Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejunum in vivo.
For the first time the human intestinal effective permeability, estimated from the luminal disappearance and intestinal metabolism of phytochemicals, sulforaphane and quercetin-3,4'-glucoside, as well as the simultaneous changes in gene expression in vivo in enterocytes, has been studied in the human jejunum in vivo (Loc-I-Gut). Both compounds as components of an onion and broccoli extract could readily permeate the enterocytes in the perfused jejunal segment. At the physiologically relevant, dietary concentration tested, the average effective jejunal permeability (Peff) and percentage absorbed (+/- S.D.) were 18.7 +/- 12.6 x 10-4 cm/s and 74 +/- 29% for sulforaphane and 8.9 +/- 7.1 x 10-4 cm/s and 60 +/- 31% for quercetin-3,4'-diglucoside, respectively. Furthermore, a proportion of each compound was conjugated and excreted back into the lumen as sulforaphane-glutathione and quercetin-3'-glucuronide. The capacity of the isolated segment to deconjugate quercetin from quercetin-3,4'-diglucoside during the perfusion was much higher than the beta-glucosidase activity of the preperfusion jejunal contents, indicating that the majority (79-100%) of the beta-glucosidase capacity derives from the enterocytes in situ. Simultaneously, we determined short-term changes in gene expression in exfoliated enterocytes, which showed 2.0 +/- 0.4-fold induction of glutathione transferase A1 (GSTA1) mRNA (p < 0.002) and 2.4 +/- 1.2-fold induction of UDP-glucuronosyl transferase 1A1 (UGT1A1) mRNA (p < 0.02). The changes in gene expression were also seen in differentiated Caco-2 cells, where sulforaphane was responsible for induction of GSTA1 and quercetin for induction of UGT1A1. These results show that food components have the potential to modify drug metabolism in the human enterocyte in vivo very rapidly.
Petri
Niclas
N
Department of Pharmacy, Biopharmaceutics Research Group Uppsala University, Uppsala, Sweden.
Tannergren
Christer
C
Holst
Birgit
B
Mellon
Fred A
FA
Bao
Yongping
Y
Plumb
Geoff W
GW
Bacon
Jim
J
O'Leary
Karen A
KA
Kroon
Paul A
PA
Knutson
Lars
L
Forsell
Patrik
P
Eriksson
Thomas
T
Lennernas
Hans
H
Williamson
Gary
G
D001937:Brassica; D018938:Caco-2 Cells / Q000201:enzymology / Q000378:metabolism; D002853:Chromatography, Liquid; D020895:Enterocytes / Q000201:enzymology / Q000378:metabolism; D018565:Food-Drug Interactions; D015870:Gene Expression; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis; D006801:Humans; D007408:Intestinal Absorption; D017879:Isothiocyanates; D007583:Jejunum / Q000201:enzymology / Q000378:metabolism*; D013058:Mass Spectrometry; D019697:Onions; D010936:Plant Extracts / Q000493:pharmacokinetics; D018547:Plant Stems; D035281:Plant Tubers; D011794:Quercetin / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013454:Sulfoxides; D013861:Thiocyanates / Q000493:pharmacokinetics*; D001617:beta-Glucosidase / Q000096:biosynthesis; D000099148:UGT1A1 Enzyme
D020719:Glucuronides; D014453:Glucuronosyltransferase; D005978:Glutathione; D005982:Glutathione Transferase; D017879:Isothiocyanates; D010936:Plant Extracts; D011794:Quercetin; D012333:RNA, Messenger; D013454:Sulfoxides; D013861:Thiocyanates; D001617:beta-Glucosidase; D000099148:UGT1A1 Enzyme; C016766:sulforaphane