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Article

Tissue Distribution of Lycopene in Ferrets and Rats after Lycopene Supplementation¹

Jean Mayer, U.S. Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University, Boston, 02111, and ^* Faculdade de Medicina UNESP, CP 584, Botucatu, SP, 18618–970, Brazil

²To whom correspondence should be addressed.

	ABSTRACT

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To determine lycopene uptake and tissue distribution in ferrets (Mustela putorius furo) and F344 rats, we supplemented orally 4.6 mg/(kg body wt·d) lycopene in a tomato oleoresin–corn oil mixture (experimental groups). After 9 wk of supplementation, the animals were killed and blood and organs were collected. Plasma and tissue carotenoids were extracted and measured using HPLC. Mean concentrations of lycopene (nmol/kg wet tissue) in saponified tissues of ferrets were as follows: liver 933, intestine 73, prostate 12.7 and stomach 9.3. Levels of lycopene (nmol/kg wet tissue) in saponified tissue of rats were as follows: liver 14213, intestine 3125, stomach 78.6, prostate 24 and testis 3.9. When these organs were extracted without saponification, the lycopene levels were lower, except for rat testis. All-trans-lycopene was the predominant isomer found in tomato oleoresin and in the majority of rat tissues, whereas cis-lycopenes were predominant in rat prostate and plasma. This pattern was reversed in ferrets. The results show the following: 1) lycopene from tomato oleoresin is absorbed and stored primarily in the liver of both animals; 2) saponification generally improves the extraction of lycopene from most tissues of both animals; 3) cis-lycopene and all-trans-lycopene are the predominant isomers in ferret and rat tissues, respectively; and 4) rats absorb lycopene more effectively than ferrets.

KEY WORDS: • lycopene • testis • prostate • ferrets • rats

	INTRODUCTION

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Recent interest in lycopene is due to the findings of an inverse association between dietary lycopene and risk for some types of cancer including those of the oral cavity, pharynx, esophagus, stomach, rectum (Franceschi et al. 1994 ), colon (Franceschi et al. 1994 , Narisawa et al. 1998 ), urinary bladder (Helzlsouer et al. 1989 , Okajima et al. 1998 ), prostate (Giovannucci et al. 1995 ) and breast (Zhang et al. 1997 ). Among those organs, prostate and stomach show the strongest inverse relationships (Giovannucci 1999 ).

Processed and fresh tomatoes are the principal dietary sources of lycopene, which is an acyclic carotenoid containing 11 conjugated double bonds arranged in an all-trans configuration (Stahl and Sies 1996 ). The presence of conjugated double bonds plays an important role in quenching singlet oxygen (¹O₂) (Di Mascio et al. 1989 ) and in trapping peroxyl radicals (Burton and Ingold 1984 ). Although lycopene has no provitamin A activity, it exhibits other biological properties such as suppression of cell proliferation of human cancer cells (Levy et al. 1995 ) and induction of gap-junction communication (Zhang et al. 1991 ).

Rats have been used frequently to investigate the absorption and uptake of several carotenoids, including ß-carotene (Ribaya-Mercado et al. 1989 ), lycopene (Zhao et al. 1998 ) and canthaxanthin (Clark et al. 1998 ), but only a few studies have investigated these characteristics in ferrets (Gugger et al. 1992 , Ribaya-Mercado et al. 1989 , Tang et al. 1993 , Wang et al. 1992 ). The sole report of lycopene absorption and uptake was carried out in lymph-cannulated ferrets (Boileau et al. 1999 ). The objective of this study is to compare plasma and tissue distribution of lycopene in male ferrets and rats, after a 9-wk supplementation period.

	MATERIALS AND METHODS

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Chemical products.

