Methoxylated flavones, a superior cancer chemopreventive flavonoid subclass?

Abstract

Dietary flavonoids and other polyphenols show great potential as cancer chemopreventive agents in cell culture studies. This does not translate well into in vivo activity, because of extensive conjugative metabolism of these compounds in the intestine and liver. This paper presents a review of a flavonoid subclass in which all hydroxyl groups are capped by methylation. This results in dramatically increased metabolic stability and membrane transport in the intestine/liver, thus improving oral bioavailability. The methoxyflavones also show increased cancer chemopreventive properties. At the cancer initiation stage, bioactivation of polyaromatic hydrocarbon carcinogens and binding to DNA are markedly diminished through effects on CYP1A1/1B1 transcription but also through direct interactions with the proteins. At the cancer promotion stage, the proliferation of cancer cells, but not normal cells, is inhibited with greater potency than with the unmethylated flavones. Limited mechanistic experiments, such as of effects on cell cycle regulation, indicate that the mechanisms of methoxyflavone activities are unique, including aromatase inhibition. The cancer preventive effects and mechanisms of the polymethoxyflavones, such as tangeretin and nobiletin, are discussed in comparison. It is concluded that the methoxyflavones have properties that may make them particularly useful as cancer chemopreventive agents.

Antioxidant activity of <i>Piper caninum</i> and Cyclooxygenase-2 inhibition by methoxylated flavones.

“…This suggest, the presence of methoxyl group at position 7-on the A ring and 4′-on the B ring, are important for COX-2 inhibition (see Figures 1 and 2). Similar observation was reported by Walle (2007) and Wu et al, (2002) where methoxyl group at position 7-on the A ring and 4′-on the B ring in other flavones having high activities respectively.…”

“…The estimation of polyphenol levels in human plasma after the consumption of polyphenol-rich foods or beverages was reported around 0.1-1.0 µM (Manach et al, 2005;Nicholson et al, 2010). In particular to 5,7-dimethoxyflavone, the plasma concentration is on peak at 2.3 µM after 1 hour of oral administration (Walle, 2007).…”

Bioavailability of Citrus Polymethoxylated Flavones and Their Biological Role in Metabolic Syndrome and Hyperlipidemia

“…The exclusive feature in the chemical structure of PMFs is the polymethylation of polyhydroxylated flavonoids, one of the major naturally occurring polyphenolic compounds. This results in increased metabolic stability and membrane transport in the intestine and liver, improving oral bioavailability (Walle, 2007). Fig.…”

Inhibition of Carcinogen-Activating Cytochrome P450 Enzymes by Xenobiotic Chemicals in Relation to Antimutagenicity and Anticarcinogenicity

“…anti-oxidative and anti-mutagenic activities, thus preventing cancer, heart disease, bone loss, and a number of diseases (121)(122)(123). These biological activities are reported to vary with the number and substitution positions of hydroxyl and/or methoxy groups in the flavonoid molecules (124)(125)(126). Inhibition of P450 enzymes by diverse flavonoid erivatives has been extensively studied in several laboratories (127)(128)(129)(130)(131)(132)(133)(134)(135)(136)(137).…”