Cyp2f2-KO Mouse

Cyp2f2, a member of the cytochrome P450 (CYP) superfamily, is preferentially expressed in the respiratory tract. CYPs are responsible for detoxifying endogenous and exogenous compounds and metabolizing medications. Cyp2f2 may be involved in various metabolic pathways related to xenobiotic metabolism [1,2,3,4,5,6,7,8,9]. Genetic models, such as gene knockout mice, are valuable for studying its function.

In adipocytes, Cyp2f2 -deficient 3T3-L1 adipocytes showed increased expression of thermogenic marker proteins and beige-fat specific genes, reduced adipogenesis and lipogenesis, and enhanced lipid catabolism. Mechanistically, Cyp2f2 impairs β3-AR activation and its downstream regulators [1]. In mouse models, Cyp2f2-mediated cytotoxic metabolism is associated with mouse-specific lung tumors. Cyp2f2-knockout mice were resistant to the lung toxicity of styrene and SO, indicating that mouse lung toxicity of these compounds is critically dependent on Cyp2f2 metabolism. Also, Cyp2f2-null mice were largely resistant to naphthalene-induced cytotoxicity in the lungs [4,6,8].

In conclusion, Cyp2f2 has a role in negatively regulating lipid catabolism and browning in white adipocytes, and its inhibition could be a potential obesity treatment strategy. In addition, Cyp2f2-mediated cytotoxic metabolism is responsible for mouse-specific lung tumors, and Cyp2f2-knockout mouse models have been crucial in revealing these functions in adipocyte-related obesity and mouse-specific lung tumorigenesis [1,6].

References:

1. Dang, Trang Thi Huyen, Choi, Minji, Pham, Huong Giang, Yun, Jong Won. 2021. Cytochrome P450 2F2 (CYP2F2) negatively regulates browning in 3T3-L1 white adipocytes. In European journal of pharmacology, 908, 174318. doi:10.1016/j.ejphar.2021.174318. https://pubmed.ncbi.nlm.nih.gov/34252443/

2. Cruzan, George, Bus, James, Banton, Marcy, Gingell, Ralph, Carlson, Gary. 2009. Mouse specific lung tumors from CYP2F2-mediated cytotoxic metabolism: an endpoint/toxic response where data from multiple chemicals converge to support a mode of action. In Regulatory toxicology and pharmacology : RTP, 55, 205-18. doi:10.1016/j.yrtph.2009.07.002. https://pubmed.ncbi.nlm.nih.gov/19589367/

3. Hill, Thomas, Conolly, Rory B. . Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice. In Toxicological sciences : an official journal of the Society of Toxicology, 172, 1-10. doi:10.1093/toxsci/kfz185. https://pubmed.ncbi.nlm.nih.gov/31407013/

4. Cruzan, G, Bus, J, Hotchkiss, J, Banton, M, Sarang, S. 2011. CYP2F2-generated metabolites, not styrene oxide, are a key event mediating the mode of action of styrene-induced mouse lung tumors. In Regulatory toxicology and pharmacology : RTP, 62, 214-20. doi:10.1016/j.yrtph.2011.10.007. https://pubmed.ncbi.nlm.nih.gov/22041433/

5. Ye, X, Lu, L, Gill, S S. . Suppression of cytochrome P450 Cyp2f2 mRNA levels in mice by the peroxisome proliferator diethylhexylphthalate. In Biochemical and biophysical research communications, 239, 660-5. doi:. https://pubmed.ncbi.nlm.nih.gov/9367824/

6. Cruzan, George, Bus, James S, Banton, Marcy I, Dodd, Darol, Andersen, Melvin E. . Editor's Highlight: Complete Attenuation of Mouse Lung Cell Proliferation and Tumorigenicity in CYP2F2 Knockout and CYP2F1 Humanized Mice Exposed to Inhaled Styrene for up to 2 Years Supports a Lack of Human Relevance. In Toxicological sciences : an official journal of the Society of Toxicology, 159, 413-421. doi:10.1093/toxsci/kfx141. https://pubmed.ncbi.nlm.nih.gov/28962520/

7. Simmonds, Andrea C, Ghanayem, Burhan I, Sharma, Ashish, Yost, Garold S, Forkert, Poh-Gek. 2004. Bioactivation of 1,1-dichloroethylene by CYP2E1 and CYP2F2 in murine lung. In The Journal of pharmacology and experimental therapeutics, 310, 855-64. doi:. https://pubmed.ncbi.nlm.nih.gov/15123768/

8. Li, Lei, Wei, Yuan, Van Winkle, Laura, Kluetzman, Kerri, Ding, Xinxin. 2011. Generation and characterization of a Cyp2f2-null mouse and studies on the role of CYP2F2 in naphthalene-induced toxicity in the lung and nasal olfactory mucosa. In The Journal of pharmacology and experimental therapeutics, 339, 62-71. doi:10.1124/jpet.111.184671. https://pubmed.ncbi.nlm.nih.gov/21730012/

9. Zhou, Xin, D'Agostino, Jaime, Li, Lei, Yost, Garold S, Ding, Xinxin. 2012. Respective roles of CYP2A5 and CYP2F2 in the bioactivation of 3-methylindole in mouse olfactory mucosa and lung: studies using Cyp2a5-null and Cyp2f2-null mouse models. In Drug metabolism and disposition: the biological fate of chemicals, 40, 642-7. doi:10.1124/dmd.111.044081. https://pubmed.ncbi.nlm.nih.gov/22228748/