All-trans-ß-carotene (type IV), lycopene and ammonium acetate were purchased from Sigma Chemical (St. Louis, MO). Lutein was purchased from Kemin Industries (Des Moines, IA). Zeaxanthin, cryptoxanthin, 13-cis-ß-carotene, 9-cis-ß-carotene and echinenone were kindly provided by Hoffmann-La Roche (Nutley, NJ). Lycopene from tomato oleoresin, Lyc-O-Mato, was a gift from LycoRed Natural Products Industries (Beer-Sheva, Israel). Solutions of carotenoids and retinoids were prepared under red light immediately before use. HPLC-grade methanol and water were obtained from J. T. Baker Chemical (Philipsburg, NJ). Methyl-tert-butyl ether was purchased from Aldrich Chemical (Milwaukee, WI). All HPLC solvents were passed through a 0.45-µm membrane filter and degassed before use. All carotenoid standards were stored at -70°C until used.

Lycopene preparation.

Tomato oleoresin, Lyc-O-Mato 10.4% dewaxed, was mixed with corn oil and stored at -20°C in the dark until used. It contained 13-cis-ß-carotene (<1%), all-trans-ß-carotene (5%) and total lycopene (95%). Of the total lycopene, 93% was in the all-trans form and 7% were cis-lycopene isomers. The tomato oleoresin–corn oil mixture was stirred for 30 min before being fed to the animals. Each milliliter of solution contained 4.6 mg total lycopene. Carotenoids were monitored at 450 nm and confirmed by diode-array spectra, as described by Yeum et al. (1995) . The stability of lycopene in corn oil was checked by HPLC. Lycopene was stable in the tomato oleoresin–corn oil mixture for 9 wk at -20°C and for 2 wk at 4°C.

Animals.

Six male ferrets (Mustela putorius furo), weighing 1300–1650 g and six male F344 rats, weighing 157–173 g were purchased from Marshall Farms (North Rose, NY) and Charles River Breeding Laboratories (Kingston, NY), respectively. The animals were housed for 9 wk in the animal facility at the USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University, and consumed either ferret or rat nonpurified diet³ (Harlan Tekland, Madison, WI) and water ad libitum. The animals were maintained individually in suspended stainless steel cages of appropriate size and their body weights were recorded weekly. Two animals from each group (ferret and rat) were used as controls and received corn oil alone [1 mL/(kg body wt·d)] for 9 wk; four experimental animals from each group received a high dose tomato oleoresin supplement mixed with corn oil [4.6 mg lycopene/(kg body wt·d)] for 9 wk. The animals received the lycopene mixture in corn oil or corn oil alone orally each morning. At the end of the study, under deep isoflurane anesthesia, the animals were killed by puncturing the abdominal aorta; this occurred after 20 h of fasting and 72 h after the last oleoresin or corn oil alone dose so as to minimize contamination of the stomachs and intestines with unabsorbed lycopene. Tissues and plasma were collected and stored at -70°C until analyzed. All animal procedures were reviewed and approved by the HNRCA Animal Care and Use Committee.

Carotenoid analyses of the diets.

To each 10 g diet, 5 mL of H₂O were added and swirled for 1 min. Extraction solution [30 mL; hexane/acetone/ethanol/toluene (50:35:30:35)] was added and swirled for 1 min, followed by 16 h in the dark at room temperature; 4 mL of 40% methanolic KOH and hexane (30 mL) were added and the mixture was left in the dark at room temperature. After 1 h, 10% Na₂SO₄ (30 mL) was added, shaken and left in dark at room temperature. After 1 h, the hexane layer was collected and the volume was recorded. Aliquots of 200 µL were evaporated completely under N₂ and the residue was redissolved in 100 µL ethanol, vortexed and sonicated for 30 s. A 50-µL aliquot of the final extract was injected onto the HPLC system.

Plasma extraction.

A 400-µL aliquot of plasma was used for carotenoid analysis. CHCl₃/CH3OH (3mL; 2:1, v/v), 500 µL of 8.5 g/L saline and 150 µL of internal standard (retinyl acetate and echinonone) were added and the mixture was vortexed and centrifuged for 10 min at 800 x g at 4°C. Hexane (3 mL) was added after the lower layer had been collected. The chloroform and hexane layers were evaporated completely under N₂ and the residue was redissolved in 150 µL ethanol, vortexed and sonicated twice for 30 s. A 50-µL aliquot was used for HPLC analysis.

Tissue preparation and extraction.

