Fmo3-KO Mouse

Fmo3, or flavin-containing monooxygenase 3, is a key hepatic microsomal enzyme. It plays a crucial role in the metabolism of many therapeutic drugs. One of its most abundant substrates is trimethylamine (TMA), which is released from dietary components by gut bacteria. Fmo3 converts odorous TMA to non-odorous trimethylamine N-oxide (TMAO), which is excreted in urine [4]. Fmo3-mediated metabolism is significant in adult human liver, and although some drugs are metabolized by it, most are also metabolized by other enzymes like cytochromes P-450 [1].

Rare Fmo3 variants can cause trimethylaminuria, a disorder where individuals cannot convert TMA to TMAO, leading to a fishy body odor due to TMA secretion [2]. More common variants, such as p.[(Glu158Lys);(Glu308Gly)], can moderately affect Fmo3 activity in vitro and in vivo, influencing drug metabolism. For example, in febrile neutropenia patients, the Fmo3 E308G genotype reduces the enzyme's activity, decreasing voriconazole metabolism, increasing its plasma concentration, and leading to more adverse reactions [7]. In liver transplant patients, donor Fmo3 polymorphisms affect tacrolimus elimination [6]. Also, Fmo3 has been associated with various diseases. Elevated plasma TMAO levels, a product of Fmo3-catalyzed reaction, have been linked to cardiovascular disease, gallstone disease, and chronic heart-failure. In gallstone-susceptible mice, a lithogenic diet increases hepatic Fmo3 expression and plasma TMAO levels, which is associated with increased cholesterol transporter expression and gallstone formation [3,5].

In conclusion, Fmo3 is essential for drug metabolism and the TMA/TMAO metabolic axis. Genetic variants of Fmo3 can lead to metabolic disorders and affect drug efficacy and toxicity. Its association with diseases like cardiovascular, gallstone, and chronic heart-failure shows its significance in disease pathophysiology. Studies on Fmo3, including those using genetic models, help us understand its role in normal biological functions and disease processes.

References:

1. Phillips, Ian R, Shephard, Elizabeth A. 2019. Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease. In Xenobiotica; the fate of foreign compounds in biological systems, 50, 19-33. doi:10.1080/00498254.2019.1643515. https://pubmed.ncbi.nlm.nih.gov/31317802/

2. Hernandez, Diana, Addou, Sarah, Lee, David, Shephard, Elizabeth A, Phillips, Ian R. . Trimethylaminuria and a human FMO3 mutation database. In Human mutation, 22, 209-13. doi:. https://pubmed.ncbi.nlm.nih.gov/12938085/

3. Chen, Yaoyao, Weng, Zhenkun, Liu, Qian, Hu, Hai, Jiang, Zhaoyan. 2019. FMO3 and its metabolite TMAO contribute to the formation of gallstones. In Biochimica et biophysica acta. Molecular basis of disease, 1865, 2576-2585. doi:10.1016/j.bbadis.2019.06.016. https://pubmed.ncbi.nlm.nih.gov/31251986/

4. Fennema, Diede, Phillips, Ian R, Shephard, Elizabeth A. 2016. Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease. In Drug metabolism and disposition: the biological fate of chemicals, 44, 1839-1850. doi:. https://pubmed.ncbi.nlm.nih.gov/27190056/

5. Wei, Haoran, Zhao, Mingming, Huang, Man, Zheng, Lemin, Wang, Dao Wen. 2021. FMO3-TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction: evidence from an Asian population. In Frontiers of medicine, 16, 295-305. doi:10.1007/s11684-021-0857-2. https://pubmed.ncbi.nlm.nih.gov/34159537/

6. Ren, Lei, Teng, Mujian, Zhang, Tao, Peng, Zhihai, Fan, Junwei. 2017. Donors FMO3 polymorphisms affect tacrolimus elimination in Chinese liver transplant patients. In Pharmacogenomics, 18, 265-275. doi:10.2217/pgs-2016-0098. https://pubmed.ncbi.nlm.nih.gov/28084894/

7. Wang, Xiaokang, Zhao, Jingjing, Wen, Ting, Liao, Xueyi, Luo, Bin. 2020. Predictive Value of FMO3 Variants on Plasma Disposition and Adverse Reactions of Oral Voriconazole in Febrile Neutropenia. In Pharmacology, 106, 202-210. doi:10.1159/000510327. https://pubmed.ncbi.nlm.nih.gov/32998136/