![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801
3To whom correspondence should be addressed. E-mail: jwerdman{at}uiuc.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
KEY WORDS: • lycopene • lycopene metabolites • tissue biodistribution • prostate • rats
The carotenoid lycopene (lyc),4 the red pigment in tomatoes, has emerged as a candidate for dietary interventions of prostate cancer (1–5) and cardiovascular disease (6–9). Among the North American population, lyc is often the primary carotenoid in human tissues and serum (10–12). Epidemiologic studies showed that the consumption of lyc-rich foods is inversely related to prostate cancer incidence (4,5,13). It was reported that the consumption of 7–10 servings/wk of tomato products reduced the risk of prostate cancer by 35% compared with consumption of <1.5 servings/wk (4). If substantiated, these findings could affect a large number of individuals because prostate cancer is estimated to affect 1 of 6 men.
In vitro studies provided additional evidence supporting antioxidant (14) and nonantioxidant (15) mechanisms by which lyc may protect the prostate. Lyc is a strong singlet-oxygen quencher; it is 10 times more potent than 
-tocopherol and 2 times more potent than ß-carotene (14). Its ability to efficiently quench singlet oxygen may be associated with its 11 conjugated double bonds. Lyc was also shown to inhibit cell cycle progression from the G0/G1 to the S phase (15), inhibit insulin-like growth factor-1 (IGF-1) (15,16), enhance gap junctional communication via connexin 43 (17), and activate the phase II detoxification enzyme, glutathione transferase (18); all of these may be associated with a decrease in the risk of cancer.
Despite broad interactions between lyc and prostate cancer risk, there has been limited research evaluating the absorption, biodistribution, and metabolism of lyc. Our laboratory previously investigated the time-course biodistribution of a single dose of 14C-lyc over 168 h in rats fed a lyc-containing diet for 30 d before dosing (19). Approximately 7% of the dose was absorbed, the liver was the primary depot for lyc, and 14C was detectable in all measured tissues 3 h after the dose. The results also suggested that a substantial percentage of the radiolabeled lyc in the prostate was metabolized. As a result of these findings, the current study was designed to compare the effects of prefeeding control or lyc-containing diets to rats on the absorption and appearance of polar metabolites, cis and trans isoforms of newly consumed 14C-lyc in tissues. We hypothesized that prefeeding lyc would reduce the absorption of a single 14C-lyc dose and would result in enhanced metabolism and increased production of lyc metabolites compared with control-prefed (CP) rats.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
Diet and 14C-Lyc doses.
Rats consumed an AIN-93G semipurified pelleted control or lyc-enriched diet (0.25 g lyc/kg diet; DYETS) ad libitum throughout the study.5 The composition of the vitamin and mineral mixes was described previously (21). The lyc administered was purified to eliminate impurities, mainly polar products. The purified dose was >98% pure and was composed of 90%, all-trans + 5-cis lyc and 8.4% other cis isomers of lyc. The radioactive lyc dose was prepared by solubilizing 6,7,6',7'-[14C]-lyc and an equivalent amount of nonradioactive lyc in 25 mL of cottonseed oil for a final specific activity of 2775 kBq/mg lyc as detailed earlier (19). Each rat was administered 421.8 kBq of 14C-lyc, which provided 0.152 mg total lyc (including 14C-lyc and nonradioactive lyc). Rats consumed 
8 mg lyc/d from the diet, which provided a daily lyc intake that was 50 times greater than that provided in the dose. A medium-sized raw tomato (100 g) contains 3 mg of lyc; thus, the amount of lyc consumed daily from the diet was 2.7 tomatoes, and the amount of lyc dosed was equivalent to about a slice of a tomato.
Preparatory HPLC method. The HPLC system used to purify and quantitate the 14C dose was comprised of a Waters 991 PDA detector (Millipore), a Rainin Dynamics gradient pump system model SD-200, a Varian Prostar model 210, and a YMC C30 Preparatory 10- x 250-mm column. The separation of all-trans-lyc, other cis-lyc, and polar impurities was accomplished using a modified method described by Yeum et al. (22). The modified gradient procedure had a flow rate of 4.73 mL/min. It was monitored from 250 to 550 nm and had the following gradient: 10% B held for 8.33 min, 20 min linear gradient to 65% B, 20 min linear gradient to 95% B, 1.7 min hold at 95% B, 1.7 min linear gradient to 10% B, and 5.3 min hold at 10% B for a final time of 57 min. The cis and trans isomers of lyc present in the 14C-dose were collected into a glass vial for purification and then dried in a Speedvac concentrator (model AS160; Savant).