Liver, testes (rats) and prostate tissues were harvested, weighed (150–200 g) and homogenized on ice with 150 µL of internal standard (retinyl acetate and echinonone) and 5 mL of CHCl₃/CH₃OH (2:1, v/v) using a Brinkmann (Westbury, NY) Polytron homogenizer. After the addition of 500 µL of 8.5 g/L saline, the mixture was vortexed and centrifuged for 10 min at 800 x g at 4°C. Hexane (3 mL) was added after the lower layer had been collected. The chloroform and hexane layers were evaporated completely under N₂ and the residue was redissolved in 150 µL ethanol, vortexed and sonicated twice for 30 s. Most of the tissues were also analyzed after saponification. The samples (150–200 g) were cut into small slices before the addition of 100 µL (0.095 mol/L) pyrogallol in ethanol, 300 µL (0.5 mol/L) KOH in H₂O and 1 mL ethanol. The mixture was vortexed and incubated at 37°C for 2 h while the tubes were covered by parafilm. After incubation, the samples were cooled to room temperature, 1 mL H₂O was added and the mixture was revortexed. Echinenone in ethanol (100 µL) was added as an internal standard. This mixture was shaken with 3 mL anhydrous ether/hexane (2:1, stabilized with 1% ethanol v/v), then vortexed, and centrifuged at 800 x g at 4°C for 5 min. The upper layer was removed, the extraction repeated and the upper layers were combined. H₂O (2mL) was added, the solution was vortexed and 2 mL ethanol was added before centrifugation at 800 x g for 5 min. The hexane layer was evaporated completely under N₂ and the residue was redissolved in 100 µL of ethanol, vortexed and sonicated twice for 30 s and centrifuged at 800 x g at 4°C for 2 min. A 50-µL aliquot was used for HPLC analysis. All sample analyses were done in duplicate. Because the amount of rat prostate tissue was small, we analyzed only carotenoids from this tissue after saponification. All sampling processing was carried out under red light. The recovery of the added internal standard was consistently >90%.

The stomach and upper half of the intestine were washed with ice-cold isotonic saline (8.5 g/L NaCl) and cut lengthwise. While on ice, the mucosa was gently scraped off with a razor blade and the wet weight was recorded (150–200 g). The mucosal scrapings underwent the same procedures as those described above. To distinguish whether the carotenoid levels found in the intestinal mucosa were from lumenal residues or from intestinal cells, we measured the carotenoid levels in the solution that was used for washing the intestine. The total saline used to wash the ferret intestine was collected and centrifuged at 800 x g for 10 min. The intermediary layer was collected and the upper (fat) and lower (mucosa) layers were discarded. CHCl₃/CH₃OH (4 mL; 2:1, v/v) and 100 µL of internal standard (retinyl acetate and echinonone) were added to a 2-mL aliquot of this intermediary layer. The mixture was vortexed and centrifuged for 10 min at 800 x g at 4°C. Hexane (3 mL) was added for second extraction and chloroform and hexane layers were evaporated completely under N₂.The residue was redissolved in 100 µL ethanol, vortexed and sonicated for 30 s. The carotenoid levels were calculated on the basis of the total volume of saline used to clean the intestine.

HPLC analyses.

The HPLC system consisted of a series 410 LC pump (Perkin-Elmer, Norwalk, CT), a Waters 717 plus autosampler (Millipore, Milford, MA), a C30 carotenoid column (3 µm, 150 x 4.6 mm, YMC, Wilmington, NC), an HPLC column temperature controller (model 7950; column heater/chiller, Jones Chromatography, Lakewood, CO), a Waters 994 programmable photodiode array detector, and a Waters 840 digital 350 data station. The Waters 994 programmable photodiode array detector was set at 340 nm for retinoids and 450 nm for carotenoids. The HPLC mobile phase was methanol/methyl-tert-butyl ether/water (83:15:2, v/v/v, 15 g/L ammonium acetate in the water, solvent A) and methanol/methyl-tert-butyl ether/water (8:90:2, v/v/v, 10 g/L ammonium acetate in the water, solvent B). The gradient procedure, at a flow rate of 1 mL/min (16°C), was as follows: 1) 100% solvent A was used for 2 min followed by a 6-min linear gradient to 70% solvent A; 2) a 3-min hold followed by a 10-min linear gradient to 45% solvent A; 3) a 2-min hold, then a 10-min linear gradient to 5% solvent A; 4) a 4-min hold, then a 2-min linear gradient back to 100% solvent A. Using this method, lutein, zeaxanthin, cryptoxanthin, 13-cis-ß-carotene, all-trans-ß-carotene, 9-cis-ß-carotene, two -cis-lycopenes and all-trans-lycopene were adequately separated. Carotenoids and retinoids were quantified by determining peak areas in the HPLC chromatograms calibrated against known amounts of standards. The amounts were corrected for extraction and handling losses by monitoring the recovery of the internal standards.

