title: Mechanism-based inhibition of recombinant human cytochrome P450 3A4 by tomato juice extract.
abstract: This study investigates whether tomato juice can inhibit cytochrome P450 (CYP) 3A4-mediated drug metabolism. Three commercially available, additive-free tomato juices, along with homogenized fresh tomato, were analyzed for their ability to inhibit testosterone 6β-hydroxylation activity using human recombinant CYP3A4. Results were compared to that of grapefruit juice. Ethyl acetate extracts of the tomato juices moderately reduced residual activity of CYP3A4 testosterone 6β-hydroxylation activity by 19.3-26.2% with 0-min preincubation. Residual activity was strongly reduced by 69.9-83.5% at 20-min preincubation, a reduction similar to that of grapefruit juice extract, known to contain constituents of mechanism-based inhibitors. One juice extract (tomato juice C) showed irreversible dose- and preincubation time-dependent and partial nicotinamide adenine dinucleotide phosphate (NADPH)-dependent inhibition of CYP3A4 activity. Furthermore, we examined whether the CYP3A4 inhibitory effect of tomato juice was substrate dependent by examining midazolam 1'-hydroxylation activity and nifedipine oxidation activity, in addition to testosterone 6β-hydroxylation activity. Tomato juice showed a potent inhibitory effect on nifedipine oxidation activity, which was comparable to that on testosterone 6β-hydroxylation activity; however, it showed a weak inhibitory effect on midazolam 1'-hydroxylation activity. We conclude that tomato juice contains one or more mechanism-based and competitive inhibitor(s) of CYP3A4. Additionally, significant CYP3A4 inhibitory activity did not result from lycopene, a major compound in tomato. Although the active compound was uncertain, a strong CYP3A4 inhibitory activity was observed in other solanaceous plants, i.e., potato, eggplant, sweet pepper, and capsicum. Therefore, responsible compounds in tomato are likely commonly shared among solanaceous vegetables.
authors.affiliation: Laboratory of Pharmacotherapy, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan. ksunaga@josai.ac.jp
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Sunaga
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ohkawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ohkubo
authors.forename: Sonoko
authors.initials: S
authors.lastname: Harada
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tsuda
mesh_terms: D000085:Acetates / Q000737:chemistry; D001628:Beverages; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D009249:NADP / Q000378:metabolism; D010936:Plant Extracts; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019657:Solanaceae / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014462:Ultrafiltration
chemical_list: D000085:Acetates; D065692:Cytochrome P-450 CYP3A Inhibitors; D010936:Plant Extracts; D011994:Recombinant Proteins; D012997:Solvents; D009249:NADP; C007650:ethyl acetate; D013250:Steroid Hydroxylases; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; C510163:CYP3A4 protein, human