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Relationship: 2703

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Up Regulation, CYP1A1 leads to Increase, Mt Dysfunction

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
AhR activation leads to increased diabetes risk non-adjacent Moderate Low Arthur Author (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
rodentia rodentia High NCBI
human Homo sapiens High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Cytochrome P4501A (CYP1A1) is a xenobiotic metabolism enzyme regulated by the aryl hydrocarbon receptor (AhR) (Nebert et al., 2004). CYP1A1 is involved in detoxifying a broad range of harmful substances. However, CYP1A1 enzyme activity can produce reactive oxygen intermediates, which contribute to oxidative stress (Kapelyukh et al., 2019; Sridhar et al., 2017). An increase in CYP1A1 induction has been associated with various measures of mitochondrial dysfunction, including reductions in oxygen consumption (Anandasadagopan et al., 2017; Ghosh et al., 2018; Raza et al., 2013; Shi et al., 2022; Tremblay-Laganière et al., 2019; Wang et al., 2019), mitochondrial mass (Li et al., 2022; Zhou et al., 2017), and mitochondrial membrane potential (Alshatwi et al., 2013).

There is also evidence suggesting the presence of Cyp1a1 and other members of the Cyp1 family is critical to mitochondrial dysfunction. Researchers who investigated the effects of β-naphthoflavone (BNF), an AhR agonist, on mitochondrial function concluded that mitochondrial impairments caused by BNF are mediated by AhR activation and CYP1A1/1A2 enzyme activity (Anandasadagopan et al., 2017). Cyp1a1/1a2 double-knockout mice and Cyp1a1/1a2/1b1 triple-knockout mice were protected against BNF-induced reduction in oxygen consumption, suggesting that the presence of Cyp1 genes is necessary for mitochondrial dysfunction. Further supporting the importance of Cyp1a genes, they also showed that BNF treatment increased Cyp1a1 and Cyp1a2 gene expression and enzyme activity in liver microsomes and mitochondria from wildtype mice (Anandasadagopan et al., 2017).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Search terms used are in Table 1. The search was limited to peer-reviewed research articles published within the last 10 years. Only experiments performed on animal models and/or cell lines that included measures of CYP1A1 induction and mitochondrial dysfunction were included. After screening, only 10 out of 128 studies retrieved from the initial search met the inclusion and exclusion criteria.

Table 1. Terms in columns were combined with “OR”, while terms in rows were combined with “AND”.

CYP1A1 Mitochondrial dysfunction
Cytochrome P4501A Mitochondria*
Cytochrome P4501*  

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

There is moderate evidence supporting this KER. Multiple peer-reviewed articles have shown an association between CYP1A1 induction and mitochondrial dysfunction. However, there may be tissue-specific effects and the quantitative understanding of this KER is limited.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Excess production of reactive oxygen species (ROS) is known to impair mitochondrial function (Bhatti et al., 2017). CYP1A1 is a monooxygenase that adds a single oxygen to its substrates and produces oxygen radicals (Sridhar et al., 2017). Studies have also consistently shown that an increase in CYP1A1 gene and protein expression is accompanied by an increase in ROS formation (Shi et al., 2022; Sun et al., 2021; Yuan et al., 2021; Zhou et al., 2017).Therefore, it is plausible that prolonged CYP1A1 activity can lead to mitochondrial dysfunction.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The effect of CYP1A1 on mitochondrial function may be tissue-specific. Raza et al. (2013) measured CYP1A1 protein levels and mitochondrial oxygen consumption in liver, heart, kidney, and lung tissues isolated from mice exposed to air or cigarette smoke. Their results showed that cigarette smoke exposure increased CYP1A1 protein activity in mouse liver, kidney, and lung, but not the heart. Moreover, the oxygen consumption of mitochondrial complex IV decreased across all tissues, but mitochondrial complex I only decreased in lung and kidney, increased in liver, and did not change in the heart (Raza et al., 2013). This suggests that some mitochondrial complexes may be more sensitive to stressors than others.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)
       
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

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This KER is applicable to all eukaryotic cells that express CYP1A1. The CYP1A1 gene is present in many species including human and non-human primates, rodents, fish, and birds (Kawashima & Satta, 2014). However, the relationship between CYP1A1 and mitochondrial dysfunction is mainly studied in humans and rodents. Although CYP1A1 is expressed in males and females, most rodent studies use male mice only (Anandasadagopan et al., 2017; Li et al., 2022; Raza et al., 2013; Shi et al., 2022). Limited information is available on how the relationship between CYP1A1 and mitochondrial dysfunction changes with age, but it has been shown in 4- to 16-week-old rodents (Anandasadagopan et al., 2017; Li et al., 2022; Tremblay-Laganière et al., 2019).

