title: Effects of anthocyanidins and anthocyanins on the expression and catalytic activities of CYP2A6, CYP2B6, CYP2C9, and CYP3A4 in primary human hepatocytes and human liver microsomes.
abstract: Anthocyanidins and anthocyanins are pharmacologically active constituents of various berry fruits, such as blueberry and cranberry. These compounds are also contained in massively used nutritional supplements based on extracts or dry matter from berry fruits. The current study evaluated the effects of anthocyanidins and anthocyanins on the expression and catalytic activity of major drug-metabolizing enzymes CYP2C9, CYP2A6, CYP2B6, and CYP3A4 in primary cultures of human hepatocytes and human liver microsomes. Expression of mRNA was quantified by qRT-PCR. Expression of proteins was evaluated by Western blotting and immunochemiluminescence. The catalytic activity of CYP enzymes was measured by HPLC using specific enzyme substrates. Tested anthocyanidins (6) and anthocyanins (21) did not induce the expression of mRNA and protein of CYP2C9, CYP2A6, CYP2B6, and CYP3A4 genes in human hepatocytes. Catalytic activities of CYP2C9, CYP2A6, CYP2B6, and CYP3A4 enzymes were inhibited by all anthocyanidins to different extents (e.g., delphinidin inhibits CYP3A4 by >90% at 100 μM with IC50 = 32 μM). Of 21 anthocyanins tested, only cyanidin-3-O-rhamnoside (CYP3A4 by >75% at 100 μM with IC50 = 44 μM) and two glycosides of delphinidin significantly inhibited examined cytochromes P450. It may be concluded that in the ranges of common ingestion of either food or dietary supplement an induction or significant inhibition of CYP2C9, CYP2A6, CYP2B6, and CYP3A4 activity is most probably not expected.
authors.affiliation: Department of Cell Biology and Genetics, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University , Slechtitelu 11, 783 71 Olomouc, Czech Republic.
authors.forename: Alzbeta
authors.initials: A
authors.lastname: Srovnalova
authors.forename: Michaela
authors.initials: M
authors.lastname: Svecarova
authors.forename: Michaela Kopecna
authors.initials: MK
authors.lastname: Zapletalova
authors.forename: Pavel
authors.initials: P
authors.lastname: Anzenbacher
authors.forename: Petr
authors.initials: P
authors.lastname: Bachleda
authors.forename: Eva
authors.initials: E
authors.lastname: Anzenbacherova
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Dvorak
mesh_terms: D000872:Anthocyanins / Q000494:pharmacology*; D055162:Biocatalysis; D029798:Blueberry Plants / Q000737:chemistry; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology*; D010936:Plant Extracts / Q000494:pharmacology*; D029799:Vaccinium macrocarpon / Q000737:chemistry
chemical_list: D000872:Anthocyanins; D010936:Plant Extracts; D065729:Cytochrome P-450 CYP2C9; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A
keywords: anthocyans; cytochrome P450; food−drug interactions; human hepatocytes; xenobiotics