Favonoids (here) are known to interact with a number of human detoxification enzymes, which greatly effects their bioactivity (here). These include both the phase I detoxification enzyme cytochrome P450 monooxygenase (CYP), and the phase II detoxification enzymes UDP-glucuronosyl transferase (UGT), glutathione S-transferase (GST), N-acetyltransferase (NAT), sulfotransferase (SULT) and methyltransferase (MT). Research shows that flavonoids are extensively metabolised in vivo, using similar systems of enzymes to other xenobiotics like pharmaceuticals and pollutants. Generally, flavonoids undergo reaction with oxygen (phase I) to increase reactivity then undergo a second reaction to add a methyl, glucuronide, glutathione, acetyl or sulfate group (phase II) to increase hydrophilicity. The phase II detoxification step aids solubility in plasma and allows effective excretion through the urine. During detoxification, flavonoids can interfere with other compounds passing though the same metabolic steps, and can also metabolised to compounds that possess altered bioactive properties.
Flavonoid absorption (here) is complex, but involves extensive metabolism within enterocytes during the absorptive process and within the liver following absorption. Xenobiotics such as drugs are absorbed and undergo phase I detoxification via the CYP family of enzymes and evidence suggests that this process is inhibited by flavanoids, possibly through competitive inhibition. The isoforms of CYP in the liver (CYP3A4 and 3A5) account for the detoxification over 50% of all prescribed drugs and the flavonols quercetin, myricetin and kaempferol, the flavanone naringenin, and the flavone apigenin, have been shown to inhibit drug metabolism by this enzyme. The grapefruit flavonoid naringenin can inhibit 3-demethylation of caffeine (via CYP1A2 the isoform responsible for the metabolism of methylxanthine drugs) in human liver microsomes, and both galangin and quercetin can also inhibit this isoform. Flavonoids in cranberry juice are though to inhibit the CYP2C9 isoform, the enzyme responsible for S-warfarin metabolism.
Interactions with phase II detoxification enzymes occur extensively in enterocytes, and this may be a mechanism to prevent absorption. Generally, flavonoids absorbed into the small intestinal cells appear to be interact with UGT, SULT and MT which results in water soluble conjugates via addition of a glucuronide, sulfate or methyl moiety, respectively. Efflux of the water soluble glucuronidated, sulfated, methylated and mixed conjugates to the lumen of the gut may result in bacterial degradation and conversion to simpler phenolics in the colon. In cell culture models, the flavonoids chrysin, quercetin, apigenin, kaempferol, baicalein and diosmetin have been shown to induce expression of UGT. Quercetin may modulate the activity of GST in rat liver cells and has also shown the ability to inhibit sulfation by inhibition of SULT in some cell studies. This suggests that flavonoids undergo phase II metabolism and may inhibit xenobiotic detoxification concomitantly.
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