Hop (Humulus lupulus L.) Extract and 6-Prenylnaringenin Induce P450 1A1 Catalyzed Estrogen 2-Hydroxylation.
Humulus lupulus L. (hops) is a popular botanical dietary supplement used by women as a sleep aid and for postmenopausal symptom relief. In addition to its efficacy for menopausal symptoms, hops can also modulate the chemical estrogen carcinogenesis pathway and potentially protect women from breast cancer. In the present study, an enriched hop extract and the key bioactive compounds [6-prenylnarigenin (6-PN), 8-prenylnarigenin (8-PN), isoxanthohumol (IX), and xanthohumol (XH)] were tested for their effects on estrogen metabolism in breast cells (MCF-10A and MCF-7). The methoxyestrones (2-/4-MeOE1) were analyzed as biomarkers for the nontoxic P450 1A1 catalyzed 2-hydroxylation and the genotoxic P450 1B1 catalyzed 4-hydroxylation pathways, respectively. The results indicated that the hop extract and 6-PN preferentially induced the 2-hydroxylation pathway in both cell lines. 8-PN only showed slight up-regulation of metabolism in MCF-7 cells, whereas IX and XH did not have significant effects in either cell line. To further explore the influence of hops and its bioactive marker compounds on P450 1A1/1B1, mRNA expression and ethoxyresorufin O-dealkylase (EROD) activity were measured. The results correlated with the metabolism data and showed that hop extract and 6-PN preferentially enhanced P450 1A1 mRNA expression and increased P450 1A1/1B1 activity. The aryl hydrocarbon receptor (AhR) activation by the isolated compounds was tested using xenobiotic response element (XRE) luciferase construct transfected cells. 6-PN was found to be an AhR agonist that significantly induced XRE activation and inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced XRE activity. 6-PN mediated induction of EROD activity was also inhibited by the AhR antagonist CH223191. These data show that the hop extract and 6-PN preferentially enhance the nontoxic estrogen 2-hydroxylation pathway through AhR mediated up-regulation of P450 1A1, which further emphasizes the importance of standardization of botanical extracts to multiple chemical markers for both safety and desired bioactivity.
UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612-7231, United States.
Shuai
S
Wang
UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612-7231, United States.
Tareisha L
TL
Dunlap
UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612-7231, United States.
Caitlin E
CE
Howell
UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612-7231, United States.
Obinna C
OC
Mbachu
UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612-7231, United States.
Emily A
EA
Rue
UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612-7231, United States.
Rasika
R
Phansalkar
UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612-7231, United States.
Shao-Nong
SN
Chen
UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612-7231, United States.
Guido F
GF
Pauli
UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612-7231, United States.
Birgit M
BM
Dietz
UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612-7231, United States.
Judy L
JL
Bolton
D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D027582:Humulus / Q000737:chemistry; D006900:Hydroxylation; D010936:Plant Extracts / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics
C521871:6-prenylnaringenin; D004967:Estrogens; D005419:Flavonoids; D010936:Plant Extracts; D012333:RNA, Messenger; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1