Supplement: Promises and Perils of Lycopene/Tomato Supplementation and Cancer Prevention
John W. Erdman, Jr3
Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL 61801
3To whom correspondence should be addressed. E-mail: firstname.lastname@example.org .
KEY WORDS: • lycopene • nutritional status • bioavailability • isomers
Recent awareness of the health implications of lycopene consumption has generated interest regarding the effects of dietary and nondietary factors upon lycopene bioavailability, tissue biodistribution, and metabolism. It is generally recognized that there is an inverse relation between dietary carotenoid concentrations and absorption, that carotenoids often have poor bioavailability from vegetables, and that mild cooking and dietary fat enhance their bioavailability. This presentation specifically reviews the differential bioavailability of cis-lycopene compared with all-trans-lycopene, the differential tissue uptake of tomato carotenoids, and the impact of hormonal status on tissue levels of lycopene.
Although about 90% of the lycopene in dietary sources is found in the all-trans conformation, human tissues contain mainly cis isomers of this carotenoid (1). Cis isomers of lycopene are produced during typical heating and processing of tomato products. Some isomerization of lycopene appears to occur in the gastrointestinal tract, especially in the stomach. Studies with lymph-cannulated ferrets (2) demonstrated that although a lycopene dose contained cis-lycopene, small intestinal mucosal cells (58%), mesenteric lymph (77%), serum (52%), and tissues (47–58%) all contained enhanced concentrations of cis-lycopene isomers, primarily the 5-cis isomer. All-trans-lycopene is a bulky, linear molecule that appears to be less soluble in bile acid micelles. In contrast, cis isomers of lycopene may have less difficulty moving across plasma membranes and appear to be preferentially incorporated into chylomicrons (2).
Carotenoids do not distribute through tissues at the same concentration levels (3–6). Liver, adrenals, and reproductive tissues generally have at least 10-fold higher carotenoid concentrations than many other tissues, including the adipose tissue, which has historically been considered as a primary depot for these compounds. The more polar carotenoids, lutein and zeaxanthin, specifically accumulate in the macular pigment of the retina of the eye. Recently, a human zeaxanthin-binding protein from the macula of the eye has been characterized; interestingly, it is an isoform of glutathione S-transferase (7). The presence of lycopene-binding or transport proteins has not been confirmed in mammals. The broad range of tissue concentrations of carotenoids is perhaps linked to the relative number of LDL receptors or relative uptake of lipoproteins among tissues (4,5). In addition, tissue concentrations also may reflect differences in their relative metabolic or oxidation rates.
Unpublished results from our laboratory demonstrate differential tissue uptake of tomato carotenoids in rats (8). The tomato contains high concentrations of lycopene, phytoene, and phytofluene, and smaller quantities of ß and carotene. For this study, we fed twenty-four F344 male rats AIN-93G diets containing 10% freeze-dried whole-tomato powder for 30 d. At that point, baseline animals (n = 8) were killed and the remaining 2 groups of rats (n = 8) received an oral gavage of 3 mg of either synthetic phytoene or phytofluene in cottonseed oil and were killed 24 h after the dose. In baseline rats, lycopene tended to be preferentially taken up by the prostate. However, phytofluene and phytoene accumulated in concentrations higher than lycopene in the liver and the adrenal. After the oral dose with phytoene or phytofluene, there were enhanced levels of the respective carotenoid in serum and all tissues measured. After dosing, the seminal vesicles and the various lobes of the prostate still remained highest in lycopene, in contrast to most other tissues, which were highest in the dosed carotenoid.
It has been observed that plasma carotenoids and lipoproteins fluctuate independently during the menstrual cycle (9,10). Plasma lycopene, phytoene, and phytofluene peak at mid-luteal phase, whereas ß carotene peaks at the late follicular phase (9,10). Hypothyroidism, anorexia nervosa, bulimia, and weight loss are associated with elevated plasma carotenoids, irrespective of diet (11).
