Cytochrome P450 1A1 expression and activity in Caco-2 cells: modulation by apple juice extract and certain apple polyphenols.
Cytochrome P450 (CYP) 1A1 plays a role in drug metabolism of intestinal cells (e.g., by activating certain chemical carcinogens such as polycyclic aromatic hydrocarbons into carcinogenic metabolites). In the human colon carcinoma cell line Caco-2, we investigated the effects of a defined polyphenolic apple juice extract (AJE), the major principle flavonoid/dihydrochalkone constituents quercetin and phloretin, and the corresponding prototype glycosides rutin and phlorizin on CYP1A1 expression and activity. Incubations were carried out with or without the potent aryl hydrocarbon receptor agonist/CYP1A1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AJE and quercetin acted as weak inducers of CYP1A1 mRNA and protein, and AJE, quercetin, and phlorizin led to a slight induction of CYP1A1-catalyzed 7-ethoxyresorufin O-deethylase (EROD) activity. However, AJE, quercetin, and phloretin were highly effective in suppressing CYP1A1 induction in co-incubations of the cells with 1 nM TCDD. The antagonistic effects were seen on the levels of mRNA, enzyme protein, and catalytic activity. In contrast, the related glycosides rutin and phlorizin were inactive as inducers or inhibitors. Inhibition of CYP1A1 induction was not related to general cytotoxicity, which could be completely abolished by the addition of ascorbic acid/alpha-tocopherol. AJE, quercetin, and phloretin also antagonized the TCDD-mediated induction of a reporter gene driven by a regulatory sequence of the human CYP1A1 gene promoter. Our findings suggest that apple juice extract can antagonize TCDD-mediated CYP1A1 induction by interfering with AhR-dependent gene transcription and by inhibiting the catalytic activity of CYP1A1. These effects may result in reduced metabolic activation of certain chemical carcinogens, in particular, under conditions of sustained AhR activation.
Pohl
Christine
C
Food Chemistry and Environmental Toxicology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany.
Will
Frank
F
Dietrich
Helmut
H
Schrenk
Dieter
D
D001628:Beverages / Q000032:analysis*; D018938:Caco-2 Cells; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005638:Fruit / Q000737:chemistry*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D027845:Malus / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004791:Enzyme Inhibitors; D010936:Plant Extracts; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D019363:Cytochrome P-450 CYP1A1