Biology Reference
In-Depth Information
7.6.3 Phase I and phase II metabolism
In the GI tract and in other tissues (mainly in the liver), EA and ETs
microbial metabolites are further metabolized either through Phase I
(hydroxylation) or Phase II (methylation, glucuronidation and
sulphation) enzymes to render them more soluble for better excretion in
urine. Hydroxylation of urolithin A, and probably B, renders them more
reactive with additional functions for conjugation, which hence
facilitates their excretion. Thus, monohydroxydibenzopyran-6-one
(urolithin B) can be hydroxylated to produce a dihydroxylated derivative,
and urolithin A (3,8-dihydroxydibenzopyran-6-one) can be further
hydroxylated to produce trihydroxylated derivatives. In a recent gene
expression study, it was shown that both urolithins A and B, but
particularly urolithin B, can induce (15- to 20-fold) the expression of
cytochrome P-450 genes in Caco-2 cells, which may explain why the
urolithin B-derived dihydroxylated compound is in general more
abundant in tissues (liver), plasma and urine. Phase II products are also
produced and methyl ethers (products of COMT), as well as different
glucuronide conjugates, are detected in different tissues and in urine.
Sulphate conjugates of the ETs metabolites are less abundant in animals
and humans than the glucuronide conjugates. These conjugates are first
produced in the intestinal cells, and further metabolized in the liver
before excretion in the urine or the bile.
7.6.4 Tissue distribution
In order to understand the biological activity of ETs and EA, it is
essential to determine which metabolites and in which concentrations are
present in the different target tissues. In rats, no ET, EA or derived
metabolites have been detected in muscle, adipose, heart, lung, or brain
tissues, although small amounts of conjugates of the microbial
metabolites have been detected in liver and kidney. A study with pigs fed
on acorns also revealed a similar distribution of metabolites in systemic
tissues. The same study also showed the accumulation of large amounts
of different conjugates of the microbial metabolites in the gall bladder,
which is indicative of entero-hepatic circulation responsible for the long
