Uridine diphosphate-5'-glucuronosyltransferases
(UGT)
UDP-glucuronosyltransferases,
which catalyze the conversion of hydrophobic substrates to more hydrophilic
glucuronides are found in human hepatic and extrahepatic tissues. Glucuronidation
is performed by a superfamily of UGT proteins which are divided into 2 families
(UGT1A, UGT2B) based upon sequence homologies. The UGT2B genes have been
mapped to chromosome 4 and consist of individual structural genes. In contrast,
a complex locus of UGT1A genes has been identified on chromosome 2,
where at least 9 functional UGT1A proteins and 3 pseudogenes are encoded. Four
exons are located at the 3’ end of the UGT1A locus and are combined with
one of a consecutively numbered array of first exon cassettes towards the 5’
end of the gene locus. The aminoterminal 280 amino acids of UGT1A proteins are
encoded by the unique exon 1 sequences. The carboxyl terminus of 245 amino
acids is encoded by exon 2-5 sequences, and is identical in all UGT1A proteins.
This strategy is believed to determine the diversity of glucuronidation in
humans. Five human UGT1A cDNAs have been identified and characterized from
liver tissue: UGT1A1, UGT1A3, UGT1A4, UGT1A6, and UGT1A9. UGT1A proteins
expressed in the liver are characterized by individual catalytic activity
profiles.
Extensive analysis of specific
catalytic activities attributed to recombinant UGT proteins has also demonstrated
a broad overlap of substrates targeted for glucuronidation. UGT1A proteins have
been found to glucuronidate a wide variety of phenolic substrates. As an
example, 1-naphthol serves as a substrate for hepatic UGT1A1, UGT1A6 and
UGT1A9. In addition, many other phenolic compounds are substrates for UGT1A1,
UGT1A6, UGT1A7 and UGT1A10. Thus, glucuronidation reactions performed in a
specific tissue may be the result of a qualitative and quantitative regulation
of individual UGT isoform expression, possibly to meet anatomically and
physiologically defined glucuronidation requirements. The analysis of
extrahepatic tissues involved in xenobiotic and endobiotic metabolism such as
the gastrointestinal tract has lead to the discovery of three specifically
extrahepatic UGT1A proteins, further adding to the diverse organization of
human glucuronidation. In 1997 we identified UGT1A10 in biliary, gastric and
colon tissues, UGT1A7 in gastric and UGT1A8 in colon tissue. UGT1A7, UGT1A8,
and UGT1A10 are not expressed in liver. UGT1A7 and UGT1A10 were found to be
catalytically active with a broad range of phenolic and flavone substrates.
UGT1A10 was found to be uniquely specific for steroid hormones such as estrone.
Both UGT1A7 and UGT1A10 are also capable of glucuronidating environmental
carcinogens such as benzo(a)pyrene metabolites. These investigations
have elucidated a putative biochemical basis for a tissue specific profile of
UGT catalyzed detoxification and xenobiotic metabolism in the gastrointestinal
tract. Recently an interindividually variable polymorphic expression of UGTs in
the small intestine was identified which may contribute to variable metabolic
profiles in the gastrointestinal tract. In addition, the isoform specific
development of human glucuronidation was studied in child livers.
Further readings regarding this subject:
Role of UGT in
the gastrointestinal tract
(PDF)
Small
intestinal glucuronidation, polymorphic expression (PDF)
Tissue specific
expression of UGT (PDF)
UGT and child
liver, development (PDF)