Inhibition of CYP3A-mediated oxidation in human hepatic microsomes by the dietary derived complex phenol, gallic acid

Plant polyphenols, such as gallic acid, have been reported to have a range of biological activities including antimutagenic effects. Previously, we reported that gallic acid (3,4,5‐trihydroxy‐benzoic acid), an agent found in wine and tea, inhibits androstenedione 6β‐hydroxylase activity (Ki 70 μM), a cytochrome P450 (CYP3A) marker in human liver microsomes. The preincubation of gallic acid (100 μM) with human liver microsomes in the absence of NADPH, as compared with the presence of NADPH, before assay of androstenedione 6β‐hydroxylase activity significantly increased the inhibitory effects of the gallic acid (0.03 ± 0.03 nmol (mg microsomal protein)−1 min−1 compared with 0.20 ± 0.06 nmol (mg microsomal protein)−1 min−1 (P< 0.05)). The antioxidant ascorbic acid and the radical scavenger glutathione prevented this observed increase in inhibition. Removal of gallic acid‐derived products from the incubation completely restored CYP3A activity. In contrast, the activities of CYP1A and CYP2E, and non‐CYP mediated reductive microsomal 17β‐hydroxysteroid dehydrogenase activity were refractory to inhibition by gallic acid.