Cyp1b1-KO Mouse

Cyp1b1, a member of the cytochrome P450 superfamily, is a heme-thiolate monooxygenase. It is involved in the metabolism of various substances such as estradiol, retinol, and procarcinogens [3,4]. By catalyzing the hydroxylation of 17β-estradiol, it generates carcinogenic metabolites, playing a role in carcinogenesis and cancer progression [3]. It is also associated with the arachidonic acid metabolism pathway [1].

In multiple disease contexts, research has provided insights into Cyp1b1's functions. In colorectal cancer, CYP1B1-derived 20-HETE activates the protein kinase C pathway, increasing FBXO10 expression which promotes ACSL4 ubiquitination and degradation, leading to ferroptosis resistance and anti-PD-1 resistance. Inhibiting CYP1B1 sensitized tumor cells to anti-PD-1 antibody in a mouse model [1]. In liver fibrosis, systemic or HSC-specific ablation and pharmacological inhibition of CYP1B1 attenuated HSC activation and protected male mice from liver fibrosis induced by various agents. This was due to an increase in trehalose in CYP1B1-deficient HSCs resulting from intestinal suppression of trehalase [2]. In ovarian cancer, down-regulating CYP1B1 expression or using specific inhibitors decreased the cellular response to Olaparib, suggesting CYP1B1 promotes PARPi-resistance through histone H1.4 interaction and increased chromatin accessibility [5].

In conclusion, Cyp1b1 is crucial in processes related to cancer and fibrosis. Gene knockout or inhibition models in mice have revealed its role in ferroptosis regulation in cancer, as well as in liver fibrosis development, providing potential therapeutic targets for colorectal cancer, liver fibrosis, and ovarian cancer treatment.

References:

1. Chen, Congcong, Yang, Yabing, Guo, Yanguan, Pan, Jinghua, Pan, Yunlong. 2023. CYP1B1 inhibits ferroptosis and induces anti-PD-1 resistance by degrading ACSL4 in colorectal cancer. In Cell death & disease, 14, 271. doi:10.1038/s41419-023-05803-2. https://pubmed.ncbi.nlm.nih.gov/37059712/

2. Tung, Hung-Chun, Kim, Jong-Won, Zhu, Junjie, Patterson, Andrew D, Xie, Wen. 2024. Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose. In Science translational medicine, 16, eadk8446. doi:10.1126/scitranslmed.adk8446. https://pubmed.ncbi.nlm.nih.gov/39321267/

3. Fabris, Marciéli, Luiza Silva, Mariana, de Santiago-Silva, Kaio Maciel, de Lima Ferreira Bispo, Marcelle, Goes Camargo, Priscila. . CYP1B1: A Promising Target in Cancer Drug Discovery. In Anti-cancer agents in medicinal chemistry, 23, 981-988. doi:10.2174/1871520623666230119103914. https://pubmed.ncbi.nlm.nih.gov/36655529/

4. Faiq, Muneeb A, Dada, Rima, Sharma, Reetika, Saluja, Daman, Dada, Tanuj. . CYP1B1: a unique gene with unique characteristics. In Current drug metabolism, 15, 893-914. doi:. https://pubmed.ncbi.nlm.nih.gov/25658124/

5. Xue, Yite, Yin, Taotao, Yuan, Shuo, Cheng, Xiaodong, Wang, Hui. 2024. CYP1B1 promotes PARPi-resistance via histone H1.4 interaction and increased chromatin accessibility in ovarian cancer. In Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 77, 101151. doi:10.1016/j.drup.2024.101151. https://pubmed.ncbi.nlm.nih.gov/39395328/