Biomedical literature is loaded with publications describing health-promoting, disease-preventing properties of various phytochemicals and these natural entities are now considered extremely safe. A number of phytochemicals (phenols and flavonoids) have been shown to modulate the CYP450 system, including the induction and/or inhibition of specific CYP450 isozymes. Among many, CYP3A isozyme has gained considerable attention because of it is ability to metabolize a wide range of therapeutic drugs and diverse chemicals. However, the modus-operandi of this isozyme with diverse phytochemicals remains unknown. In the past, our laboratory primarily focused on unraveling mechanisms underlying antitoxic and anticancer properties of structurally/functionally diverse phytochemicals; this in vivo study was specifically designed to explore changes in the expression of liver CYP3A with or without DEX (Dexamethasone) and GSPE (Grape Seed Proanthocyanidin Extract). GSPE was chosen because of its reported antioxidant and antitoxic properties, whereas, DEX was used for two reasons: (i) its ability to induce CYP3A and its popularity as a steroid in medicine, and (ii) because DEX and GSPE has conflicting action on CYP3A. In order to unravel these mechanisms, [Male] SD rats (∼250g) were treated as follows for 14 days: Gr-1: Con (saline, ip and po); Gr-2: GSPE (100mg/kg from day 0 through day14, po); Gr-3: GSPE (500mg/kg from day 0 through dayl4, po); Gr-4: DEX (ip 100mg/kg day11 through day14); Gr-5: GSPE (100mg/kg day0 through day14, po) + DEX (day11 through day14, ip) and Gr-6: GSPE (500mg/kg day0 through day14, po) + DEX (day11 through day14, ip). All the animals were sacrificed at day 15 and the livers were collected and flash-frozen. Microsomal fractions were isolated following well-established methods and CO binding method was used to measure the total CYP450 contents. CYP3A specific activity was determined in the purified microsomal protein preparations via Erythromycin N-demethylation. It was observed that 100 mg/kg GSPE-alone did not influence demethylation at all, 500 mg/kg GSPE-alone increased (88%), and DEX alone caused nearly a 7-fold (580%) increase. Surprisingly, 100mg GSPE exposure decreased the DEX-induced CYP3A activity to nearly 200%, whereas, 500mg GSPE did not interfere with DEX induction (596%) at all. These dual-action type scenarios are not uncommon, since GSPE inhibits CYP3A activity in vitro but it acts like an inducer in vivo. Thus, this study suggests that GSPE or GSPE-like bioflavonoids, at different doses, can alter the action of DEX and has the potential to modulate a therapeutic outcome. Therefore, consumption of phytochemicals, nutraceuticals, dietary supplements and/or special types of fruits and vegetables must be carefully monitored during DEX or DEX-like drug therapy.