Statistical analysis.

Results are expressed as means ± SEM. Comparisons of carotenoid levels in the diets given to the ferrets and rats were made with Student’s t test. Comparisons between the two extraction methods (saponification and nonsaponification) of identical tissues from the experimental groups were calculated by the paired t test. Differences were considered significant at P < 0.05. The significance of differences was calculated using SigmaStat version 2 (Jandel Scientific Software, San Rafael, CA).

	RESULTS

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No lycopene was detected in the diets but the levels of lutein and zeaxanthin were 8 and 6 mg/kg, respectively. Carotenoid levels were similar in ferret and rat diets (P > 0.05). From the tomato oleoresin + corn oil mixture, both species received 0.77, 2.02 and 4.6 mg/(kg body wt · d) of 13-cis-ß-carotene, all-trans-ß-carotene and total lycopene, respectively. Consumption of the lycopene-containing corn oil mixture had no effect on weight gain of either rats or ferrets.

Effect of lycopene supplementation on total lycopene levels in plasma and tissues.

There was no detectable lycopene in the plasma or tissues of the control ferrets or rats. After 9 wk of tomato oleoresin supplementation, the plasma levels of total lycopene reached 22.4 nmol/L in rats and 11.2 nmol/L in ferrets. After tissue saponification, the highest total lycopene levels in rats were found in liver, followed by intestine, with much smaller amounts in the stomach, prostate and testis. In the case of the nonsaponified extract, the total lycopene levels from rat tissues were highest in the liver, followed by intestine, with a much smaller amount in the testis, whereas no lycopene was detectable in stomach. After saponification, the highest total lycopene levels from ferret tissues were found in liver, followed by intestine, with much smaller amounts in the prostate and stomach. The nonsaponified extract of ferret tissue showed the highest levels of total lycopene in liver, with much less in the intestine and very small amounts in the stomach. Lycopene was not detectable in the prostate in the nonsaponified extract (Tables 1 and 2).

Saponification resulted in a tendency to improve the extraction efficiency of all-trans-lycopene from rat intestine (P = 0.06) and a significant improvement in extraction efficiency from the stomach (P < 0.05). However, in the rat testes, saponification decreased all-trans-lycopene extraction (P < 0.05) (Table 1) . All-trans-lycopene was the major isomer identified in saponified liver (79%), intestine (75%), stomach (56%) and testis (62%) of rats. When these organs were extracted without saponification, the all-trans-isomer was the major isomer in liver (72%), intestine (64%) and testis (57%). Cis-lycopene was the major isomer in saponified prostate tissue (85%) and in plasma (70%) after direct extraction.

As observed in rat tissues, saponification of ferret tissues showed an improvement of extraction efficiency of lycopene, which in some tissues proved to be significant (Table 2) . For example, significantly (P = 0.03) greater amounts of cis-lycopene were detected in liver after saponification, and saponification significantly (P < 0.05) increased the yield of both trans- and cis-lycopene in the stomach (Table 2) . For the ferret liver, intestine and stomach, saponification resulted in the appearance of the cis-isomer as the major form of lycopene. In the prostate, where lycopene could be detected only after saponification, the amount of cis-lycopene was only 23%, similar to the amount found in plasma (33%).

