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The purpose of this study was to identify antimutagens in yogurt active against the experimental colon carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Our initial experiments showed that acetone extracts of yogurt, or milk fermented by various lactic acid bacteria were antimutagenic against MNNG and 3,2'-dimethyl-4-aminobiphenyl (DMAB) in the Ames test (Salmonella typhimurium TA 100). Further experiments carried out with milk fermented by Lactobacillus delbrueckii ssp. bulgaricus 191R showed that the putative compounds were more soluble in DMSO than in water, and that extractability of activity against MNNG and DMAB varied with pH, suggesting the presence of ionizable groups. Subsequent experiments demonstrated the antimutagenicity of yogurt. An acetone extract of yogurt was found to be active against a range of mutagens and promutagens in the Ames test. Simulation of fermentation by addition of lactic acid, lactic acid bacteria, or both to milk did not increase antimutagenicity, suggesting that compounds responsible for the activity may be formed during fermentation. Conjugated linoleic acid (CLA), a known dairy anticarcinogen, did not inhibit MNNG or DMAB indicating that other antimutagens may be present in yogurt. Fractionation of the acetone extract by HPLC showed that anti- MNNG and anti-DMAB activities did not co-elute, indicating that different compounds were responsible for the two activities. Using the Ames test to direct purification, isolation of an anti-MNNG active compound was accomplished using silica gel, Sephadex LH-20 and C18 reversed phase medium pressure chromatographies. The antimutagen was identified as palmitic acid by: a) co-elution with authentic palmitic acid on GC and HPLC columns, and b) by comparison of mass and ¹³C-NMR spectra. Minor components of milk fat such as iso methyl branched fatty acids (isopalmitic acid, isomargaric acid, isomyrsitic acid, and isostearic acid) were found to be more active than their straight chain counterparts. Isopalmitic acid also inhibited 4-nitroquinoline-N-oxide (4NQO) and the P450-mediated activation of 7,12-dimethylbenz[a]anthracene (DMBA). The mechanism of antimutagenesis against MNNG has not been established. / Graduation date: 1996

Thesis (Ph. D.)--Illinois State University, 1992. / Title from title page screen, viewed January 30, 2006. Dissertation Committee: Herman E. Brockman (chair), Alan J. Katz, Brian J. Wilkinson, Lynne A. Lucher, Radheshaym Jayaswal. Includes bibliographical references (leaves 115-123) and abstract. Also available in print.

Thesis (Ph. D.)--Illinois State University, 1993. / Title from title page screen, viewed March 10, 2006. Dissertation Committee: Herman E. Brockman (chair), Lynne A. Lucher, Marjorie A. Jones, Alan J. Katz, Anthony E. Liberta. Includes bibliographical references (leaves 138-144) and abstract. Also available in print.

Thesis (Ph. D.)--Illinois State University, 1993. / Title from title page screen, viewed March 7, 2006. Dissertation Committee: Herman E. Brockman (chair), Alan J. Katz, Brian J. Wilkinson, David F. Weber, Radheshyam K. Jayaswal. Includes bibliographical references (leaves 162-177) and abstract. Also available in print.

Thesis (Ph. D.)--Illinois State University, 1993. / Title from title page screen, viewed March 10, 2006. Dissertation Committee: Alan J. Katz (chair), Herman E. Brockman, David F. Weber, Brian J. Wilkinson, Marjorie A. Jones. Includes bibliographical references (leaves 146-159) and abstract. Also available in print.

Thesis (MScVoedselwet)--University of Stellenbosch, 2005. / Bibliography. Also available via the Internet.

