Investigation of Thymoquinone as an Inhibitor of CYP2C8/EET Axis

Cytochrome P450 2C8 (CYP2C8) is known to cause drug interactions via pharmacokinetic alterations of drugs, but it's also explicitly crucial for endogenous metabolism, like the generation of epoxyeicosatrienoic acids (EETs) from arachidonic acid. CYP2C8 expression is reported to be altered in various cancers, where CYP2C8-mediated EETs promote tumorigenesis. Conversely, thymoquinone, an extensively used complementary medicine, has emerged as a promising candidate against cancer due to its ability to curb tumorigenesis. Nevertheless, to date, limited information is available about the impact of thymoquinone on CYP2C8 inhibition. Therefore, we planned to explore the same using in silico, in vitro, and in vivo approaches. The current results reveal the followings: (a) thymoquinone could markedly inhibit CYP2C8 based on study using amodiaquine N-deethylation in human liver microsomes (HLM); (b) thymoquinone could strongly interact with the active site of the human CYP2C8 as demonstrated by molecular docking analysis; (c) thymoquinone could restrict the metabolic depletion of repaglinide (a CYP2C8 substrate) in rat liver microsomes; (d) thymoquinone altered the pharmacokinetic profile of repaglinide (a CYP2C8 substrate) in rats, resulting in repaglinide's increased systemic exposure and reduced clearance; (e) thymoquinone could retard EET's formation in HLM. Further studies are warranted to evaluate the biological significance of thymoquinone-mediated modulation of the CYP2C8/EET axis in relevant cancer models.