Saponified and nonsaponified intestinal extracts from both animal species had high levels of lutein and zeaxanthin. Saponified intestine of ferrets yielded lutein and zeaxanthin levels of ~190 and 230 nmol/kg wet tissue in the control and experimental groups, respectively, whereas the lutein and zeaxanthin levels were ~27 and 38 nmol/L, respectively, in the intestinal wash solutions from these groups. Although carotenoids were not measured in the wash solutions from rats, the mean lutein and zeaxanthin levels (nmol/kg wet tissue) were also high in rat intestine from experimental (333 and 112, respectively) and control groups (254 and 109, respectively). However lycopene, all-trans-ß-carotene and 9-cis-ß-carotene levels were not detected in the intestinal wash solutions used in the experimental and control ferret groups.

	DISCUSSION

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Effect of lycopene supplementation on total lycopene levels in plasma and tissues.

Oral treatment with 4.6 mg lycopene/(kg body wt · d) for 9 wk resulted in the appearance of lycopene in plasma and all tissues studied in both rats and ferrets (Tables 1 and 2) . Ferret plasma contained 11.2 nmol/L total lycopene, 33% of which was present as cis isomers. Boileau et al. (1999) reported the presence of 52% cis isomers in ferret serum 2 h after the intestine was perfused with Lycored in soybean oil (40 mg/kg body wt). In our study, postsupplement rat plasma contained 22.4 nmol/L total lycopene, which is similar to the report of Narisawa et al. (1998) . In that study, serum lycopene levels were < 19 nmol/L in Fischer rats supplemented with either tomato juice [1.7 mg/(kg body wt · d)] or by Lycored [1.8 mg/(kg body wt · d)] added to tap water for 35 wk. However, it is not clear whether this value represents the limit of detection in that study. Another study was not able to detect serum lycopene levels in mice 0–24 h after a single lycopene intraperitoneal administration of 10 mg/kg body wt (Glise et al. 1998 ). In contrast, humans reach peak serum concentrations (>300 nmol/L) 24 and 48 h after consumption of heated tomato juice (Stahl and Sies 1992 ).

The animals were killed 72 h after the last lycopene dose to minimize lycopene residues in the gastrointestinal tract. The low lycopene plasma levels observed in both animal species may be due to the fact that peak absorption had been reached before 72 h. The peak accumulation of lycopene in rat plasma has been reported to occur between 4 and 8 h after a single gavage dose of [¹⁴C] lycopene, and between 8 and 48 h in monkeys, followed by a rapid disappearance (Mathews-Roth et al. 1990 ).

We compared our lycopene supplementation study with a ß-carotene supplementation study [Ribaya-Mercado et al. (1989) ], which found 25-fold higher serum levels of ß-carotene in ferrets (285 nmol/L) than in rats (11.2 nmol/L). In contrast, this study found plasma lycopene levels in ferrets (11.2 nmol/L) were half of those found in rats (22.4 nmol/L) after the same supplementation dose (Tables 1 and 2) . We also detected significantly higher total lycopene levels in rats than in ferrets in saponified liver, intestine, stomach and prostate (Tables 1 and 2) , whereas Ribaya-Mercado et al. (1989) found large amounts of ß-carotene in ferret liver and none in rat liver after ß-carotene supplementation. These differences show that rats absorb lycopene more effectively than ß-carotene, whereas ferrets absorb ß-carotene more effectively than lycopene.

Our findings in tissues are consistent with previous reports in which lycopene supplementation resulted in lycopene accumulation in the livers of rats and only small amounts accumulating in the stomach and testis (Mathews-Roth et al. 1990 ). In a previous study with Fischer rats fed a tomato oleoresin, sevenfold higher liver lycopene levels and 12-fold higher plasma levels were reported (Zhao et al. 1998 ) at a dose of tomato oleoresin that was twice as high as that administered in this study. However, Zhao et al. (1998) added lycopene directly to the diet, whereas we fed corn oil with tomato oleoresin separately from the diet.

Evaluation of saponification on lycopene isomer levels.

