RT Journal Article SR Electronic T1 Polymorphic Expression of the UDP-GlucuronosyltransferaseUGT1A Gene Locus in Human Gastric Epithelium JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 647 OP 654 VO 54 IS 4 A1 Christian P. Strassburg A1 Nghia Nguyen A1 Michael P. Manns A1 Robert H. Tukey YR 1998 UL http://molpharm.aspetjournals.org/content/54/4/647.abstract AB 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. PolymorphicUGT1A 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. The American Society for Pharmacology and Experimental Therapeutics