This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Renal protein alkylation leading to kidney toxicity
Point of Contact
- Angela Mally
|Author status||OECD status||OECD project||SAAOP status|
|Not under active development||Under Development||1.43||Included in OECD Work Plan|
This AOP was last modified on June 04, 2021 15:04
|Alkylation, Protein||September 16, 2017 10:14|
|Dysfunction, Mitochondria||October 25, 2017 07:49|
|Decrease, Mitochondrial ATP production||September 16, 2017 10:14|
|Increase, Cytotoxicity (renal tubular cell)||March 03, 2022 15:14|
|Occurrence, Kidney toxicity||March 04, 2022 10:58|
|Alkylation, Protein leads to Dysfunction, Mitochondria||October 25, 2017 09:23|
|Dysfunction, Mitochondria leads to Decrease, Mitochondrial ATP production||October 25, 2017 09:23|
|Decrease, Mitochondrial ATP production leads to Increase, Cytotoxicity (renal tubular cell)||October 25, 2017 09:24|
|Increase, Cytotoxicity (renal tubular cell) leads to Occurrence, Kidney toxicity||March 08, 2022 11:46|
It is well established that bioactivation of xenobiotics to reactive intermediates that covalently bind to proteins presents a major mechanism by which xenobiotics may cause proximal tubule injury. Examples for compounds that form covalent protein adducts in proximal tubule cells include haloalkenes (e.g. trichloroethylene, tetrachloroethylene, hexachloro-1,3-butadiene, chloroform), quinones (derived from e.g. hydroquinone, bromobenzene, 4-aminophenol), cephalosporins, and N-(3,5-dichlorophenyl)succinimide [1-6]. Covalent interaction of a chemical or a metabolite with cellular proteins represents the molecular initiating event (MIE) that triggers perturbation of cellular functions, of which mitochondrial dysfunction (KE1) leading to ATP depletion (KE2) appears to be most critical for proximal tubule cell death (KE3) by apoptosis and/or necrosis [5, 7-10]. Tubular obstruction and inflammatory responses to proximal tubule injury including activation of complement may cause secondary toxicity and thus amplify kidney injury, resulting in a progressive decline in kidney function (evidenced by e.g. rise in serum creatinine and blood urea nitrogen) (AO).
AOP Development Strategy
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|MIE||244||Alkylation, Protein||Alkylation, Protein|
|KE||1483||Dysfunction, Mitochondria||Dysfunction, Mitochondria|
|KE||40||Decrease, Mitochondrial ATP production||Decrease, Mitochondrial ATP production|
|KE||709||Increase, Cytotoxicity (renal tubular cell)||Increase, Cytotoxicity (renal tubular cell)|
|AO||814||Occurrence, Kidney toxicity||Occurrence, Kidney toxicity|
Relationships Between Two Key Events (Including MIEs and AOs)
|Alkylation, Protein leads to Dysfunction, Mitochondria||adjacent||Not Specified||Low|
|Dysfunction, Mitochondria leads to Decrease, Mitochondrial ATP production||adjacent||High||Low|
|Decrease, Mitochondrial ATP production leads to Increase, Cytotoxicity (renal tubular cell)||adjacent||High||Low|
|Increase, Cytotoxicity (renal tubular cell) leads to Occurrence, Kidney toxicity||adjacent||High||Moderate|
Life Stage Applicability
|All life stages||Not Specified|
|Human, rat, mouse||Human, rat, mouse||High||NCBI|
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Concordance of dose-response relationships
This is still a qualitiative description of the pathway. There is at present no quantitative information on dose-response relationships. Experiments are underway to provide quantitative understanding of dose-response relationships and response-response relationships between upstream and downstream KEs.
Temporal concordance among the key events and adverse outcome
The individual KEs are shown to occur prior to or concomitant with the onset of nephrotoxicity.
Strength, consistency, and specificity of association of adverse outcome and initiating event
The scientific evidence on the association between protein alkylation by reactive intermediates and kidney toxicity (AO) is strong and consistent. The MIE is not specific for kidney toxicity and is well established to lead to damage to other organs, whereby the site of toxicity is largely determined by the toxicokinetics of the parent compound or active metabolite.
Biological plausibility, coherence, and consistency of the experimental evidence
The described AOP is biologically plausible, coherent and well supported by experimental data.
Alternative mechanism(s) that logically present themselves and the extent to which they may distract from the postulated AOP
There are no alternative mechanism(s) that logically present themselves, although a contribution of other mechanisms such as generation of oxidative stress to the overall AO is possible.
Uncertainties, inconsistencies and data gaps
This AOP is plausible and consistent with general biological knowledge. However, there is currently little understanding as to which target proteins are critical to toxicity mediated by alkalation damage. Quantitative information on dose response-relationships as well as response-response relationships for upstream and downstream KEs is needed to support its applicability for the development of alternative in vitro tests for nephrotoxicity testing.
Known Modulating Factors
Quantitative data on KERs between upstream and downstream KE are still lacking.
Considerations for Potential Applications of the AOP (optional)
The described AOP is intended to provide a mechanistic framework for the development of in vitro bioactivity assays capable of predicting quantitative points of departure for safety assessment with regard to nephrotoxicity. Such assays may form part of an integrated testing strategy to reduce the need for repeated dose toxicity studies (e.g. OECD Guideline 407; OECD Guideline 407).
1. Birner, G., et al., Metabolism of tetrachloroethene in rats: identification of N epsilon-(dichloroacetyl)-L-lysine and N epsilon-(trichloroacetyl)-L-lysine as protein adducts. Chem Res Toxicol, 1994. 7(6): p. 724-32.
2. Pahler, A., et al., Generation of antibodies to Di- and trichloroacetylated proteins and immunochemical detection of protein adducts in rats treated with perchloroethene. Chem Res Toxicol, 1998. 11(9): p. 995-1004.
3. Kleiner, H.E., et al., Immunochemical detection of quinol--thioether-derived protein adducts. Chem Res Toxicol, 1998. 11(11): p. 1283-90.
4. Lau, S.S., Quinone-thioether-mediated nephrotoxicity. Drug Metab Rev, 1995. 27(1-2): p. 125-41.
5. Tune, B.M., Nephrotoxicity of beta-lactam antibiotics: mechanisms and strategies for prevention. Pediatr Nephrol, 1997. 11(6): p. 768-72.
6. Griffin, R.J. and P.J. Harvison, In vivo metabolism and disposition of the nephrotoxicant N-(3, 5-dichlorophenyl)succinimide in Fischer 344 rats. Drug Metab Dispos, 1998. 26(9): p. 907-13.
7. Groves, C.E., et al., Pentachlorobutadienyl-L-cysteine (PCBC) toxicity: the importance of mitochondrial dysfunction. J Biochem Toxicol, 1991. 6(4): p. 253-60.
8. Chen, Y., et al., Role of mitochondrial dysfunction in S-(1,2-dichlorovinyl)-l-cysteine-induced apoptosis. Toxicol Appl Pharmacol, 2001. 170(3): p. 172-80.
9. Hill, B.A., T.J. Monks, and S.S. Lau, The effects of 2,3,5-(triglutathion-S-yl)hydroquinone on renal mitochondrial respiratory function in vivo and in vitro: possible role in cytotoxicity. Toxicol Appl Pharmacol, 1992. 117(2): p. 165-71.
10. Aleo, M.D., et al., Toxicity of N-(3,5-dichlorophenyl)succinimide and metabolites to rat renal proximal tubules and mitochondria. Chem Biol Interact, 1991. 78(1): p. 109-21.