Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice

Abstract

Naturally occurring coumarins possess anti-carcinogenic activities in part by inducing carcinogendetoxifying enzymes glutathione S-transferase (GST) and/or NAD(P)H quinone oxidoreductase (NQO1). Our goal was to determine whether citrus coumarins induce hepatic GST and/or NQO1 via activation of Nrf2 and the antioxidant response element. First, HepG2 cells stably transfected with the ARE and a green fluorescent protein (GFP) reporter were treated with increasing concentrations of coumarins and compared to positive controls. tert-butylhydroquinone (TBHQ) and oltipraz increased GFP fluorescence, as did coumarin, limettin, auraptene, imperatorin, and 7,8-benzoflavone, suggesting that they activate the ARE, whereas isopimpinellin did not increase GFP fluorescence. Next, the effects of orally-administered coumarins and oltipraz on hepatic GST and NQO1 activities were compared in Nrf2 knockout mice or Nrf2 heterozygous mice exhibiting the wild-type phenotype. Oltipraz, auraptene, imperatorin, isopimpinellin, and auraptene all significantly increased liver cytosolic GST activities in Nrf2 heterozygous mice. This effect was abrogated in Nrf2 (−/−) mice dosed with oltipraz, attenuated in mice Nrf2(−/−) mice treated with auraptene and imperatorin, and still significant in Nrf2(−/−) mice treated with isopimpinellin. Of these compounds, only isopimpinellin significantly increased liver cytosolic NQO1 activities, and this effect was not attenuated in Nrf2(−/−) mice. These results strongly suggest that imperatorin and auraptene induce murine liver cytosolic GST activities via the Nrf2/ARE mechanism. Although structurally similar, isopimpinellin did not appear to activate HepG2-ARE-GFP and the Nrf2 knockout mouse study suggests that isopimpinellin may induce GST and NQO1 via additional mechanisms.

Simultaneous and sensitive determination of xanthotoxin, psoralen, isoimpinellin and bergapten in rat plasma by liquid chromatography–electrospray ionization mass spectrometry

“…Xanthotoxin (8-methoxypsoralen), psoralen, isoimpinellin (5,8-dimethoxypsoralen) and bergapten (5-methoxypsoralen) (see Fig. 1) are four major coumarins present in Radix Glehniae extract which demonstrated activities like photosensitization [11], anticancer [12][13][14], inducing hepatic drug-metabolizing enzymes [15] and inactivation of infectious pathogens and leukocytes in platelets and plasma [16]. Therefore, pharmacokinetic study of these coumarins is helpful to better understand the pharmacological and clinical effects of Radix Glehniae.…”

Quantum dots enhance Cu2+-induced hepatic l02 cells toxicity: involvement of Nrf2

“…GST induction is known to occur through xenobiotic response element (XRE) or ARE (Prince et al 2009). Comparison of elevated oxidative stress induced by Cu 2þ or Cu 2þ plus QD was thus evaluated.…”

“…Xenobiotics are chemical substances that are foreign to biological systems, including naturally occurring compounds, drugs, and environmental agents (Casalino et al 2007). Toxic metals represent a major class of environmental and occupational sources of toxicity, particularly through generation of ROS (He, Chen, and Ma 2008;Jorge and Gonsebatt 2009;Prince et al 2009). It is known that GST induction may occur through ARE (Prince et al 2009) and Nrf2/ARE system serves as a genetic program of cellular defense against oxidative stress (He, Chen, and Ma 2008).…”

Hypotensive activity of auraptene, a monoterpene coumarin fromCitrusspp.

“…Auraptene has also anti-obesity effects and inhibits hepatic triglyceride accumulation through enhancement of lipolysis in the liver (Nagao et al, 2010). Besides, auraptene exerts antioxidant activity and suppresses oxygen radical generation (Murakami et al, 1997;Prince et al, 2009), and mitigates inflammation through a number of mechanisms including induction of peroxisome proliferatoractivated receptors a (PPAR-a) and g (PPAR-g) (Kuroyanagi et al, 2008), down regulation of pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a) (Murakami et al, 2000) and attenuation of cyclooxygenase . In summary, the present findings indicated a moderate hypotensive activity for auraptene.…”