References

List of the literature that was cited for this KER description. More help

Alshatwi, A. A., Periasamy, V. S., Subash-Babu, P., Alsaif, M. A., Alwarthan, A. A., & Lei, K. A. (2013). CYP1A and POR gene mediated mitochondrial membrane damage induced by carbon nanoparticle in human mesenchymal stem cells. Environmental Toxicology and Pharmacology, 36(1), 215–222. https://doi.org/10.1016/j.etap.2013.03.009

Anandasadagopan, S. K., Singh, N. M., Raza, H., Bansal, S., Selvaraj, V., Singh, S., Chowdhury, A. R., Leu, N. A., & Avadhani, N. G. (2017). β-naphthoflavone-induced mitochondrial respiratory damage in Cyp1 knockout mouse and in cell culture systems: Attenuation by resveratrol treatment. Oxidative Medicine and Cellular Longevity, 2017. https://doi.org/10.1155/2017/5213186

Bhatti, J. S., Bhatti, G. K., & Reddy, P. H. (2017). Mitochondrial dysfunction and oxidative stress in metabolic disorders — A step towards mitochondria based therapeutic strategies. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1863(5), 1066–1077. https://doi.org/10.1016/J.BBADIS.2016.11.010

Ghosh, J., Chowdhury, A. R., Srinivasan, S., Chattopadhyay, M., Bose, M., Bhattacharya, S., Raza, H., Fuchs, S. Y., Rustgi, A. K., Gonzalez, F. J., & Avadhani, N. G. (2018). Cigarette smoke toxins-induced mitochondrial dysfunction and pancreatitis involves aryl hydrocarbon receptor mediated Cyp1 gene expression: Protective effects of resveratrol. Toxicological Sciences, 166(2), 428–440. https://doi.org/10.1093/toxsci/kfy206

Kapelyukh, Y., Henderson, C. J., Scheer, N., Rode, A., & Wolf, C. R. (2019). Defining the contribution of CYP1A1 and CYP1A2 to drug metabolism using humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 knockout mice. Drug Metabolism and Disposition, 47(8), 907–918. https://doi.org/10.1124/dmd.119.087718

Kawashima, A., & Satta, Y. (2014). Substrate-dependent evolution of cytochrome P450: Rapid turnover of the detoxification-type and conservation of the biosynthesis-type. PLOS ONE, 9(6), e100059. https://doi.org/10.1371/JOURNAL.PONE.0100059

Li, S., Yuan, J., Che, S., Zhang, L., Ruan, Z., & Sun, X. (2022). Decabromodiphenyl ether induces ROS-mediated intestinal toxicity through the Keap1-Nrf2 pathway. Journal of Biochemical and Molecular Toxicology, 36(4). https://doi.org/10.1002/jbt.22995

Nebert, D. W., Dalton, T. P., Okey, A. B., & Gonzalez, F. J. (2004). Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. Journal of Biological Chemistry, 279(23), 23847–23850. https://doi.org/10.1074/JBC.R400004200

Raza, H., John, A., & Nemmar, A. (2013). Short-term effects of nose-only cigarette smoke exposure on glutathione redox homeostasis, cytochrome P450 1A1/2 and respiratory enzyme activities in mice tissues. Cellular Physiology and Biochemistry, 31(4–5), 683–692. https://doi.org/10.1159/000350087

Senft, A. P., Dalton, T. P., Nebert, D. W., Genter, M. B., Puga, A., Hutchinson, R. J., Kerzee, J. K., Uno, S., & Shertzer, H. G. (2002). Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor. Free Radical Biology and Medicine, 33(9), 1268–1278. https://doi.org/10.1016/S0891-5849(02)01014-6

Shi, F., Zhang, Z., Wang, J., Wang, Y., Deng, J., Zeng, Y., Zou, P., Ling, X., Han, F., Liu, J., Ao, L., & Cao, J. (2022). Analysis by metabolomics and transcriptomics for the energy metabolism disorder and the aryl hydrocarbon receptor activation in male reproduction of mice and GC-2spd cells exposed to PM2.5. Frontiers in Endocrinology, 12. https://doi.org/10.3389/fendo.2021.807374

Sridhar, J., Goyal, N., Liu, J., & Foroozesh, M. (2017). Review of ligand specificity factors for CYP1A subfamily enzymes from molecular modeling studies reported to-date. Molecules (Basel, Switzerland), 22(7), 1143. https://doi.org/10.3390/molecules22071143

Sun, Y., Shi, Z., Lin, Y., Zhang, M., Liu, J., Zhu, L., Chen, Q., Bi, J., Li, S., Ni, Z., & Wang, X. (2021). Benzo(a)pyrene induces MUC5AC expression through the AhR/mitochondrial ROS/ERK pathway in airway epithelial cells. Ecotoxicology and Environmental Safety, 210. https://doi.org/10.1016/j.ecoenv.2020.111857

Tremblay-Laganière, C., Garneau, L., Mauger, J. F., Peshdary, V., Atlas, E., Nikolla, A. S., Chapados, N. A., & Aguer, C. (2019). Polychlorinated biphenyl 126 exposure in rats alters skeletal muscle mitochondrial function. Environmental Science and Pollution Research, 26(3), 2375–2386. https://doi.org/10.1007/S11356-018-3738-8/FIGURES/5

Wang, S., Zhang, Q., Zheng, S., Chen, M., Zhao, F., & Xu, S. (2019). Atrazine exposure triggers common carp neutrophil apoptosis via the CYP450s/ROS pathway. Fish and Shellfish Immunology, 84, 551–557. https://doi.org/10.1016/j.fsi.2018.10.029

Yuan, J., Sun, X., Che, S., Zhang, L., Ruan, Z., Li, X., & Yang, J. (2021). AhR-mediated CYP1A1 and ROS overexpression are involved in hepatotoxicity of decabromodiphenyl ether (BDE-209). Toxicology Letters, 352, 26–33. https://doi.org/10.1016/j.toxlet.2021.09.008

Zhou, B., Wang, X., Li, F., Wang, Y., Yang, L., Zhen, X., & Tan, W. (2017). Mitochondrial activity and oxidative stress functions are influenced by the activation of AhR-induced CYP1A1 overexpression in cardiomyocytes. Molecular Medicine Reports, 16, 174–180. https://doi.org/10.3892/mmr.2017.6580