Possible inhibitory mechanism of Curcuma drugs on CYP3A4 in 1alpha,25 dihydroxyvitamin D3 treated Caco-2 cells.
Curcuma longa and C. zedoaria, belonging to genus Curcuma, have become prevalent as supplements in East Asia. Curcumin is the most well-studied bioactive component isolated from rhizomes of C. longa and other Curcuma species except C. zedoaria. In this study, we investigated the affects of C. longa, C. zedoaria from Japan and curcumin on CYP3A4. Caco-2 cells, in which CYP3A4 expression was induced by 1alpha,25-(OH)(2)-D(3), were used to mimic the metabolism of small intestine. Caco-2 cells were treated with methanol extracts from two Curcuma rhizomes (0.1mg/ml) or curcumin (30 microM) for 72 h. Both extracts significantly decreased the activity of CYP3A4 by about 85-98%. The 50% inhibitory concentrations of C. longa and C. zedoaria extracts were 0.019 and 0.014 mg/ml, respectively. They caused a 60-70% decrease in CYP3A4 protein. Otherwise, curcumin treatment caused a 30-40% decrease in CYP3A4 catalytic activity and a 38% decrease in CYP3A4 protein expression. Moreover, it was found that both Curcuma extracts and curcumin treatment had no influence on CYP3A4 mRNA expression. Our results suggested that administration of Curcuma drugs might inhibit the catalytic activity of intestinal CYP3A4. However, curcumin was not the major compound responsible for this inhibitory effect.
Hou
Xiao-Long
XL
Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Takahashi
Kyoko
K
Kinoshita
Natsumi
N
Qiu
Feng
F
Tanaka
Ken
K
Komatsu
Katsuko
K
Takahashi
Koichi
K
Azuma
Junichi
J
D018938:Caco-2 Cells; D002117:Calcitriol / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D030024:Curcuma / Q000737:chemistry; D003474:Curcumin / Q000032:analysis / Q000494:pharmacology* / Q000633:toxicity; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D041743:Herb-Drug Interactions; D006801:Humans; D006900:Hydroxylation; D020128:Inhibitory Concentration 50; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007654:Ketoconazole / Q000494:pharmacology; D009543:Nifedipine / Q000378:metabolism; D010084:Oxidation-Reduction; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D027343:Rhizome; D012293:Rifampin / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D012333:RNA, Messenger; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002117:Calcitriol; D009543:Nifedipine; D003474:Curcumin; D007654:Ketoconazole; D012293:Rifampin