Furocoumarins are natural plant constituents present in medicinal plants and in a variety of foods such as grapefruit juice. They are phototoxic and act as potent inhibitors of
drug metabolism. We have investigated the interaction of four
furocoumarins angelicin,
bergamottin,
isopimpinellin, and
8-methoxypsoralen with the expression and activity of
aryl hydrocarbon receptor (AhR)-regulated
CYP1A1 in rat hepatocytes in primary culture, both in the presence and absence of light. In intact hepatocytes pretreated with
2,3,7,8-tetrachlorodibenzo-p-dioxin and in microsomes isolated thereof, all
furocoumarins tested acted as potent inhibitors of
CYP1A1 activity
bergamottin being the most potent inhibitor in microsomes with an IC(50) of 10 nM in the presence and 60 nM in the absence of light.
8-Methoxypsoralen and
angelicin led to a significant induction of
CYP1A1 mRNA in hepatocytes, while all
furocoumarins except
bergamottin increased
xenobiotic-responsive
element-driven reporter gene expression in transfected H4IIE rat
hepatoma cells when light was excluded. Furthermore, all
furocoumarins tested induced the expression of endogenous, immunoreactive
CYP1A1 protein, primarily in the dark. In conclusion, our results demonstrate that individual
furocoumarins present in food and medicinal plants can interfere with AhR-regulated
CYP1A1 expression and activity in at least three major ways, i.e., (i) act as highly potent inhibitors of the catalytic activity of
CYP1A1 both in the presence and absence of light, (ii) induce
CYP1A1 gene expression in the absence of light via activation of the AhR, and (iii) induce
CYP1A1 gene expression without activation of the AhR.