|Grant Number:||5R01CA070913-03 Interpret this number|
|Primary Investigator:||Potter, John|
|Organization:||Fred Hutchinson Cancer Research Center|
|Project Title:||Glutathione Transferases in Humans: Dietary Influences|
DESCRIPTION: (Adapted from Investigator's Abstract) Higher intake of plant food is associated with lower risk of cancer in humans. There are a large number of bioactive constituents present in plant foods or derived from them in the human GI tract. There is an extensive body of animal experimental literature to show that many of these bioactive compounds have specific effects at the biochemical and molecular level - including important influences on xenobiotic metabolism. At present, however, evidence regarding mechanisms of cancer risk reduction in humans is almost totally lacking. To test the hypothesis that induction of Phase II enzyme systems through increased intakes of vegetable and fruits is a plausible mechanism for reduced cancer risk the applicants propose to examine the effects of vegetable and fruit consumption on glutathione-S-transferase (GST) isoenzyme activity in humans. The specific aims of the proposal are: 1) to examine, in a cross-sectional design, the associations of vegetable and fruit intake with serum GST alpha concentrations, overall serum GST activity and lymphocyte GSTu activity; 2) to determine whether these associations differ by GSTM1 genotype; 3) to measure the effect of feeding specific vegetables and fruit under controlled dietary conditions on serum GST alpha concentration, overall serum GST activity and lymphocyte GSTu activity; and 4) to explore whether the results are modulated by other xenobiotic metabolizing enzymes. The proposed project will be implemented in two parts: 1) a cross-sectional study and 2) a controlled randomized cross-over feeding trial. For the cross-sectional study, the applicants will recruit 200 non-smokers, 20-40 years of age. They will genotype them for GST1, measure serum GST alpha concentration, overall serum GST activity and lymphocyte GSTu activity, and will assess diet by food frequency questionnaire, 3-day food records, and the following serum and plasma markers of dietary exposure: ascorbic acid, beta carotene, thiocyanate and phytoestrogens (genistein, daidzein, equol, O-desmethylangolensin, enterolactone and enterdiol). They will correlate the measures of GST in the GSTM1 null and non-null participants with consumption of vegetables and fruit, nutrient intakes and the serum markers. For the feeding trial they will recruit a subset of 48 participants (24 GSTM1 null and 24 non-null) from the 200 in the cross-sectional study to take part in four 7-day feeding periods to examine the effects of various vegetable groupings (cruciferous vegetables, allium vegetables, and a mixture of vegetables and fruits) compared to a basal diet on induction of GST activity under controlled dietary conditions. They will measure serum GSTalpha concentration, overall serum GST activity and lymphocyte GSTu activity at the end of each feeding period. Concurrently, they will monitor induction of Phase I enzyme CYP1A2 by measuring urinary caffeine metabolites to determine whether alterations in GST activity are specific Phase II effects or reflect overall shifts in xenobiotic metabolism.
Cruciferous vegetables have variable effects on biomarkers of systemic inflammation in a randomized controlled trial in healthy young adults.
Authors: Navarro SL, Schwarz Y, Song X, Wang CY, Chen C, Trudo SP, Kristal AR, Kratz M, Eaton DL, Lampe JW
Source: J Nutr, 2014 Nov;144(11), p. 1850-7.
EPub date: 2014 Aug 27.
Reliability of serum biomarkers of inflammation from repeated measures in healthy individuals.
Authors: Navarro SL, Brasky TM, Schwarz Y, Song X, Wang CY, Kristal AR, Kratz M, White E, Lampe JW
Source: Cancer Epidemiol Biomarkers Prev, 2012 Jul;21(7), p. 1167-70.
EPub date: 2012 May 7.
Cruciferae interact with the UGT1A1*28 polymorphism to determine serum bilirubin levels in humans.
Authors: Peterson S, Bigler J, Horner NK, Potter JD, Lampe JW
Source: J Nutr, 2005 May;135(5), p. 1051-5.
Validation of a soy food-frequency questionnaire and evaluation of correlates of plasma isoflavone concentrations in postmenopausal women.
Authors: Frankenfeld CL, Patterson RE, Horner NK, Neuhouser ML, Skor HE, Kalhorn TF, Howald WN, Lampe JW
Source: Am J Clin Nutr, 2003 Mar;77(3), p. 674-80.
Validation of a soy food frequency questionnaire with plasma concentrations of isoflavones in US adults.
Authors: Frankenfeld CL, Patterson RE, Kalhorn TF, Skor HE, Howald WN, Lampe JW
Source: J Am Diet Assoc, 2002 Oct;102(10), p. 1407-13.
Brassica, biotransformation and cancer risk: genetic polymorphisms alter the preventive effects of cruciferous vegetables.
Authors: Lampe JW, Peterson S
Source: J Nutr, 2002 Oct;132(10), p. 2991-4.
Modulation of human glutathione S-transferases by botanically defined vegetable diets.
Authors: Lampe JW, Chen C, Li S, Prunty J, Grate MT, Meehan DE, Barale KV, Dightman DA, Feng Z, Potter JD
Source: Cancer Epidemiol Biomarkers Prev, 2000 Aug;9(8), p. 787-93.
Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets.
Authors: Lampe JW, King IB, Li S, Grate MT, Barale KV, Chen C, Feng Z, Potter JD
Source: Carcinogenesis, 2000 Jun;21(6), p. 1157-62.
Prevalence of polymorphisms in the human UDP-glucuronosyltransferase 2B family: UGT2B4(D458E), UGT2B7(H268Y), and UGT2B15(D85Y).
Authors: Lampe JW, Bigler J, Bush AC, Potter JD
Source: Cancer Epidemiol Biomarkers Prev, 2000 Mar;9(3), p. 329-33.
Health effects of vegetables and fruit: assessing mechanisms of action in human experimental studies.
Authors: Lampe JW
Source: Am J Clin Nutr, 1999 Sep;70(3 Suppl), p. 475S-490S.
UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations.
Authors: Lampe JW, Bigler J, Horner NK, Potter JD
Source: Pharmacogenetics, 1999 Jun;9(3), p. 341-9.