With the exception of the rat testes, saponification resulted in a higher extraction efficiency of lycopene isomers from the tissues of both animals (Tables 1 and 2) . All-trans-lycopene was the major isomer detected in the rat tissues, except for the prostate, either by saponification or by direct extraction (Table 1) . Previous reports from human tissues are similar to our findings in rats. Stahl and Sies (1992) suggested that in vivo isomerization mechanisms might result; these could explain why feeding all-trans-lycopene in processed tomato juice resulted in a predominant increase in 9-cis-lycopene in serum. Human autopsy studies have also shown a predominance of all-trans-lycopene in testes and of cis isomers in serum (Stahl et al. 1992 ). On the other hand, Clinton et al. (1996) reported the predominance of cis-lycopene in prostate tissue (benign and malignant) and in serum from patients with prostate cancer.

In marked contrast to rats, ferret tissues had predominantly cis-lycopene in most tissues, whereas all-trans-lycopene was the major isomer in the prostate and plasma (Table 2) . Thus, there are species differences in the ability to absorb and store lycopene in vivo and in the ability to absorb and concentrate the various lycopene isomers in specific tissues. The biological significance of lycopene isomer accumulation in plasma or tissues remains unknown. In agreement with our study, Boileau et al. (1999) reported a predominance of cis-lycopene isomers in serum, in saponified liver and intestinal mucosa of ferrets, after feeding an oral dose of lycopene that contained 91% all-trans-lycopene.

The temperature used in the saponification procedure could cause isomerization of trans-lycopene to cis-lycopene. However, the same predominance of trans-lycopene in tomato oleoresin was detected by both methods, and most tissues showed a consistent isomerization pattern (although species specific) using either method.

Lutein and zeaxanthin levels in intestinal mucosa vs. intestinal wash solution.

The amounts of these carotenoids found in the intestines of rats and ferrets were high in both groups. In addition, lutein and zeaxanthin levels represented 100% of total carotenoids found in the washing solution. After a 20-h fast, we did not expect to find any food in the intestine. However, because high levels of lutein and zeaxanthin (87% of total carotenoids) were detected in the rat and ferret food, it is possible that the high intestinal levels of these carotenoids represent food residues. Alternatively, these carotenoids could be contained in sloughed intestinal epithelial cells.

In conclusion, after consumption of a tomato oleoresin, the liver of rats and ferrets contain the largest amount of lycopene. Saponification improved lycopene extraction efficiency in all tissues of ferrets and rats, with the exception of rat testes. All-trans-lycopene was the predominant isomer found in rat tissue, with the exception of prostate. Cis-lycopene was the predominant isomer found in ferrets, with the exception of prostate and plasma. The high levels of lutein and zeaxanthin found in intestines of all animals are the result of diet residues or sloughed intestinal epithelial cells in the lumen.

	ACKNOWLEDGMENTS

 
The authors would like to thank Guangwen Tang, Jian Qin and Hyunwook Baik for technical assistance and LycoRed Natural Products Industries, Beer-Sheva, Israel, for supplying the tomato oleoresin.

	FOOTNOTES

 
¹ Supported in part by a grant from BASF, Ludwigshafen, Germany and by Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP, São Paulo, SP, Brazil under contract number 97/2502–9, and by the U.S. Department of Agriculture, under agreement number 58–1950-9–001. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

³ Carotenoid composition of ferret and rat diets: each kilogram of diet contained 16.15 mg total carotenoids, 8 mg lutein, 6 mg zeaxanthin, 0.6 mg cryptoxanthin, 0.85 mg all-trans-ß-carotene, 0.7 mg 9-cis-ß-carotene, and undetectable lycopene and 13-cis-ß-carotene.

Manuscript received September 28, 1999. Initial review completed December 20, 1999. Revision accepted January 25, 2000.

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23. Zhang L.-X, Cooney R. V., Bertram J. S. Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H/10T1/2 cells: relationship to their cancer chemopreventive action. Carcinogenesis 1991;12:2109-2114[Abstract/Free Full Text]

24. Zhang S., Tang G., Russell R. M., Mayzel K. A., Stampfer M. J., Willet W. C., Hunter D. J. Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of concentrations in breast cancer cases and control subjects. Am. J. Clin. Nutr. 1997;66:626-632[Abstract/Free Full Text]

25. Zhao Z., Khachik F., Richie J. P., Jr, Cohen L. A. Lycopene uptake and tissue disposition in male and female rats. Proc. Soc. Exp. Biol. Med. 1998;218:109-114[Abstract]

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