Biology Reference
In-Depth Information
through Caco-2 monolayer), indicating a facile absorptive transport
across the apical membrane. As much as 93% of the cellular EA was
irreversibly bound to macromolecules (proteins and DNA). Thus, EA
appears to accumulate in the epithelial cells of the aerodigestive tract. In
a recent study, the metabolism of punicalagin and ellagic acid by Caco-2
cells was reported (Larrosa
et al.
, 2006a). This study showed that
punicalagin is hydrolyzed in the cell medium to yield EA, which enters
Caco-2 cells. The first EA-derived metabolite produced by these cells
was a dimethylated EA, which involved the active participation of
COMT. Second, Caco-2 cells conjugation with glucuronic acid yielded
the corresponding dimethylated EA glucuronide, which was the most
abundant metabolite detected. Other metabolites detected in smaller
amounts included two isomers of dimethylated EA sulphates. All of
these metabolites were detected in both the cell culture medium and
within the cells (Larrosa
et al.
, 2006a).
EA and ETs are further converted by the intestinal microflora into
the dibenzopyranone metabolites, urolithins A and B (Fig. 7.2). These
urolithins are largely absorbed in the intestinal cells and glucuronidated.
In this case, no methyl ether is produced, for urolithins do not feature any
ortho
-dihydroxylphenyl unit in their structure. In the case of urolithin A
(3,8-dihydroxy-6
H
-dibenzo-[b,d]pyran-6-one), a hydroxylation by
cytochrome P-450 may also be possible to increase the possibilities of
glucuronidation and hence enhance the excretion of the metabolite.
7.5.3 Animal models
Animal studies are usually first recommended to rule out toxicity of a
new test compound, for larger doses can often be attained in animals than
in humans. The bioavailability of EA and ETs has been directly or
indirectly evaluated in animals and results are available.
The bioavailability of orally gavaged
3
H-EA was already evaluated
in mice by Teel and Martin in 1988. In this study, mice were provided
with 0.3 μg of EA/g of body weight (the equivalent of a human dose of
21 mg for a person of 70 kg). Both free EA and some conjugates
(sulphate ester, glucuronide and glutathione conjugates) were detected in