Animals and study design. The University of Illinois Laboratory Animal Care and Use Committee approved the animal protocol and all principles of laboratory care were followed. Male F344 rats (n = 48) were purchased from Harlan. Rats were housed individually in wire-bottomed cages in a controlled facility and were acclimated to their new environment. At 40 d of age, rats were assigned to 4 groups (n = 12) based on body weight (113 ± 2 g). They were weighed and provided with fresh AIN-93G control or AIN-93G lyc-enriched diet (0.25 g lyc/kg) (23) every other day for 30 d. Treatment groups were assigned as follows: 1) control diet for 30 d and killed 5 h after the 14C dose; 2) control diet for 30 d and killed 24 h after the 14C dose; 3) lyc diet for 30 d and killed 5 h after the 14C dose; 4) lyc diet for 30 d and killed 24 h after the 14C dose. At 70 d of age, rats weighed 254 ± 7 g; they were deprived of food for 6 h and then orally intubated with a single dose of 421.8 kBq of 14C -lyc solubilized in 0.5 mL cottonseed oil. Immediately after dosing, rats were placed in metabolic cages to facilitate urine and feces collection at 3, 6, and 24 h and were provided with their respective diets. Termination procedures (CO2 asphyxiation), tissue collection, and storage methods were followed as previously described (19).
Analysis of total 14C in tissues, serum, and feces. Total 14C in tissues, serum, and feces was measured as described previously (19).
Analytical method for quantifying nonradioactive and radioactive chemical forms of lyc and lyc metabolites. The HPLC-PDA system was used to measure the nonradiolabeled lyc concentrations in tissue and serum samples as previously described (19,22,24). A ß-ram online radioactive detector was placed in series with an HPLC-PDA, which allowed for measurement of 14C-lyc and 14C-labeled products. The analytical HPLC analysis was identical to the preparatory HPLC method, except that an analytical YMC C30 column (4.6 x 50 mm) was used. The gradient method was followed as described by Yeum et al. (22). The ß-ram method included mixing 3 mL/min of Biosafe II with the eluent from the HPLC system (1 mL/min) and collecting radioactivity data every 6 s for a total of 38 min/sample. To maximize accuracy and reliability for recovery of radioactivity in the testes and serum, 2 samples within groups were pooled, resulting in a sample size of 6. For analysis of nonradioactive lyc in the prostate, adrenals, and seminal vesicles, 6 rats/group were pooled, resulting in a sample size of 2. The 2 samples for each tissue were analyzed individually for lyc using HPLC, and the eluent for the 2 samples was collected into the same vial in 30-s intervals, resulting in a sample size of 1 for radioactive analysis of the prostate, adrenals, and seminal vesicles using an external scintillation counter. Serum total radioactivity was calculated by assuming that serum accounts for 5.46 g/100 g total body weight (25).
Assignment of all-trans, cis-lyc and 14C-labeled products. Standards, spectra, and literature were used to identify the HPLC peaks (20,22,23,26,27). Peaks were combined into the following 3 groups: hexane soluble polar products (1–5.5 min); other cis isomers, such as 9-, 13-, and 15-cis lyc (20.5–26 min); and all-trans + 5-cis lyc (27–30 min).
Statistical analysis.
