To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KE:80

Event: 80

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Up Regulation, CYP1A1

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Explore in a Third Party Tool

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
eukaryotic cell

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
gene expression	cytochrome P450 1A1	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
AhR activation to steatosis	KeyEvent	Agnes Aggy (send email)	Under Development: Contributions and Comments Welcome
AhR activation leads to increased diabetes risk	KeyEvent	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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI
human	Homo sapiens	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
All life stages	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Cytochrome P4501A1 (CYP1A1) is a member of a heme-containing family of xenobiotic metabolism enzymes. CYP1A1 adds an oxygen group to its substrates to increase their polarity and facilitate further breakdown by other enzymes (Mescher & Haarmann-Stemmann, 2018). CYP1A1 is involved in the detoxification of a wide range of xenobiotics, but it can also produce harmful reactive oxygen species and activate procarcinogens (Kapelyukh et al., 2019; Shimada & Fujii-Kuriyama, 2004).

Cyp1a1 gene expression is regulated by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor (Nebert et al., 2004). AhR ligands include environmental toxicants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant, and benzo-[a]-pyrene (BaP), a carcinogen (Stejskalova et al., 2011). Endogenous compounds like flavonoids and tryptophan derivatives have also been shown to activate AhR (Stejskalova et al., 2011). Upon activation, the AhR receptor translocates into the nucleus and activates the expression of its gene targets (Stockinger et al., 2014). Although Cyp1a1 is reliably induced by AhR activation, not all AhR ligands are efficiently metabolized by CYP1A1 (Hankinson, 2016; Shinkyo et al., 2003). For example, TCDD is a potent AhR agonist but is a poor CYP1A1 substrate (Shinkyo et al., 2003).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Reverse-transcription quantitative PCR (RT-qPCR) can be used to measure Cyp1a1 gene expression from isolated mRNA (Ghosh et al., 2018). CYP1A1 protein can be detected with a Western blot (Zhou et al., 2017) and protein activity can be measured using fluorescent enzyme assays (Ibrahim et al., 2020). Finally, 7-ethoxy-resorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation (MROD) activities have also been used as markers for CYP1A1 and CYP1A2 enzyme activity, respectively (Diliberto et al., 1995; Zamaratskaia & Zlabek, 2009).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

CYP1A1 is present in fish and vertebrates, including human and non-human primates, rodents, and birds (Kawashima & Satta, 2014). Both males and females express CYP1A1, but there may be sex-based differences in gene regulation (Lu et al., 2020; Penaloza et al., 2014). CYP1A1 enzyme activity is present from the embryonic stage to adulthood (Pałasz et al., 2012; Penaloza et al., 2014).

References

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

Diliberto, J. J., Akubue, P. I., Luebke, R. W., & Birnbaum, L. S. (1995). Dose-response relationships of tissue distribution and induction of CYP1A1 and CYP1A2 enzymatic activities following acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Toxicology and Applied Pharmacology, 130(2), 197–208. https://doi.org/10.1006/taap.1995.1025

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

Hankinson, O. (2016). The role of AHR-inducible cytochrome P450s in metabolism of polyunsaturated fatty acids. Drug Metabolism Reviews, 48(3), 342–350. https://doi.org/10.1080/03602532.2016.1197240

Ibrahim, M., MacFarlane, E. M., Matteo, G., Hoyeck, M. P., Rick, K. R. C., Farokhi, S., Copley, C. M., O’Dwyer, S., & Bruin, J. E. (2020). Functional cytochrome P450 1A enzymes are induced in mouse and human islets following pollutant exposure. Diabetologia, 63, 162–178. https://doi.org/10.1007/s00125-019-05035-0

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

Lu, J., Shang, X., Zhong, W., Xu, Y., Shi, R., & Wang, X. (2020). New insights of CYP1A in endogenous metabolism: a focus on single nucleotide polymorphisms and diseases. Acta Pharmaceutica Sinica. B, 10(1), 91. https://doi.org/10.1016/J.APSB.2019.11.016

Mescher, M., & Haarmann-Stemmann, T. (2018). Modulation of CYP1A1 metabolism: From adverse health effects to chemoprevention and therapeutic options. Pharmacology and Therapeutics, 187, 71–87. https://doi.org/10.1016/j.pharmthera.2018.02.012

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

Pałasz, A., Wiaderkiewicz, A., Wiaderkiewicz, R., Czekaj, P., Czajkowska, B., Lebda-Wyborny, T., Piwowarczyk, A., & Bryzek, A. (2012). Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine. Genes & Nutrition, 7(2), 197. https://doi.org/10.1007/S12263-011-0240-Z

Penaloza, C. G., Estevez, B., Han, D. M., Norouzi, M., Lockshin, R. A., & Zakeri, Z. (2014). Sex-dependent regulation of cytochrome P450 family members Cyp1a1, Cyp2e1, and Cyp7b1 by methylation of DNA. The FASEB Journal, 28(2), 966. https://doi.org/10.1096/FJ.13-233320

Shimada, T., & Fujii-Kuriyama, Y. (2004). Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1. In Cancer Science (Vol. 95, Issue 1, pp. 1–6). https://doi.org/10.1111/j.1349-7006.2004.tb03162.x

Shinkyo, R., Sakaki, T., Ohta, M., & Inouye, K. (2003). Metabolic pathways of dioxin by CYP1A1: species difference between rat and human CYP1A subfamily in the metabolism of dioxins. In Archives of Biochemistry and Biophysics (Vol. 409). www.elsevier.com/locate/yabbiABB

Stejskalova, L., Dvorak, Z., & Pavek, P. (2011). Endogenous and exogenous ligands of aryl hydrocarbon receptor: Current state of art. Current Drug Metabolism, 12(2), 198–212. https://doi.org/10.2174/138920011795016818

Stockinger, B., Meglio, P. di, Gialitakis, M., & Duarte, J. H. (2014). The aryl hydrocarbon receptor: Multitasking in the immune system. Annual Review of Immunology, 32, 403–432. https://doi.org/10.1146/annurev-immunol-032713-120245

Zamaratskaia, G., & Zlabek, V. (2009). EROD and MROD as markers of cytochrome P450 1A activities in hepatic microsomes from entire and castrated male pigs. Sensors, 9, 2134–2147. https://doi.org/10.3390/s90302134

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