UDP-glucuronosyltransferases (UGT) represent an evolutionary highly conserved family of enzymes which catalyze the detoxification and elimination of xenobiotics (carcinogens, drugs) and endobiotics (hormones, bilirubin, steroids). During the past five years factors were studied which significantly influence human detoxification and therefore are likely to exert an influence on the disposition toward diseases, drug toxicity and chronic inflammation. On the one hand a pattern of tissue specificity was elucidated which represents the biochemical basis of organ-specific glucuronidation and the metabolic barrier function of the gastrointestinal mucosa. On the other had a surprisingly high frequency and number of genetically determined UGT variants were described which modify enzymatic activities of the individual. Based on these findings it was recognized that single nucleotide polymorphisms (SNP) are also located within the 5’ untranslated gene regions and provide additional means of modulating enzymatic activity in a tissue. The picture of glucuronidation in man that emerges from our data is therefore heavily influenced by the identified genetic variants and their permutations.

Aim of our research is therefore to identify and characterize UGT variant haplotypes relevant to human diseases, and to identify surrogate markers for their detection in an effort to predict metabolic pathophysiological principles predisposing to mucosal disease. So far, a functional polymorphism of the UGT1A7 gene was identified. UGT1A7 is a main detoxification enzyme of the SN38 metabolite of the chemotherapeutic agent irinotecan. Its genetically determined functional variation influences drug-induced intestinal toxicity. In addition, an association of the UGT1A7*1 genotype with ulcerative colitis was demonstrated. Haplotyp analyses have shown a close association of hepatic and extrahepatic UGT variants, i.e. the UGT1A1*28 variant associated with Gilbert’s disease which is linked to UGT variants expressed in the intestine. Aim of the continued research within this project is to establish genotype-phenotype correlations regarding the human UGT1A gene locus, the definition of haplotypes and the identification and characterization of SNPs in regulatory elements of UGT1A transcription. These data will serve to correlate genetic variants with diseases such as chronic inflammatory bowel disease, irritable bowel syndrome, chemical intestinal toxicity, and to broaden our understanding of gastrointestinal glucuronidation. The results of this project are expected to integrate our understanding of metabolism, cytokine and chemokine expression in chronic inflammatory states, the gene-environment interaction as well as the individual reactions of humans to the exposure with therapeutic drugs.