UDP-glucuronosyltransferase (UGT) isozymes detoxify metabolites, drugs, toxins, and environmental chemicals via conjugation to glucuronic acid. Based on the extended UGT1 locus combined with Northern blot analysis and in situ hybridization, we determined the distribution of UGT1A1 and UGT1A7 through UGT1A10 mRNAs and found them for the first time segmentally distributed in the mucosal epithelia layer of the gastrointestinal tract. Biochemically, recombinant isozymes exhibited pH optima of 5.5, 6.4, 7.6, 8.5, and/or a broad pH range, and activities were found to be unaffected or progressively inhibited by increasing substrate concentrations after attaining V max for certain chemicals. Under different optimal conditions, all exhibited wide substrate selections for dietary and environmentally associated chemicals. Evidence also suggests tandem effects of isozymes in the time for completion of reactions when comparing short-and long-term incubations. Moreover, treatment of colon cells with certain dietassociated constituents, curcumin and nordihydroguaiaretic acid, reversibly targets UGTs causing inhibition without affecting protein levels; there is no direct inhibition of control UGT using curcumin as substrate in the in vitro assay. In summary, we demonstrate that UGTs are located in gastrointestinal mucosa, have vast overlapping activities under differential optimal conditions, and exhibit marked sensitivity to certain dietary substrates/constituents, representing a first comprehensive study of critical properties concerning glucuronidating isozymes in alimentary tissues. Additionally, the highly dynamic, complex, and variable properties necessarily impact absorption of ingested chemicals and therapeutic drugs.The gastrointestinal (GI) 1 system has the critical function of absorbing nutrients from the diet and, simultaneously, acting as a barrier to ingested toxins and unwanted chemicals. To this end, the human UGT1 complex locus, which encodes multiple UDP-glucuronosyltransferase (UGT) isozymes distributed in the GI tract, participates in the broad and critical function of detoxifying lipid-soluble phenols derived metabolically or ingested as part of the diet, its contaminants, and as medications. UGT conjugates glucuronic acid to the acceptor substrate, converting the lipophile to an inactive glucuronide that undergoes facilitated excretion. The isozymes metabolize endogenous substrates such as bilirubin, steroids, bile acids, retinoic acid, and thyroid hormones. Equally important, isozymes also metabolize four categories of dietary phytochemicals that could pose risks for humans and animals when absorbed in excess. Highly abundant dietary flavonoids found in plants are shown to inhibit aromatase (1), and less abundant anthraquinones and two types of phytoestrogens (2-4) can also cause cellular damage. Particular anthraquinones were mutagenic when bioactivated (3) and were carcinogens in long-term feeding experiments in mice (5). Injurious effects of diets were demonstrated by extensive lesions in the reprodu...