The inverse relation of androgen status with lycopene metabolism is of great interest because of the clear impact of higher androgens on prostate cancer risk. In conjunction with Dr. Clinton of Ohio State University, we have investigated the impact of castration, food restriction, and testosterone implants upon tissue levels of lycopene in F344 rats (12,13). For example, castration of rats results in doubling of hepatic lycopene, despite a 20% lower lycopene consumption in castrated rats. In addition, a 20% dietary food restriction also dramatically increases hepatic lycopene, a result that is reversed by testosterone implants. Similar findings were reported for liver vitamin E by Feingold and co-workers in intact and castrated rats (14). Thus, with higher androgen levels or greater consumption of energy, there may be enhanced lycopene (and perhaps other selective antioxidants) metabolism and degradation. Ho and colleagues have recently pointed out that a coelevation of estrogen and testosterone increases men’s risk for prostate cancer (15). They hypothesize that these effects are the result of prolonged activation of the redox-sensitive transcription factor NFkB, which initiates and amplifies an inflammatory cascade within the prostate and results in sustained oxidative and nitrative damage.
Some laboratories have reported that feeding or dosing rats with superphysiological quantities of lycopene induces selective P450 and phase II enzymes, which can then result in the metabolic changes of this carotenoid. At levels of lycopene used in our studies with F344 rats, we did not see an activation of phase I enzymes while hepatic quinone reductase (a phase II enzyme) was elevated with short-term lycopene feeding (16). It also appears that lycopene has a high affinity for carotenoid monooxygenase cleavage enzyme II, in vitro, which could result in excentric cleavage of this hydrocarbon, although further in vivo evidence is needed. Mechanisms for the metabolic or oxidative production of lycopene need considerably more study and delineation.
It is concluded that 1) cis isomer forms of lycopene are more bioavailable than is all-trans-lycopene, 2) lycopene accumulation in some tissues is inversely related to androgen status and appears to be inversely related to energy intake, and that 3) tomato carotenoids differentially distribute in tissues of F344 rats. These results clearly demonstrate that all tomato carotenoids cannot be assumed to be absorbed and metabolized the same. Moreover, their absorption and metabolism is affected by hormonal status of the host and perhaps the overall redox state of the tissue.
1 Presented as part of the conference "Promises and Perils of Lycopene/Tomato Supplementation and Cancer Prevention," February 17–18, 2005, Bethesda, MD. This conference was sponsored by the Division of Cancer Prevention, Division of Cancer Epidemiology and Genetics, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Department of Health and Human Services (DHHS); Office of Dietary Supplements (ODS), NIH, DHHS; and the Agricultural Research Services (ARS), USDA. Guest editors for the supplement publication were Cindy D. Davis, NCI, NIH; Johanna Dwyer, ODS, NIH; and Beverly A. Clevidence, ARS, USDA.
2. Boileau, A. C., Merchen, N. R., Wasson, K., Atkinson, C. A. & Erdman, J. W., Jr (1999) Cis-lycopene is more bioavailable that trans-lycopene in vitro and in vivo in lymph-cannulated ferrets. J. Nutr. 129:1176-1181.
3. Clinton, S. K., Emenhiser, C., Schwartz, S. J., Bostwick, D. G., Williams, A. W., Moore, B. J. & Erdman, J. W., Jr (1996) Cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol. Biomark. Prev. 5:823-833.
7. Bhosale, P., Larson, A. J., Frederick, J. M., Southwick, K., Thulin, C. D. & Bernstein, P. S. (2004) Identification and characterization of the Pi isoform of glutathione S-transferase (GSTP1) as a zeaxanthin-binding protein in the macula of the human eye. J. Biol. Chem. 279:49447-49454.
9. Forman, M. R., Beecher, G. R., Muesing, R., Lanza, E., Olson, B., Campbell, W. S., McAdam, P., Raymond, E., Schulman, J. D. & Graubard, B. I. (1996) The fluctuation of plasma carotenoid concentrations by phase of the menstrual cycle: a controlled diet study. Am. J. Clin. Nutr. 64:559-565.
10. Forman, M. R., Johnson, E. J., Lanza, E., Graubard, B. I., Beecher, G. R. & Muesing, R. (1998) Effect of menstrual cycle phase on the concentration of individual carotenoids in lipoproteins of premenopausal women: a controlled dietary study. Am. J. Clin. Nutr. 67:81-87.
12. Boileau, T.W.-M., Clinton, S. K. & Erdman, J. W., Jr (2000) Tissue lycopene concentrations and isomer patterns are affected by androgen status and dietary lycopene concentration in male F344 rats. 2000. J. Nutr. 130:1613-1618.
16. Zaripheh, S., Miksanek, J., Keck, A. S., Jeffery, E. H. & Erdman, J. W., Jr (2005) Does feeding lycopene for different lengths of time result in the activation of phase I and phase II detoxification enzymes in tissues of F344 rats?. FASEB J. 19:3656 (abs.).