The experiment was conducted as a post-hoc 2 x 2 factorial arrangement of treatments with 2 diets (control or lyc) and 2 times (5 or 24 h). The method of statistical analysis used was multiple linear regression in which the full model consisted of the main effects and interaction effects. The following regression equation was used: 
= B0 + B1 (time) + B2 (diet) + B3 (time x diet). The data were log10 transformed when the homogeneity of variance assumption was violated. If the interaction term was not significant at P < 0.05, it was removed and the model equation used was = B0 + B1 (time) + B2 (diet). The model, main effects, and interactions were considered significant when P 
0.05. In addition, to assess the differences between dietary groups at a specific time point, t tests were performed where indicated in the text, and differences were considered significant when P < 0.05. Due to the small weight of tissues, prostate, adrenal, and seminal vesicles were pooled within groups for quantification of nonradioactive lyc (n = 2) or radioactive lyc (n = 1) for each tissue; thus statistical analysis could not be performed for these tissues. Values are means ± SEM.
|
RESULTS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
Accumulation of nonradiolabeled lyc in liver, prostate and serum.
As early as 5 h, all tissues in both LP and CP rats contained measurable lyc. Serum total lyc increased over time in both dietary groups (Table 1); however, the concentration was greater in LP rats than in CP rats, irrespective of time (P < 0.05). The hepatic lyc concentration in CP rats was significantly less than in the LP rats, irrespective of time (P 0.05). Hepatic lyc increased from 5 to 24 h in CP rats (P 0.05) but not in LP rats (Table 1).
|
Elimination of radioactivity from rats was primarily through the feces, with a minor portion eliminated through urine. The total radiolabel excreted did not differ between the dietary groups at either time point (data not shown). Within the first 24 h, 12 and 10% of the 14C dose was excreted from the body through feces in the LP and CP rats, respectively. The percentage of the 14C dose excreted through urine was 0.088 ± 0.009 and 0.091 ± 0.0087% in LP and CP rats, respectively. We assumed that all of the 14C in urine was absorbed and metabolized 14C-labeled metabolic products.
Total radioactivity in the gastrointestinal tract, serum, and tissues. The gastrointestinal (GI) tract was divided into the stomach wall, small intestinal wall, cecum, large intestinal wall, stomach contents, small intestinal contents, and large intestinal contents. Total radioactivity (T-rad) in each section of the GI-tract wall (Table 2) changed over time; i.e., it decreased in the stomach and increased in the cecum and large intestine. The concentration of T-rad in the stomach contents of LP rats was greater (P < 0.01) than that of CP rats, irrespective of time. When both time points were considered, CP rats contained more T-rad/L in the large intestinal contents (P < 0.002) than LP rats.
|
All extrahepatic tissues examined contained measurable amounts of T-rad at both time points, but the concentrations varied depending on the tissue and time (Table 2). Diet affected the distribution of T-rad in the spleen, heart, and hindbrain in that CP rats had more T-rad than LP rats, irrespective of time (P < 0.05). Although the 14C in the spleen increased from 5 to 24 h in both dietary groups (P < 0.05), CP rats had more T-rad at 24 h than LP rats (P < 0.02, t test).
At 5 h after dosing, levels of T-rad in the prostate, adrenals, and seminal vesicles were low but detectable in both groups (Fig. 1). Although the seminal vesicles were at least 3 times larger in size than the prostate and adrenals, the T-rad/g in the prostate and adrenal was at least 2 times greater than the T-rad in the seminal vesicles.
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
The following can be concluded from the data presented: 1) the surfeit of lyc in the GI tract and in tissues of LP rats resulted in decreased absorption of a single oral dose of 14C; 2) prefeeding lyc resulted in differential concentrations of 14C, and to a lesser extent of 14C-lyc isomers or 14C-polar products in tissues; and 3) compared with other tissues, there was a percentage increase in the 14C-polar products in the prostate and seminal vesicles, suggesting increased accumulation of 14C-polar products in these tissues, irrespective of prior dietary treatment. In addition, these data along with findings from the previous study (19) suggest that extrahepatic tissues take up 14C-lyc from the postprandial triglyceride-rich lipoprotein (TRL) fraction.
We evaluated total 14C in tissues by solubilizing tissue samples with tissue solubilizer to measure T-rad (Table 2). In addition, we evaluated the hexane-soluble extract from tissues, serum, and feces to enable us to focus on the lyc and hexane-soluble lyc metabolites. For example, 67% of the T-rad in the liver of LP rats was accounted for in the hexane extract (data not shown), and hexane-soluble compounds in the feces of LP and CP rats accounted for only 10 and 27% of the total, respectively. Separation and analysis of more 14C-polar products from the ethanol:water extract was not carried out.
