 knockout alone prevented porphyrin accumulation, but with the addition of iron and ALA to the triple knockout, modest porphyria was observed. Therefore, under extreme porphyric conditions, UROX leading to porphyria can occur in the absence of the CYP1A2 enzyme.
Altogether, these results indicate that while CYP1A2 is a major catalysis of UROX activity, other CYPs and/or modulating factors are involved in the pathway.
Iron
Iron status can profoundly modify the level of uroporphyrin accumulation 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 [15-16]. In human suffering from uroporphyrin accumulation, it was found that lowering body iron stores by bleeding or now chelators causes remission [17].
Cycling between the ferrous (Fe2+) and ferric (Fe3+) redox states allows Fe to catalyze the Haber-Weiss reaction, in which highly reactive •OH is generated from H2O2 and O2•−. Thus, by catalyzing the formation of reactive oxygen species, it is suggested that iron can increase the rate at which uroporphyrinogen is oxidized to uroporphyrin and therefore enhance uroporphyrin formation [18].
Ascorbic acid
Ascorbic acid (AA) can prevent uroporphyrin accumulation experimental uroporphyria, but only when hepatic iron stores are normal or mildly elevated [19]. It was shown in chick embryo liver cells that AA could prevent uroporphyrin accumulation caused by treatment with 3,3',4,4'-tetrachlorobiphenyl and 5-aminole-vulinate by competitively inhibiting microsomal CYP1A2-catalyzed oxidation of uroporphyrinogen[20]. Oppositely, in a spontaneous mutant rat that requires dietary AA, hepatic uroporphyrin accumulation caused by treatment with 3-methylcholanthrene or hexachlorobenzene was found to be enhanced when the animals were maintained on a very low AA dietary intake[21].
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?
UROX is positively correlated with CYP1A2/5 activity[12] but this relationship has not been quantitatively describes. It has been noted however, that a CYP1A2 induction of just 2-fold dramatically induces porphyrin accumulation in iron-loaded mice[5].