**2. CYP3A**

Cytochrome P450 enzymes (CYP) are the most versatile enzyme system involved in detoxification and oxidative metabolism of various endogenous substrates (steroid hormones, lipids, and bile acids) and xenobiotics (drugs, environmental pollutants, and dietary products) [26, 27]. It consists of over 400 isoforms, and their activities can be increased or decreased by many drugs either by inducing the biosynthesis or by directly inhibiting its activity, which is a major source for drug-induced toxicity via DDI. CYP3A enzymes, which constitute the predominant phase I drug-metabolizing enzymes, are estimated to metabolize between 50 and 70% of currently administered drugs [28]. Alone CYP3A4, which is the most abundant congener of the CYP3A family contributes approximately 30% of hepatic CYP activity and more than 70% of intestinal CYP activity [29]. Many drugs used in different types of therapies are substrates for CYP3A4, and it is presented at high levels in both liver and intestine [30, 31]. Reports from *in vitro* and *in vivo* studies have already established that naturally occurring dietary supplements and phytoconstituents can modulate hepatic and enterocytic CYP activity.

CYP inhibition-mediated DDI is widely recognized, and the necessity of the enzyme inhibition studies is included in the guidance from the USFDA [32]. Usually, two types of CYP inhibition occur: (1) reversible inhibition represented by competitive inhibition, which is concentration-dependent inhibition and (2) irreversible inhibition, also called mechanism-based inhibition (MBI), where during inhibition process enzyme is inactivated by stable complex formation with a metabolite. In MBI, enzyme reduction activity continues until the inactivated CYP is replaced by a newly synthesized CYP, the duration of the elevated blood concentration of a drug coadministered with a mechanism-based inhibitor is longer. Therefore, MBI requires more attention because they have been reported to cause unanticipated adverse effects [33, 34].
