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Vol. 29, Issue 8, 1074-1079, August 2001
Puracyp, LLC, San Diego, California (S.A.); La Jolla Institute for
Molecular Medicine, San Diego California (L.M., J.R.); and Section of
Medical Toxicology, Department of Medicine, University of Colorado
Health Science Center, Denver, Colorado (S.W., L.Q.)
We examined the effects of several agents, including dietary
flavonoids, on CYP1A1 expression utilizing a recently developed high-throughput screening system for assessing human cytochrome P450 (CYP) induction. HepG2 cells, stably integrated with
regulatory regions of human CYP1A1, were treated with resveratrol,
apigenin, curcumin, kaempferol, green tea extract (GTE),
(
)-epigallocatechin gallate (EGCG), quercetin, and naringenin. Of
these flavonoids, resveratrol produced the greatest increase in
CYP1A1-mediated luciferase activity (10-fold), whereas GTE, apigenin,
curcumin, and kaempferol produced 2- to 3-fold increases in activity.
Compared with 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD), omeprazole, or benzanthracene, where increases in luciferase
activity ranged from 12- to 35-fold, these flavonoids exhibited weak
agonist activity. The remaining compounds, EGCG, quercetin, and
naringenin, produced negligible effects. Cotreatment of cells with TCDD
and GTE, naringenin, and apigenin resulted in 58, 77, and 74%
reductions, respectively, in TCDD-mediated CYP1A1 induction, indicating
that these flavonoids exhibit potential antagonist activity toward the
aryl hydrocarbon (Ah) receptor. Furthermore, results also suggest that
GTE and apigenin possess Ah receptor antagonist and weak agonist
activities. Thus, we have shown that a 96-well plate assay allowing
high-throughput screening for P450 induction in less than 24 h was
efficient in determining the effects of flavonoids on human CYP1A
expression. Signal-to-noise ratios were low, and well-to-well and
replicate variability was below 10%, allowing induction to be easily
detected in this system. These features illustrate the reliability and feasibility of this high-volume screening system for identifying CYP
inducers. Furthermore, results produced with the stable cell line were
corroborated in HepG2 cells and primary cultures of human hepatocytes,
suggesting that stably integrated cell lines harboring enhancer
elements of P450 genes may be highly conducive to high-throughput screening.
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