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Up Regulation, CYP1A1 leads to Increase, Mt Dysfunction
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|All life stages||Moderate|
Key Event Relationship Description
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
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”.
Evidence Supporting this KER
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.
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
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
|Modulating Factor (MF)||MF Specification||Effect(s) on the KER||Reference(s)|
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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).
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