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Title: Limited appearance of apocarotenoids is observed in plasma after consumption of tomato juices: a randomized human clinical trial

item COOPERSTONE, JESSICA - The Ohio State University
item Novotny, Janet
item RIEDL, KEN - The Ohio State University
item CICHON, MORGAN - The Ohio State University
item FRANCIS, DAVID - The Ohio State University
item CURLEY, ROBERT - The Ohio State University
item SCHWARTZ, STEVEN - The Ohio State University
item HARRISON, EARL - The Ohio State University

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/2/2018
Publication Date: 9/18/2018
Citation: Cooperstone, J.L., Novotny, J., Riedl, K.M., Cichon, M.J., Francis, D.M., Curley, R.W., Schwartz, S.J., Harrison, E.H. 2018. Limited appearance of apocarotenoids is observed in plasma after consumption of tomato juices: a randomized human clinical trial. American Journal of Clinical Nutrition. 108:784-792.

Interpretive Summary: In epidemiological studies, high intakes of carotenoids (red, orange, and yellow pigments in vegetables and fruits) have been associated with lower cancer risk. Moreover, there was a particularly strong association suggesting that individuals consuming high intakes of beta-carotene had protection against lung cancer. Thus, a large clinical trial was launched with more than 18,000 participants receiving beta-carotene supplements or a placebo. Surprisingly, the group receiving beta-carotene supplements had higher incidence of lung cancer rather than lower incidence. The reason for the unexpected result has never been understood, but it has been speculated that high doses of carotenoids may result in formation of metabolites called apocarotenals and apolycopenals, some of which have been shown to have capabilities of controlling aspects of cell function. Unfortunately, these compounds are very difficult to measure in blood, thus it has never been possible to investigate the formation of these compounds in the human body. We have developed a new method to measure these compounds in humans, and we have completed a study to test how carotenoid intake changes blood levels of these compounds. In our study, adult volunteers consumed one of 3 juices: tomato juice high in beta-carotene, tomato juice high in lycopene, or a carotenoid-free cucumber juice. We collected their blood to demonstrate which carotenoid metabolites were formed, and we can now use this information to further investigate why high beta-carotene intake may have increased incidence of lung cancer. This information will be used by scientists.

Technical Abstract: Nonvitamin A apocarotenoids occur in foods. Some function as retinoic acid receptor antagonists in vitro, though it is unclear if apocarotenoids are absorbed or accumulate to levels needed to elicit biological function. The aim of this study was to quantify carotenoids and apocarotenoids (ß-apo-8'-, -10'-, -12'-, and -14'-carotenal, apo-6'-, -8'-, -10'-, -12'-, and -14'-lycopenal, retinal, acycloretinal, ß-apo-13-carotenone, and apo-13-lycopenone) in human plasma after controlled consumption of carotenoid-rich tomato juices. Healthy subjects (n = 35) consumed a low-carotenoid diet for 2 wk, then consumed 360 mL of high-ß-carotene tomato juice (30.4 mg of ß-carotene, 34.5 µg total ß-apocarotenoids/d), high-lycopene tomato juice (42.5 mg of lycopene, 119.2 µg total apolycopenoids/d), or a carotenoid-free control (cucumber juice) per day for 4 wk. Plasma was sampled at baseline (after washout) and after 2 and 4 wk, and analyzed for carotenoids and apocarotenoids using high-pressure liquid chromatography (HPLC) and HPLC-tandem mass spectrometry, respectively. The methods used to analyze the apocarotenoids had limits of detection of ~ 100 pmol/L. Apocarotenoids are present in tomato juices at 0.1–0.5% of the parent carotenoids. Plasma lycopene and ß-carotene increased (P < 0.001) after consuming high-lycopene and ß-carotene tomato juices, respectively, while retinol remained unchanged. ß-Apo-13-carotenone was found in the blood of all subjects at every visit, although elevated (P < 0.001) after consuming ß-carotene tomato juice for 4 wk (1.01 ± 0.27 nmol/L) compared with both baseline (0.37 ± 0.17 nmol/L) and control (0.46 ± 0.11 nmol/L). Apo-6'-lycopenal was detected or quantifiable in 29 subjects, while ß-apo-10'- and 12'-carotenal were detected in 6 and 2 subjects, respectively. No other apolycopenoids or apocarotenoids were detected. ß-Apo-13-carotenone was the only apocarotenoid that was quantifiable in all subjects, and was elevated in those consuming high-ß-carotene tomato juice. Levels were similar to previous reports of all-trans-retinoic acid. Other apocarotenoids are either poorly absorbed or rapidly metabolized or cleared, and so are absent or limited in blood. ß-Apo-13-carotenone may form from vitamin A and its presence warrants further investigation. This trial was registered at as NCT02550483.