Cyp2a5-KO Mouse

Cyp2a5, a murine gene with human orthologue CYP2A6, encodes an enzyme crucial for metabolizing diverse drugs, including nicotine, nitrosamines, aflatoxin B1, and the chemotherapeutic prodrug tegafur [2,3]. It is also known as "Coumarin 7-hydroxylase" due to its activity towards coumarin. Cyp2a5 is involved in multiple pathways, such as those related to oxidative stress (where the Nrf2-related pathway plays a role in its induction) and circadian rhythm regulation [1,4,5]. Its induction during liver-injurious conditions indicates its potential role in the liver's adaptive response to stress [2,4].

Gene knockout (KO) mouse models have significantly advanced the understanding of Cyp2a5's function. In Cry1-null or Cry2-null mice, Cyp2a5 expression and activity were reduced, with blunted diurnal rhythms, and these mice showed exacerbated coumarin-induced hepatotoxicity, suggesting CRY1/2 positively regulate Cyp2a5 rhythmic expression through repression of E4BP4 [1]. In Cyp2a5 -/- mice, nicotine failed to enhance alcoholic fatty liver as seen in wild-type mice, indicating nicotine's effect is Cyp2a5-dependent and related to ROS production during nicotine metabolism [7]. Also, in colitis mouse models, activated hepatic nuclear factor-κB downregulated Cyp2a5 transcription, leading to altered metronidazole disposition [6].

In conclusion, Cyp2a5 is vital for drug metabolism and exhibits circadian rhythmicity. Its induction during liver injury may be a protective mechanism. KO mouse models have been instrumental in uncovering its role in diseases like alcoholic liver disease, colitis-related drug disposition, and nicotine-enhanced fatty liver, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Lin, Luomin, Huang, Yuwei, Wang, Jinyi, Guo, Lianxia, Wu, Baojian. 2023. CRY1/2 regulate rhythmic CYP2A5 in mouse liver through repression of E4BP4. In Biochemical pharmacology, 217, 115843. doi:10.1016/j.bcp.2023.115843. https://pubmed.ncbi.nlm.nih.gov/37797722/

2. Kirby, Gordon M, Nichols, Kathleen D, Antenos, Monica. . CYP2A5 induction and hepatocellular stress: an adaptive response to perturbations of heme homeostasis. In Current drug metabolism, 12, 186-97. doi:. https://pubmed.ncbi.nlm.nih.gov/21395539/

3. Yoshida, Yuya, Fukuda, Taiki, Tanihara, Tomohito, Matsunaga, Naoya, Ohdo, Shigehiro. 2024. Circadian rhythms in CYP2A5 expression underlie the time-dependent effect of tegafur on breast cancer. In Biochemical and biophysical research communications, 708, 149813. doi:10.1016/j.bbrc.2024.149813. https://pubmed.ncbi.nlm.nih.gov/38522403/

4. Morgan, Larry, Antenos, Monica, Kirby, Gordon M. 2022. Nrf2-mediated induction of Cyp2a5 partially protects against reductive endoplasmic reticulum stress in mouse hepatocytes. In Toxicology, 471, 153162. doi:10.1016/j.tox.2022.153162. https://pubmed.ncbi.nlm.nih.gov/35341795/

5. Abu-Bakar, A'edah, Hakkola, Jukka, Juvonen, Risto, Raunio, Hannu, Lang, Matti A. . Function and regulation of the Cyp2a5/CYP2A6 genes in response to toxic insults in the liver. In Current drug metabolism, 14, 137-50. doi:. https://pubmed.ncbi.nlm.nih.gov/22497566/

6. Ma, Luyao, Zeng, Wanying, Tan, Zhiyi, Li, Feng, Wang, Shuai. 2022. Activated Hepatic Nuclear Factor-κB in Experimental Colitis Regulates CYP2A5 and Metronidazole Disposition. In Molecular pharmaceutics, 20, 1222-1229. doi:10.1021/acs.molpharmaceut.2c00890. https://pubmed.ncbi.nlm.nih.gov/36583631/

7. Chen, Xue, Owoseni, Emmanuel, Salamat, Julia, Cederbaum, Arthur I, Lu, Yongke. 2018. Nicotine enhances alcoholic fatty liver in mice: Role of CYP2A5. In Archives of biochemistry and biophysics, 657, 65-73. doi:10.1016/j.abb.2018.09.012. https://pubmed.ncbi.nlm.nih.gov/30222954/