Two forms of NAD-dependent d-mandelate dehydrogenase (d-ManDHs) were purified from Enterococcus faecalis IAM 10071. While these two enzymes consistently exhibited high activity toward large 2-ketoacid substrates that were branched at the C3 or C4 position, they gave distinctly different Km and V max values for these substrates and had distinct molecular weights by gel electrophoresis and gel filtration.
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.Key words tomato juice; mechanism-based inhibition; food-drug interaction; human recombinant cytochrome P450 3A4 Many foods and/or beverages have recently been found to influence drug metabolism or transport, sometimes resulting in clinically important drug interactions. This food-drug interaction is a critical aspect of pharmacotherapy. Food-drug interaction can be viewed in terms of pharmacokinetics and pharmacodynamics. Pharmacokinetic interactions can involve enzymes and transporters that are implicated in drug absorption, distribution, metabolism, or excretion. Pharmacodynamic interactions involve the pharmacological effect of a drug or physiologic effect of a dietary constituent. 1)Foods that inhibit drug metabolism enzymes, such as cytochrome P450 (CYP), elevate the blood concentration of co-administered drugs, resulting in a food-drug interaction, which sometimes causes adverse effects. [2][3][4] In vitro screening assays with beverages and foods such as beer, red wine, black and herbal tea, garlic, spices, mace, nutmeg, fruits, and fruit juices have all shown the ability to inhibit enzyme-mediated drug metabolism. [5][6][7][8][9][10] CYP...
Abstract. Rosehip, the fruit of Rosa canina L., has traditionally been used to treat urate metabolism disorders; however, its effects on such disorders have not been characterized in detail. Therefore, the present study investigated the effects of hot water, ethanol and ethyl acetate extracts of rosehip on xanthine oxidase (XO) activity in vitro. In addition, the serum urate lowering effects of the rosehip hot water extract in a mouse model of hyperuricemia (male ddY mice, which were intraperitoneally injected with potassium oxonate) were investigated. Furthermore, the influence of rosehip hot water extract on CYP3A4 activity, which is the most important drug-metabolizing enzyme from a herb-drug interaction perspective, was investigated. Rosehip extracts of hot water, ethanol and ethyl acetate inhibited XO activity [half maximal inhibitory concentration (IC 50 ) values: 259.6±50.6, 242.5±46.2 and 1,462.8±544.2 µg/ml, respectively]. Furthermore, the administration of 1X rosehip hot water extract significantly reduced the levels of serum urate at 8 h, which was similar when compared with the administration of 1 mg/kg allopurinol. Rosehip hot water extract only marginally affected CYP3A4 activity (IC 50 value, >1 mg/ml). These findings indicate that rosehip hot water extract may present as a functional food for individuals with a high urate level, and as a therapeutic reagent for hyperuricemic patients.
Recently, with increasing interest in the cancer-preventive effects of complementary and alternative medicine CAMs including functional foods and herbs, their use as health foods has been increasing among cancer patients. Although the antitumoral or cytotoxic activities of CAMs have been well examined, little is known about possible interactions between foods used as CAMs and chemotherapeutic agents. Therefore, in the present study, the effects of ethyl acetate extracts of eight foods or herbs commonly used by cancer patients on the antitumor activity of doxorubicin DOX , melphalan L-PAM or methotrexate MTX , were investigated in the hepatoma cell line HepG2. The reduction of cell number induced by L-PAM was inhibited by citrus unshiu peel, spinach or green tea extracts, and also the reduction in cell number induced by DOX was inhibited by citrus unshiu peel, broccoli or green tea extracts.
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