Tissue distribution in mice and metabolism in murine and human liver of apigenin and tricin, flavones with putative cancer chemopreventive properties

Abstract

Purpose: The flavones apigenin and tricin, which occur in leafy vegetables and rice bran, respectively, possess cancer chemopreventive properties in preclinical rodent models. Their pharmacology is only poorly understood. We compared their tissue levels in mice in vivo and their metabolism in liver fractions in vitro. Methods: Mice received apigenin or tricin (0.2%) with their diet for 5-7 days, and flavone levels were compared in the plasma, liver and gastrointestinal mucosa using HPLC-UV. Flavone metabolism was investigated in murine and human liver microsomes or cytosol in vitro co-incubated with uridine 5'-diphosphoglucuronic acid or 3'-phosphoadenosine-5' phosphosulfate. Flavone metabolites were characterized by on-line HPLCmass spectrometry. Results: After dietary administration of flavones for 7 days, levels of tricin in plasma, liver and mucosa exceeded those of apigenin by 350, 33 and 100 %, respectively.Apigenin was more rapidly glucuronidated than tricin in liver microsomes, whilst tricin underwent swifter sulfonation than apigenin in liver cytosol. For either flavone the rate of glucuronidation was much faster than that of sulfonation. Flavone monoglucuronides and monosulfates were identified as metabolites in microsomal and cytosolic incubations, respectively. Conclusions:When consumed with the diet in mice tricin seems to be more available than apigenin in blood and tissues. Differences in their glucuronidation may account for their differential availability. Thus tricin may have a pharmacokinetic advantage over apigenin. This type of information may help decide which flavonoids to select for clinical development.

The Identification of Maize and Arabidopsis Type I FLAVONE SYNTHASEs Links Flavones with Hormones and Biotic Interactions

“…Although flavones are generally colorless, they can function as copigments with anthocyanins to alter the color of flowers (Goto and Kondo, 1991;Tanaka et al, 1998;Shiono et al, 2008;Kalisz et al, 2013;Tanaka and Brugliera, 2013) and leaves (Ishikura, 1981;Fossen et al, 2007). On the other hand, flavones as dietary constituents or supplements have beneficial effects, as they have antioxidant properties, they can prevent cancer, they reduce the risks of cardiovascular diseases, they decrease cholesterol levels, and they show antiviral activities (Bontempo et al, 2007;Cai et al, 2007;Liu et al, 2007;Park et al, 2007;Baek et al, 2009;Dharmarajan and Arumugam, 2012;Yarmolinsky et al, 2012;Dajas et al, 2013).…”

Completion of Tricin Biosynthesis Pathway in Rice: Cytochrome P450 75B4 Is a Unique Chrysoeriol 5′-Hydroxylase

“…Very recently, tricin was demonstrated to be a flavonoid monomer in monocot lignin, representing the first nonmonolignol monomer involved in lignification (Lan et al, 2015). In addition, tricin is widely recognized as a promising multifunctional nutraceutical because of its antioxidant (Duarte-Almeida et al, 2007), anticancer (Cai et al, 2007), anti-inflammatory (Shalini et al, 2012), and cardiovascular-protective (Chang et al, 2010) properties. The lipophilicity nature of methoxylated flavones is believed to enhance their access to target cells and tissues (Walle, 2007).…”

Cytochrome P450 93G1 Is a Flavone Synthase II That Channels Flavanones to the Biosynthesis of Tricin O-Linked Conjugates in Rice

“…In plants, flavones play important physiological roles, including UV protection (Schmitz-Hoerner and Weissenböck, 2003), interactions with other organisms (Peters et al, 1986;Kong et al, 2007), regulation of auxin transport (Mathesius et al, 1998), and copigmentation in flowers (Goto and Kondo, 1991). On the other hand, flavones as dietary constituents or supplements have become increasingly popular due to their health-beneficial effects, such as cancer prevention (Bontempo et al, 2007;Cai et al, 2007;Liu et al, 2007), antioxidation (Park et al, 2007), antiviral activities (Yarmolinsky et al, 2012), reduction of risks of cardiovascular diseases (Baek et al, 2009), and suppression of cholesterol levels (Dharmarajan and Arumugam, 2012).…”