Chlorophyllin (CHL), a water-soluble derivative of the green plant pigment, chlorophyll, is an effective antimutagen and anticarcinogen in various model systems when used as a modulator against a class of carcinogens that, in general, have a structure consisting of at least three fused rings. Dibenzo[a,l]pyrene (DBP), an extremely potent environmental carcinogen, has been isolated from urban air samples, tobacco smoke, and coal smoke condensate. A study was conducted to evaluate the complex interrelationships among dietary DBP doses with co-exposure to a range of CHL doses. In order to achieve adequate statistical power in the generation of multiple dose-response curves, this dose-dose matrix experiment utilized over 12,000 rainbow trout. The resulting DNA adducts were assessed and evaluated as biomarkers of exposure to discern their relationship with the final tumor outcome. CHL was highly effective in reducing DBP-initiated DNA adduct formation in the liver and stomach and strongly inhibited tumor formation in the liver (56-79% inhibition), stomach (30-68%), and swim bladder (over 80% at the highest DBP dose). Molecular dosimetry revealed adduct formation to be predictive of final tumor response in both organs regardless of CHL dose. Other parameters evaluated were consistent with CHL-mediated protection. A clinical CHL preparation, evaluated in a human population subsequent to the seminal demonstration of CHL chemopreventive properties against AFB��� in trout (1), revealed CHL to be just as effective in reducing biomarkers of alfatoxin exposure to humans (2). Dietary administration of this clinical preparation along with DBP in the rainbow trout demonstrated CHL protective capacity against DBP-initiated multi-organ DNA adduct formation and final tumor incidence. Sucrose was evaluated, deemed unlikely to be sequestered in a complex with CHL, and was used as a control in a pharmacokinetic study evaluating the biodistribution of DBP with and without CHL. The results provide evidence against a non-specific masking mechanism for CHL-mediated blocking of DBP (or aflatoxin)-initiated tumorigenesis. CHL at multiple doses provided significant protection against multi-dose DBP-initiated DNA adduction and tumor formation in multiple organs. CHL-mediated protection, primarily by reduced carcinogen biouptake and consistent with a complexation mechanism, is supported by these results. / Graduation date: 2003

Thesis (MSc Food Sc )--Stellenbosch University, 2003. / ENGLISH ABSTRACT: Please refer to fulltext for abstract / AFRIKAANSE OPSOMMING: Sien volteks vir opsomming

The antimutagenic potency of wheat grain and berry extracts was studied in vitro against several heterocyclic amines (HCAs) using the Salmonella mutagenicity assay and the anticarcinogencity of wheat grain was studied in vivo using the rat colonic aberrant crypt focus assay. Wheat bran, which binds HCAs in vitro, as well as refined wheat and unrefined whole wheat, inhibited the mutagenic activities of 2-amino-3- methylimidazo [4, 5-f] quinoline (IQ), 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) when they were co-incubated and the supernatant (minus grain) was added to the Salmonella mutagenicity assay. The water-soluble fraction alone from refined and unrefined wheat, but not bran, also inhibited these mutagens in vitro. In vivo, AIN- 93G diets containing refined wheat or unrefined wheat were examined for their ability to inhibit IQ-induced colonic aberrant crypt foci (ACF) in the F344 rat. A slight increase in the number of aberrant crypts/ACF (AC/ACF) was seen after 16 weeks in rats treated post-initiation with refined wheat (p<0.05), and fewer foci with 2 or 3 aberrant crypts (ACF-2) were found in rats given unrefined whole wheat post-initiation compared with animals treated with the same diet during the initiation phase (p<0.05). There was no significant difference in the profile of IQ urinary metabolites or excretion of promutagens 0-48 hours after carcinogen dosing, and grains had no effect on hepatic cytochrome P450 (CYP) 1A1, CYP1A2, aryl sulfotransferase, or N-acetyltransferase activities; however, a slightly higher UDP-glucuronosyl transferase activity was observed in rats fed unrefined wheat compared with refined wheat diets (p<0.05). Thus, despite their antimutagenic activities in vitro, only marginal effects were seen with refined and unrefined wheat in vivo with respect to induction of hepatic enzyme activities, carcinogen metabolism, or IQ-induced ACF in the rat colon. The fresh juice and extract of crandall black currant (Ribes aureum) were not mutagens in the Salmonella mutagenicity assay. Berry extract or fresh juice at levels to 50 ��l (22 mg berry) in a 500 ��l pre-incubation system significantly inhibited the mutagenicity of IQ, a mutagen from cooked meat, by 32% when rat liver S9 bioactivation system was present. One hundred ��l of crandall black currant extract gave 89% inhibition of IQ mutagenicity (p<0.05). However, the mutagenicity of 2-hydroxyamino-3-methylimidazo[4,5-f] quinoline (N-hydroxy- IQ), a direct-acting metabolite of IQ, was not affected. An in vitro fluorometric assay showed the activity of cytochrome P 450 (CYP) 1A1 and CYP 1A2 was decreased. Inhibition of CYP 1A2 activity may be an important mechanism of antimutagenicity of crandall black currant extract. Similar results were also observed with other berry samples. Key word: cereal grains, black currant, berry, aberrant crypt foci, heterocyclic amines, CYP1A1, CYP1A2, Salmonella mutagenicity assay. / Graduation date: 2003