UDP-Glucuronosyltransferases
and Carcinogenesis
Compounds
that are implicated in gastrointestinal carcinogenesis are present in our food
and our environment. During the incomplete incineration of organic material
polycyclic aromatic hydrocarbons (PAH) are generated which enter the body via
the air, tobacco smoke and prepared foods. Benzo(a)pyrenes and heterocyclic
amines are of particular biological relevance. Evidence has been provided that
the normal preparation of meat leads to the generation of PAH which are also
present in tobacco smoke, beer, wine, and which function as strong mutagens. In
animal models heterocyclic amines can induce tumors of different organs which
include lung, colon and liver cancer. For mutagenic activity to be present,
these molecules require metabolic activation usually involving N-linked
hydroxylation.
This leads
to the generation of the ultimate electrophilic carcinogen and is catalyzed by
cytochrome P450s such as CYP1A1, CYP1A2 and other CYPs. Animal and cell culture
experiments have shown that PAH exposure leads to a strong induction of CYP1A1
which in turn leads to an increased activation of carcinogens. In this respect
celluar detoxification and metabolic enzymes play a key role in chemical
carcinogenesis. UGTs are capable of direct inactivation
of carcinogen precursors or their metabolites before radical oxygen species are
generated, which lead to adduct formation with cellular macromolecules and DNA.
Our
laboratory has shown that patients with liver, colon, esophageal, gastric, oral
and pancreatic cancer display genetic polymorphisms of the UGT1A7 gene
more frequently than healthy controls. The so-called UGT1A7*3 polymorphisms
encodes a variant of the UGT1A7 enzyme which has considerably reduced tobacco
smoke mutagen detoxification activity compared to the wild type protein. Patients
with gastrointestinal tumors carry the UGT1A7*3 allele significantly more often
than healthy individuals. This finding establishes UGT1A7*3 as a risk factor of
gastrointestinal carcinogenesis. We are presently analyzing the relevance of
this polymorphisms for inflammatory diseases as well as the presence of
additional UGT1A polymorphisms.
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