Differential concentrations of T-rad among tissues.
Prefeeding lyc resulted in differential concentrations of radioactivity in the small intestinal mucosa, spleen, heart, and hindbrain, and LP rats contained less radioactivity than CP rats. Of the postabsorptive tissues analyzed, the liver and spleen contained the greatest concentration of T-rad/g, irrespective of diet. The liver weight was considerably higher than that of the spleen (16 times greater in this study); thus, T-rad was much greater in whole-liver tissue. The differential uptake of lyc into tissues is likely due to both LDL receptor–dependent (10,12) and LDL receptor–independent pathways, as seen with -tocopherol.
-Tocopherol tissue uptake is affected by the presence of scavenger receptor class B type 1 (SR-B1). SR-B1 is responsible for selective uptake of lipids into tissues (29); it is highly concentrated in human and rat liver and in steroidogenic tissues (29,30). In SR-B1–deficient mice, -tocopherol uptake into the testes, ovary, lung, and brain was increased but the -tocopherol uptake into the liver, spleen, kidney, and adipose tissue was reduced (31). This suggests that the selective tissue uptake of -tocopherol may be the result of 2 separate pathways, and the predominant pathway for uptake is dependent on tissue type. These findings are interesting because in the current study, the liver, spleen, kidney, and androgen-dependent tissues were the tissues most highly concentrated with T-rad, which suggests selective uptake of T-rad into tissues, potentially mediated through 2 separate pathways (SR-B1 and LDL receptor).
The observed concentration differences in tissues may also suggest the presence of a lyc-binding protein. Carotenoids such as ß-carotene, lutein, and zeaxanthin were thought to utilize a binding and/or transport protein for absorption and/or uptake into tissues (32–37). Although a binding protein specific to lyc has not yet been verified, it is plausible that one exists, which could explain the preferential uptake of 14C in some tissues of CP rats.
Accumulation of hexane soluble 14C-polar metabolites of lyc in the prostate and seminal vesicles in the 2 treatment groups. Interestingly, the percentage of 14C-polar products increased over time in the prostate and seminal vesicles, whereas the total concentration of 14C-lyc + 14C-polar products decreased, irrespective of diet (note that these were pooled samples due to small tissue weights). This suggests an increased accumulation of 14C-polar products in the prostate and seminal vesicles, but not in the liver or mucosal cells, where the percentage of 14C-polar products was unchanged over time. The 14C-lyc + 14C-polar products also decreased in the adrenals in both groups, but the percentage of 14C-polar products, which was already high, did not change.
We previously reported that polar products of 14C-lyc appeared in the prostate of rats prefed lyc for 30 d as early as 3 h after the single oral dose (19). We suggested that in addition to the singlet-oxygen quenching capacity of intact lyc, the 14C-polar products in the prostate may act at the gene level to modulate the expression of androgen-related genes (19). A recent publication indirectly supported this hypothesis by demonstrating that after 60 d of lyc feeding to Copenhagen rats, there was depressed expression of several androgen-metabolizing enzymes, IGF-I, and a number of basal inflammatory signals in the prostate compared with control-fed rats (38). Although the authors of that study did not suggest that the observed transcriptional changes were a result of lyc metabolites, we suggest that transcriptional regulation is more likely to occur as a result of lyc metabolites than intact lyc. The lyc concentration in the total rat prostate tissue in their study (38) was 0.46 nmol/g, essentially identical to that in the current study (0.43 nmol/g at 24 h).
Uptake of 14C from triglyceride-rich fractions into extrahepatic tissues. Within the enterocyte of the small intestine, lyc is incorporated into the chylomicrons and VLDL (TRL fraction) and then secreted into the lymph system for transportation into the bloodstream (39). Upon entering the bloodstream, the activation of lipoprotein lipase results in the delipidation of the TRL fraction, before the uptake of chylomicron remnants by the liver. It was suggested that before hepatic uptake, carotenoids may be partially taken up by extrahepatic tissues during delipidation and passage through extrahepatic tissues (40).
