AUTHOR=Li Dawei , Lin Yuxin , Lv Xia , Wu Yuzhuo , Han Chaoyan , Cao Peng , Zhang Guixin , Leng Aijing , Zhou Jian , Wang Chao 

TITLE=Triterpenoids from Ganoderma lucidum inhibit cytochrome P450 enzymes interfering with the metabolic process of specific clinical drugs

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1485209

DOI=10.3389/fphar.2024.1485209

ISSN=1663-9812

ABSTRACT=<sec><title>Background</title><p><italic>Ganoderma lucidum</italic> (<italic>G. lucidum</italic>), which possesses various biological effects, has been widely used as traditional medicine and functional food in Asian countries, especially China. In consideration of its various biological effects on human healthcare, <italic>G</italic>. <italic>lucidum</italic> was usually used in combination with other drugs. However, the potential drug-drug interaction induced by <italic>G</italic>. <italic>lucidum</italic> through cytochrome P450 enzymes (CYPs) remain unknown.</p></sec><sec><title>Methods</title><p>Using the <italic>in vivo</italic> activity assay of CYPs, the inhibitory effects of <italic>G. lucidum</italic> and its constituents could be evaluated. The interference of <italic>G. lucidum</italic> on the metabolic processes of clinical drugs could be investigated. The chemical constituents of <italic>G</italic>. <italic>lucidum</italic> could be identified using LC-MS. The interaction between bioactive compounds and CYPs could be proposed through <italic>in silico</italic> docking analysis and molecular dynamics.</p></sec><sec><title>Results</title><p>The dichloromethane extract of <italic>G</italic>. <italic>lucidum</italic> could inhibit various CYP450 subtypes <italic>in vitro</italic> and interfere with the pharmacokinetics of four drugs in rats. Triterpenoids were identified as the main constituents of the dichloromethane extract by Q-TOF-MS<sup>n</sup> in preliminary analyses. Then, a triterpenoid library containing 66 compounds was established to evaluate their inhibitory effects against CYP 1A2, 2D6, 3A4, 2A6, 2B6, 2C9, and 2C19. CYP 1A2 was inhibited by most lanostane triterpenoids, indicating a strong affinity for these compounds. Among triterpenoids, compound <bold>25</bold> displayed a broad inhibitory effect against CYPs, except for CYP 3A4, 2D6, 2C9, and 2C19. Finally, compounds <bold>6</bold> and <bold>25</bold> exhibited interference with the metabolism of 16 drugs through the inhibition of CYPs <italic>in vitro</italic>. In silico molecular docking analyses for assaying the interaction between compound <bold>25</bold> and CYPs indicated that the hydrogen bonds formed between the hydroxyl groups and amino acid residues.</p></sec><sec><title>Conclusion</title><p><italic>G</italic>. <italic>lucidum</italic> displayed broad inhibitory effects on CYPs, with triterpenoids as the main bioactive constituents, which may induce potential drug-drug interaction. This information should be helpful for the rational use of <italic>G</italic>. <italic>lucidum</italic> in promoting human health.</p></sec>