Abstract
Meranzin hydrate (MH), an absorbed bioactive compound from the Traditional Chinese Medicine (TCM) Chaihu-Shugan-San (CSS), was first isolated in our laboratory and was found to possess anti-depression activity. However, the role of cytochrome P450s (CYPs) in the metabolism of MH was unclear. In this study, we screened the CYPs for the metabolism of MH in vitro by human liver microsomes (HLMs) or human recombinant CYPs. MH inhibited the enzyme activities of CYP1A2 and CYP2C19 in a concentration-dependent manner in the HLMs. The Km and Vmax values of MH were 10.3±1.3 µM and 99.1±3.3 nmol/mg protein/min, respectively, for the HLMs; 8.0±1.6 µM and 112.4±5.7 nmol/nmol P450/min, respectively, for CYP1A2; and 25.9±6.6 µM and 134.3±12.4 nmol/nmol P450/min, respectively, for CYP2C19. Other human CYP isoforms including CYP2A6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 showed minimal or no effect on MH metabolism. The results suggested that MH was simultaneously a substrate and an inhibitor of CYP1A2 and CYP2C9, and MH had the potential to perpetrate drug-drug interactions with other CYP1A2 and CYP2C19 substrates.
Highlights
Depression is a severe and recurrent mental disorder that often leads to a significant impairment of daily functions [1,2,3]
The drug interactions of meranzin hydrate (MH) were one of the critical questions to be resolved. These interactions might occur through the inhibition or induction of drugmetabolizing enzymes and lead to serious adverse events or decreased drug efficacy [12]
The cytochrome P450 (CYP) enzymes are a large family of drugmetabolizing enzymes that play a critical role in Phase I drug metabolism, and most of the endogenous and exogenous substances are the substrates of cytochrome P450s (CYPs) [13]
Summary
Depression is a severe and recurrent mental disorder that often leads to a significant impairment of daily functions [1,2,3]. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) were commonly used to treat depression [4, 5]. Drug interactions could lead to serious adverse events or decreased drug efficacy. These interactions might occur through the inhibition or induction of hepatic and intestinal drug-metabolizing enzymes (e.g., CYPs) and transporters (e.g., p-glycoprotein) [18, 19]. We examined the CYP enzymes responsible for the metabolism of MH and the potential interactions of MH with typical substrates of the CYP enzymes in vitro
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