Flavonoids are phenolic compounds synthesised as secondary metabolites in plants. Flavonoids have been shown to possess beneficial health properties in epidemiological studies. In particular, high intakes of flavonoids are associated with a reduced risk of cardiovascular disease, cancer, inflammation, neurodegeneration, oxidative stress, and microbial infection. Flavonoids have been shown to be bioavailable in humans, and cell culture studies have elucidated a number of possible mechanisms by which their activity may be beneficial to human health. From these studies it appears that flavonoids possess strong antioxidant properties and account of their polyphenolic structure, and are also able to alter genes expression in human cells. However, controversy still surrounds their absorption and their exact mechanism of action. This is because interaction with human enzymes alters the structure of flavonoids, and with it their chemical and physical properties.
Flavonoids are present in plants in their glucoside form (bonded to a sugar). Upon ingestion, it is thought that deglycosylation occurs in the small intestine via the brush border enzyme lactase phlorizin hydrolase (LPH). This hydrolysis reaction results in the production of the aglycone form of the flavonoid, a molecule with more lipophilic properties. As a result, the flavonoid is able to diffuse across the apical surface of the enterocytes of the small intestine. Alternatively, some evidence suggests that the glycoside form may be absorbed actively via the sodium glucose linked transporter 1 (SGLT1), and then hydrolysed intracellularly by cytosolic β-glucosidase. Once formed intracellularly, the aglycone form is extensively metabolised to form glucuronide, sulfate, methylated and mixed conjugates. Some of these may be absorbed across the basolateral membrane, but many are effluxed back to the lumen of the small intestine, where they pass to the colon and are further metabolised before absorption or excretion.
The extensive metabolism of the flavonoids by the enterocytes is complicated during first pass metabolism where hepatic enzymes further metabolise the newly formed flavonoid conjugates. The forms that reach the circulation tend to be glucuronidated, sulphated, methylated or mixed conjugates. These forms are more polar and therefore more water soluble that their aglycone forms, and there is evidence that they circulate in the blood before excretion in the bile or urine. Much of the cell culture work has been performed using the aglycone forms of the flavonoids, but it is unclear as to whether the conjugated forms are able to function in the same way in vivo. It is also unclear as to whether the more water soluble conjugated forms are able to enter cells in the same way as the aglycone form. Unpublished work from my own research suggests that kaempferol 3-glucuronide is unable to enter intestinal cells for example.
The enzyme β-glucuronidase is known to occur in mammalian cells as a lysosomal enzyme and is also known to be released from neutrophils and eosinophils during inflammation. Luteolin monoglucuronide has been shown to be converted to the free aglycone form during inflammation using human neutrophils and rats. Luteolin, a flavone flavonoid, has been shown to possess antiinflammatory effects in vitro, which may suggest a similar role in vivo. It is also known that luteolin is present in the circulation after ingestion as luteolin monoglucuronide. Evidence suggests that following inflammation or injury, β-glucuronidase is released from neutrophils or injured cells and appears in the blood and other body fluids. This circulating β-glucuronidase then hydrolyses the glucuronide conjugates forming the aglycone at the site of inflammation. The low pH of tissue fluids at the site of inflammation may be conductive to β-glucuronidase activity, which has an optimal range from pH 4 to 5.
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