The monitoring of carotenoids in the postprandial TRL has been a valuable tool with which to study the relative bioavailability and bioefficacy of carotenoids such as dietary ß-carotene and newly formed retinol (41). Research showed that lyc is most concentrated in the postprandial TRL at 6 h in humans (42) and between 4 and 8 h in rats (43). Newly absorbed lyc is repackaged in the liver as VLDL and LDL and peaks in serum at 24–27 h in humans (42,44) and 24 h in rats (43). Because lyc is primarily in the postprandial TRL between 4 and 8 h in rats, the presence of 14C in tissues as early as 3 h [the previous study, (19)] and 5 h (the current study) strongly supports the hypothesis that TRL delivers a portion of the newly absorbed lyc to the extrahepatic tissues. Preliminary kinetic analysis using compartmental modeling of lyc absorption, distribution, and elimination in rats from our earlier study (19) suggests transport of lyc directly from TRL to extrahepatic tissues such as lung, adipose, adrenal, heart, kidney, testes, and prostate (45).
Lyc degradation products formed during freezer storage were shown to activate the antioxidant response element (ARE) in vitro (46), which suggests that metabolic products of lyc may also activate the ARE and potentially activate phase II detoxification enzymes (46). Furthermore, a potential lyc metabolite, acyclo-retinoic acid, was shown to activate the transcription of a retinoic acid receptor (47), a receptor responsible for modulating numerous target genes. The results from our biodistribution studies [(19) and current study] and molecular-based studies (38,46,47) support the theory that lyc and lyc metabolites may play a role in reducing the risk of prostate cancer by modulating the expression of relevant genes.
Our findings lead us to conclude that routine consumption of lyc decreases absorption and thus the accumulation of 14C from a single oral dose of 14C-lyc in most tissues. These data also support our earlier observation (19) that extrahepatic tissues can take up 14C from the postprandial TRL fraction. The relative accumulation of 14C-polar products and/or the rate of metabolism of 14C-lyc was greater in the prostate, seminal vesicles, and adrenals than in other tissues, regardless of dietary treatment. These results indirectly suggest that the absorption of 14C, 14C-lyc, and 14C-polar products is a facilitated mechanism. Interestingly, we observed that androgen-dependent tissues and the spleen [related to immune function (10,12,48)] tended to have high concentrations of lyc. Ongoing research in our laboratory includes studies designed to identify lyc metabolites formed in vivo and to determine which enzymes are responsible for the observed catabolism of lyc.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
2 This material is based on work supported by the Initiative for Future Agriculture and Food Systems/U.S. Department of Agriculture under Award no. 00–52101-9695. Any opinions, findings, conclusions or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the USDA.
4 Abbreviations used: ARE, antioxidant response element; 14C, 14C-lycopene; CP rats, control-prefed rats; GI, gastrointestinal tract; IGF-1, insulin-like growth factor-1; lyc, lycopene; LP rats, lycopene-prefed rats; PDA, photodiode array; SR-B1, scavenger receptor class B type 1; T-rad, total radioactivity; TRL, triglyceride-rich lipoprotein.
5 Composition of modified AIN-93G purified placebo- and lycopene-containing diets are described as (g/kg diet): 200 g casein, 379.83 g cornstarch, 115.75 g dextrose, 100 g sucrose, 50g cellulose, 100 g soybean oil, 0.02 g t-butylhydroquinone, 35 g salt mix #2100251, 10 g vitamin mix # 3100251, 3 g L-cystine and 1.4g choline chloride. The placebo diet also included 5 g placebo beadlets which are identical in composition to the lycopene beadlets but do not contain lycopene. The lycopene-containing diet included 5 g of lycopene beadlets which are composed of 5 g lycopene/100 g beadlets. The vitamin and mineral mix compositions are described in (21).
Manuscript received 2 March 2005. Initial review completed 29 March 2005. Revision accepted 30 May 2005.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
1. Boileau, T. W., Liao, Z., Kim, S., Lemeshow, S., Erdman, J. W., Jr & Clinton, S. K. (2003) Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J. Natl. Cancer Inst. 95:1578-1586.
