CYP39A1, an oxysterol 7α -hydroxylase, is a metabolic enzyme that preferentially catalyzes the 7α -hydroxylation of 24 -hydroxycholesterol [5,6]. It is involved in the alternative bile acid synthesis pathway in the liver and may play a role in cholesterol homeostasis, immune response, and the pathophysiology of neurodegenerative diseases [5].

In hepatocellular carcinoma (HCC), CYP39A1 expression is downregulated. Overexpression of CYP39A1 inhibits the viability of HepG2 and SMMC-7721 cells, while knockout of CYP39A1 promotes HCC cell growth, suggesting it may act as a tumor suppressor gene [1]. In a mouse model, exogenous CYP39A1 blocked tumor formation and reduced the sex disparity of hepatocarcinogenesis [4]. In exfoliation syndrome, carriers of functionally deficient mutations in CYP39A1 have an increased risk of glaucoma and blindness, with the G204E mutation being particularly impactful [2,3].

In summary, CYP39A1 is an important enzyme in oxysterol metabolism. Its downregulation is associated with HCC carcinogenesis, and functional-deficient mutations are related to an increased risk of glaucoma and blindness in exfoliation syndrome patients. Studies using gene knockout or overexpression models have been crucial in revealing these disease-related roles of CYP39A1.

References:

1. Li, Dan, Yu, Tao, Hu, Junjie, Gu, Lijuan, Zeng, Zhi. 2021. Downregulation of CYP39A1 Serves as a Novel Biomarker in Hepatocellular Carcinoma with Worse Clinical Outcome. In Oxidative medicine and cellular longevity, 2021, 5175581. doi:10.1155/2021/5175581. https://pubmed.ncbi.nlm.nih.gov/35003516/

2. Bell, Katharina, Ozaki, Mineo, Mori, Kazuhiko, Khor, Chiea Chuen, Aung, Tin. 2021. Association of the CYP39A1 G204E Genetic Variant with Increased Risk of Glaucoma and Blindness in Patients with Exfoliation Syndrome. In Ophthalmology, 129, 406-413. doi:10.1016/j.ophtha.2021.11.001. https://pubmed.ncbi.nlm.nih.gov/34763023/

3. Li, Zheng, Wang, Zhenxun, Lee, Mei Chin, Tam, Wai Leong, Khor, Chiea Chuen. . Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye. In JAMA, 325, 753-764. doi:10.1001/jama.2021.0507. https://pubmed.ncbi.nlm.nih.gov/33620406/

4. Ji, Fubo, Zhang, Jianjuan, Liu, Niya, Zheng, Xin, Ji, Junfang. 2022. Blocking hepatocarcinogenesis by a cytochrome P450 family member with female-preferential expression. In Gut, 71, 2313-2324. doi:10.1136/gutjnl-2021-326050. https://pubmed.ncbi.nlm.nih.gov/34996827/

5. Grabovec, I P, Smolskaya, S V, Baranovsky, A V, Usanov, S A, Strushkevich, N V. 2019. Ligand-binding properties and catalytic activity of the purified human 24-hydroxycholesterol 7α-hydroxylase, CYP39A1. In The Journal of steroid biochemistry and molecular biology, 193, 105416. doi:10.1016/j.jsbmb.2019.105416. https://pubmed.ncbi.nlm.nih.gov/31247323/

6. Ikeda, Hiromi, Ueda, Masamichi, Ikeda, Masataka, Kobayashi, Hiroshi, Honda, Yoshihito. . Oxysterol 7alpha-hydroxylase (CYP39A1) in the ciliary nonpigmented epithelium of bovine eye. In Laboratory investigation; a journal of technical methods and pathology, 83, 349-55. doi:. https://pubmed.ncbi.nlm.nih.gov/12649335/