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Vol. 54, Issue 4, 647-654, October 1998
Department of Pharmacology, Cancer Center, University of
California, San Diego, La Jolla, California 92093 (C.P.S., N.N.,
R.H.T.) and
Department of Gastroenterology and Hepatology, Medizinische
Hochschule Hannover, 30625 Hannover, Germany (M.P.M.)
The human UDP-glucuronosyltransferase (UGT) 1A (UGT1A)
locus is regulated in a tissue specific fashion in liver and
extrahepatic tissues. Three extrahepatic UGT1A proteins, UGT1A7,
UGT1A8, and UGT1A10, have been discovered and are believed to
contribute to the diversity of extrahepatic glucuronidation. UGTs
eliminate by glucuronidation a broad variety of endobiotic and
xenobiotic substrates, which include bilirubin, therapeutic drugs, and
carcinogens. Human gastric mucosa represents a primary location of
tissue contact with dietary constituents, pharmaceutical drugs, and
environmental carcinogens. To study the role and regulation of UGT1A
gene products in stomach UGT1A mRNA expression and UGT catalytic
activities were investigated in a panel of 14 normal gastric
mucosa/adenocarcinoma sample pairs. UGT1A mRNA levels were
differentially regulated in stomach, a feature not found in hepatic
tissue. Normal gastric epithelium consistently expressed extrahepatic
UGT1A7 and UGT1A10. However, polymorphic expression of UGT1A1 (29%),
UGT1A3 (21%), and UGT1A6 (36%) was detected. Polymorphic
UGT1A regulation was confirmed in adenocarcinoma samples
with the additional observation of differential down-regulation of
UGT1A1, UGT1A3, UGT1A6, and UGT1A10 and up-regulation of UGT1A7 mRNA.
The polymorphic UGT1A regulation in stomach contrasts the
homogeneous regulation of UGT1A gene products in human liver. Activity
assays demonstrated 2- to 4-fold interindividual differences in UGT
activity and qualitative differences between individuals. The
polymorphic regulation of UGT1A gene products in gastric tissue may be
the biological basis that determines interindividual differences in
extrahepatic microsomal drug metabolism.
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