2. Bowen, P., Chen, L., Stacewicz-Sapuntzakis, M., Duncan, C., Sharifi, R., Ghosh, L., Kim, H. S., Christov-Tzelkov, K. & van Breemen, R. (2002) Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp. Biol. Med. 227:886-893.
3. Clinton, S. K. (1998) Lycopene: chemistry, biology, and implications for human health and disease. Nutr. Rev. 56:35-51.[Medline]
4. Giovannucci, E., Ascherio, A., Rimm, E. B., Stampfer, M. J., Colditz, G. A. & Willett, W. C. (1995) Intake of carotenoids and retinol in relation to risk of prostate cancer. J. Natl. Cancer Inst. 87:1767-1776.
5. Giovannucci, E., Rimm, E., Liu, Y., Stampfer, M. J. & Willett, W. C. (2002) A prospective study of tomato products, lycopene, and prostate cancer risk. J. Natl. Cancer Inst. 94:391-398.
6. Arab, L. & Steck, S. (2000) Lycopene and cardiovascular disease. Am. J. Clin. Nutr. 71:1691S-1695S discussion 1696S–1697S.
7. Rissanen, T. H., Voutilainen, S., Nyyssonen, K., Lakka, T. A., Sivenius, J., Salonen, R., Kaplan, G. A. & Salonen, J. T. (2001) Low serum lycopene concentration is associated with an excess incidence of acute coronary events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br. J. Nutr. 85:749-754.[Medline]
8. Rissanen, T., Voutilainen, S., Nyyssonen, K. & Salonen, J. T. (2002) Lycopene, atherosclerosis, and coronary heart disease. Exp. Biol. Med. 227:900-907.
9. Ruiz Rejon, F., Martin-Pena, G., Granado, F., Ruiz-Galiana, J., Blanco, I. & Olmedilla, B. (2002) Plasma status of retinol, alpha- and gamma-tocopherols, and main carotenoids to first myocardial infarction: case control and follow-up study. Nutrition 18:26-31.[Medline]
10. Schmitz, H. H., Poor, C. L., Wellman, R. B. & Erdman, J. W., Jr (1991) Concentrations of selected carotenoids and vitamin A in human liver, kidney and lung tissue. J. Nutr. 121:1613-1621.
11. 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.[Abstract]
12. Kaplan, L. A., Lau, J. M. & Stein, E. A. (1990) Carotenoid composition, concentrations, and relationships in various human organs. Clin. Physiol. Biochem. 8:1-10.
13. Giovannucci, E. (1999) Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J. Natl. Cancer Inst. 91:317-331.
14. Di Mascio, P., Kaiser, S. & Sies, H. (1989) Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch. Biochem. Biophys. 274:532-538.[Medline]
15. Karas, M., Amir, H., Fishman, D., Danilenko, M., Segal, S., Nahum, A., Koifmann, A., Giat, Y., Levy, J. & Sharoni, Y. (2000) Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. Nutr. Cancer 36:101-111.
16. Siler, U., Barella, L., Spitzer, V., Schnorr, J., Lein, M., Goralczyk, R. & Wertz, K. (2004) Lycopene and vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model. FASEB J. 18:1019-1021.
17. Livny, O., Kaplan, I., Reifen, R., Polak-Charcon, S., Madar, Z. & Schwartz, B. (2002) Lycopene inhibits proliferation and enhances gap-junction communication of KB-1 human oral tumor cells. J. Nutr. 132:3754-3759.
18. Breinholt, V., Lauridsen, S., Daneshvar, B. & Jakobsen, J. (2000) Dose-response effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat. Cancer Lett. 154:201-210.[Medline]
19. Zaripheh, S., Boileau, T. W., Lila, M. A. & Erdman, J. W., Jr (2003) [14C]-lycopene and [14C]-labeled polar products are differentially distributed in tissues of F344 rats prefed lycopene. J. Nutr. 133:4189-4195.
20. Britton, G., Liaaen-Jensen, S. & Pfander, H. (1995) [14C]-lycopene and [14C]-labeled polar products are differentially distributed in tissues of F344 rats prefed lycopene. Carotenoids: Spectroscopy Birkhauser Verlag Basel, Switzerland.
21. Reeves, P. G., Nielsen, F. H. & Fahey, G. C., Jr. (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J. Nutr. 123:1939-1951.
