|Grant Number:||5R01CA092288-04 Interpret this number|
|Primary Investigator:||Lampe, Johanna|
|Organization:||Fred Hutchinson Cancer Research Center|
|Project Title:||Glucuronidation in Humans-Genotypes and Phenotypes|
DESCRIPTION (provided by applicant): Glucuronidation is an important detoxification process that plays a critical rote in the defense against chemical induced carcinogenesis. drug toxicities, and hormonal imbalances. UDP-glucuronosyltransferases (UGTs) catalyze the transfer of the glucuronyl group from uridine 5'-disphosphoglucuronic acid to endogenous molecules, such as bilirubin and steroid hormones, and exogenous substrates, such as drugs, plant-food Constituents, environmental pollutants, and carcinogens. The resulting glucuronyl products are more polar, generally water-soluble, less toxic, and more easily excreted than the substrate molecules. Polymorphisms in several UGT isoforms influence glucuronidation of xenobiotic compounds, as well as bile acids and some steroid hormones. The opposite reaction, the hydrolysis of such glucuronide moieties by human beta-glucuronidase (f3-G) can restore biologic activity of xenobiotics and steroid hormones. Thus, the impact of beta-G as part of the glucuronidation cycle should also be considered. We postulate that the induction of UGTs and the inhibition of beta-G are plausible mechanisms by which a diet high in vegetables and fruit (V&F) may reduce risk of various diseases. We propose to examine the effects of V&F consumption on UGT and beta-G activities, considering the potential interaction with genetic polymorphisms in several relevant UGTs. The specific aims of this proposal are: 1) To determine whether UGT activity, as measured by acetaminophen and aspirin glucuronide formation and serum bilirubin concentrations, differs by UGT genotypes for the following isozyme polymorphisms: UGTIAI*28, UGT/A6*2, and UGT2B15(D85Y); 2) To measure the effect of feeding specific V&F under controlled dietary conditions on UGT and beta-G activity; and 3) To determine whether the effects of these plant foods on UGT activity differ by UGTgenotypes (UGTJA1*28, UGTIA6*2, UGT2BI5(D85Y)). The project will be implemented in two parts: 1) a cross-sectional study and 2) a feeding study. For the cross-sectional study, we will recruit 300 non-smokers, aged 20-40 years, and who are not taking any medication. We will genotype them for UGTIAI*28, (UGTIA6*2, and UGT2B15(D85Y), measure acetaminophen, aspirin metabolite, and bilirubin conjugation, and serum beta-G activity, and assess diet using a food frequency questionnaire and 3-day food records. For the feeding study, we will recruit a subset of the 300 (30 men and 30 women), based on their UGT genotypes, to take part in two, 14-day feeding periods. We will examine the effect of a high-V&F diet compared to a basal (low-phytochemical) diet on UGT and beta-G activities. The randomized cross-over design will allow us to test efficiently for diet effects within individuals, as well as for gene-by-diet and sex-by-diet interactions.