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-trihydroxybenzoic acid), an agent found in wine and tea, inhibits androstenedione 6beta-hydroxylase activity (Ki 70 microm), a cytochrome P450 (CYP3A) marker in human liver microsomes. The pre-incubation of gallic acid (100 microM) with human liver microsomes in the absence of NADPH, as compared with the presence of NADPH, before assay of androstenedione 6beta-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 17beta-hydroxysteroid dehydrogenase activity were refractory to inhibition by gallic acid.
Stupans
Leva
L
Center for Pharmaceutical Research, School of Pharmaceutical, Molecular and Biomedical Sciences, University of South Australia, Australia. ieva.stupans@unisa.edu.au
Tan
Hai-Wei
HW
Kirlich
Amra
A
Tuck
Kellie
K
Hayball
Peter
P
Murray
Michael
M
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases; D001205:Ascorbic Acid / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004032:Diet; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005707:Gallic Acid / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D009249:NADP; D005707:Gallic Acid; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating; D005978:Glutathione; D001205:Ascorbic Acid