22. Yeum, K. J., Booth, S. L., Sadowski, J. A., Liu, C., Tang, G., Krinsky, N. I. & Russell, R. M. (1996) Human plasma carotenoid response to the ingestion of controlled diets high in fruits and vegetables. Am. J. Clin. Nutr. 64:594-602.
23. Boileau, T. W., 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. J. Nutr. 130:1613-1618.
24. Boileau, T. W., Boileau, A. & Erdman, J. W., Jr (2002) Bioavailability of all-trans and cis-isomers of lycopene. Exp. Biol. Med. 227:914-919.
25. Lombardi, B. & Oler, A. (1967) Choline deficiency fatty liver. Protein synthesis and release. Lab. Investig. 17:308-321.[Medline]
26. Khachik, F., Bernstein, P. S. & Garland, D. L. (1997) Identification of lutein and zeaxanthin oxidation products in human and monkey retinas. Investig. Ophthalmol. Vis. Sci. 38:1802-1811.
27. Boileau, T. W., Clinton, S. K., Zaripheh, S., Monaco, M. H., Donovan, S. M. & Erdman, J. W., Jr (2001) Testosterone and food restriction modulate hepatic lycopene isomer concentrations in male F344 rats. J. Nutr. 131:1746-1752.
28. Rissanen, T., Voutilainen, S., Nyyssonen, K., Salonen, R. & Salonen, J. T. (2000) Low plasma lycopene concentration is associated with increased intima-media thickness of the carotid artery wall. Arterioscler. Thromb. Vasc. Biol. 20:2677-2681.
29. Acton, S., Rigotti, A., Landschulz, K. T., Xu, S., Hobbs, H. H. & Krieger, M. (1996) Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science (Washington, DC) 271:518-520.[Abstract]
30. Landschulz, K. T., Pathak, R. K., Rigotti, A., Krieger, M. & Hobbs, H. H. (1996) Regulation of scavenger receptor, class B, type I, a high density lipoprotein receptor, in liver and steroidogenic tissues of the rat. J. Clin. Investig. 98:984-995.[Medline]
31. Mardones, P., Strobel, P., Miranda, S., Leighton, F., Quinones, V., Amigo, L., Rozowski, J., Krieger, M. & Rigotti, A. (2002) Alpha-tocopherol metabolism is abnormal in scavenger receptor class B type I (SR-BI)-deficient mice. J. Nutr. 132:443-449.
32. Hollander, D. & Ruble, P. E., Jr (1978) ß-Carotene intestinal absorption: bile, fatty acid, pH, and flow rate effects on transport. Am. J. Physiol. 235:E686-E691.
33. Amano, O., Kanda, T., Ono, T. & Iseki, S. (1992) Immunocytochemical localization of rat intestinal 15 kDa protein, a member of cytoplasmic fatty acid-binding proteins. Anat. Rec. 234:215-222.[Medline]
34. Bhosale, P., Larson, A. J., Frederick, J. M., Southwick, K., Thulin, C. D. & Bernstein, P. S. (2004) Identification and characterization of a 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.
35. Jouni, Z. E. & Wells, M. A. (1996) Purification and partial characterization of a lutein-binding protein from the midgut of the silkworm Bombyx mori. J. Biol. Chem. 271:14722-14726.
36. Lakshman, M. R. & Rao, M. N. (1999) Purification and characterization of cellular carotenoid-binding protein from mammalian liver. Methods Enzymol. 299:441-456.[Medline]
37. Tabunoki, H., Sugiyama, H., Tanaka, Y., Fujii, H., Banno, Y., Jouni, Z. E., Kobayashi, M., Sato, R., Maekawa, H. & Tsuchida, K. (2002) Isolation, characterization, and cDNA sequence of a carotenoid binding protein from the silk gland of Bombyx mori larvae. J. Biol. Chem. 277:32133-32140.
38. Herzog, A., Siler, U., Spitzer, V., Seifert, N., Denelavas, A., Buchwald Hunziker, P., Hunziker, W., Goralczyk, R. & Wertz, K. (2005) Lycopene reduced gene expression of steroid targets and inflammatory markers in normal rat prostate. FASEB J. 19:272-274.
