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Carotenoid metabolism in mice and prostate cancer risk

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Title: Carotenoid metabolism in mice and prostate cancer risk
Author(s): Ford, Nikki A.
Director of Research: Erdman, John W., Jr.
Doctoral Committee Chair(s): Nakamura, Manabu T.
Doctoral Committee Member(s): Erdman, John W., Jr.; Drackley, James K.; Jeffery, Elizabeth
Department / Program: Nutritional Sciences
Discipline: Nutritional Sciences
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): lycopene carotenoid prostate cancer androgen estrogen
Abstract: Prostate cancer is the second most abundant cancer with a 32% mortality rate world-wide. Epidemiological studies suggest an inverse relationship between risk of prostate cancer and intake of tomato products or higher blood levels of lycopene. β-carotene is centrally cleaved by carotene monoxygenase I (CMO-I) to form vitamin A and further metabolism results in formation of retinoic acid and other retinoids. The metabolism of β-carotene has been extensively studied, but very little is known about the metabolism of other carotenoids. We and others have hypothesized that other acyclic carotenoids, like lycopene, are eccentrically cleaved by carotene monoxygenase II (CMO-II). Like retinoids, we propose that carotenoid metabolites produced by CMO-II enzymatic cleavage are bioactive at small concentrations in tissues. The primary aims of this proposal were to delineate tissue specific expression of CMO-I and CMO-II and evaluate resulting carotenoid bioaccumulation in CMO-I KO, CMO-II KO, and wild-type mice. Secondly, we investigated the effects of lycopene metabolties on human prostate cancer cells, in vitro. Thirdly, we investigated the effects of carotenoid metabolism in CMO-I KO, CMO-II KO, and WT mice on sex steroid hormone status. Lycopene preferentially accumulated in CMO-II KO mice while β-carotene preferentially accumulated in CMO-I KO mice. Phytofluene and phytoene accumulation was not altered by genotype. Together these data suggest that lycopene is eccentrically metabolized by CMO-II and β-carotene is centrally metabolized to retinal by CMO-I. Phytoene and phytofluene may not be substrates for either CMO-I or CMO-II cleavage or did not accumulate in high enough concentrations in the liver to induce cleavage by these enzymes. We also report that the mRNA expression of CMO-I and CMO-II were not altered by the carotenoid-containing diets used in iii our studies. Interestingly, serum and testes testosterone were reduced and related sex steroid metabolizing genes were altered in CMO-I KO mice. We hypothesize that due to induced expression of CMO-II in the testes of CMO-I KO mice that lycopenoids are at least in part responsible for these effects. Lastly, we demonstrate anti-proliferative effects of the lycopene-metabolite, apo-12’-lycopenal in androgen-dependent DU145 prostate cancer cells. Overall, our findings provide support for previous in vitro data to suggest that lycopene is metabolized by the CMO-II enzyme, in vivo. Furthermore, we have evidence to suggest that lycopene metabolites reduce proliferation of prostate cancer cells in vitro and may beneficially alter sex steroid status in mice.
Issue Date: 2011-01-21
URI: http://hdl.handle.net/2142/18540
Rights Information: Copyright 2010 Nikki A. Ford
Date Available in IDEALS: 2011-01-21
2013-01-22
Date Deposited: 2010-12
 

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