39. Williams, A. W., Boileau, T. W. & Erdman, J. W., Jr (1998) Factors influencing the uptake and absorption of carotenoids. Proc. Soc. Exp. Biol. Med. 218:106-108.[Medline]
40. van den Berg, H. & van Vliet, T (1998) Effect of simultaneous, single oral doses of beta-carotene with lutein or lycopene on the beta-carotene and retinyl ester responses in the triacylglycerol-rich lipoprotein fraction of men. Am. J. Clin. Nutr. 68:82-89.[Abstract]
41. van Vliet, T., Schreurs, W. H. & van den Berg, H. (1995) Intestinal beta-carotene absorption and cleavage in men: response of beta-carotene and retinyl esters in the triglyceride-rich lipoprotein fraction after a single oral dose of beta-carotene. Am. J. Clin. Nutr. 62:110-116.
42. Diwadkar-Navsariwala, V., Novotny, J. A., Gustin, D. M., Sosman, J. A., Rodvold, K. A., Crowell, J. A., Stacewicz-Sapuntzakis, M. & Bowen, P. E. (2003) A physiological pharmacokinetic model describing the disposition of lycopene in healthy men. J. Lipid Res. 44:1927-1939.
43. Mathews-Roth, M. M., Welankiwar, S., Sehgal, P. K., Lausen, N. C., Russett, M. & Krinsky, N. I. (1990) Distribution of [14C]canthaxanthin and [14C]lycopene in rats and monkeys. J. Nutr. 120:1205-1213.
44. Gustin, D. M., Rodvold, K. A., Sosman, J. A., Diwadkar-Navsariwala, V., Stacewicz-Sapuntzakis, M., Viana, M., Crowell, J. A., Murray, J., Tiller, P. & Bowen, P. E. (2004) Single-dose pharmacokinetic study of lycopene delivered in a well-defined food-based lycopene delivery system (tomato paste-oil mixture) in healthy adult male subjects. Cancer Epidemiol. Biomark. Prev. 13:850-860.
45. Novotny, J. A., Zaripheh, S. & Erdman, J. W., Jr (2004) Compartmental modeling of 14C-lycopene in the F344 rat. FASEB J. 18:A157 (abs.).
46. Ben-Dor, A., Steiner, M., Gheber, L., Danilenko, M., Dubi, N., Linnewiel, K., Zick, A., Sharoni, Y. & Levy, J. (2005) Carotenoids activate the antioxidant response element transcription system. Mol. Cancer Ther. 4:177-186.
47. Ben-Dor, A., Nahum, A., Danilenko, M., Giat, Y., Stahl, W., Martin, H. D., Emmerich, T., Noy, N., Levy, J. & Sharoni, Y. (2001) Effects of acyclo-retinoic acid and lycopene on activation of the retinoic acid receptor and proliferation of mammary cancer cells. Arch. Biochem. Biophys. 391:295-302.[Medline]
48. Porrini, M., Riso, P. & Testolin, G. (1998) Absorption of lycopene from single or daily portions of raw and processed tomato. Br. J. Nutr. 80:353-361.[Medline]
This article has been cited by other articles:
|
|
 |
|
  K. Canene-Adams, B. L. Lindshield, S. Wang, E. H. Jeffery, S. K. Clinton, and J. W. Erdman Jr. Combinations of Tomato and Broccoli Enhance Antitumor Activity in Dunning R3327-H Prostate Adenocarcinomas Cancer Res., January 15, 2007; 67(2): 836 - 843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gajic, S. Zaripheh, F. Sun, and J. W. Erdman Jr. Apo-8'-Lycopenal and Apo-12'-Lycopenal Are Metabolic Products of Lycopene in Rat Liver J. Nutr., June 1, 2006; 136(6): 1552 - 1557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zaripheh, T. Y. Nara, M. T. Nakamura, and J. W. Erdman Jr. Dietary Lycopene Downregulates Carotenoid 15,15'-Monooxygenase and PPAR-{gamma} in Selected Rat Tissues J. Nutr., April 1, 2006; 136(4): 932 - 938. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
