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Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801 and * Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Division of Hematology and Oncology, The Ohio State University, Columbus, OH 43210-1240
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • lycopene • testosterone • rats • prostate cancer
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The consumption of lycopene-rich
foods as well as greater concentrations of blood lycopene are
associated with a decrease in prostate cancer risk (Gann et al. 1999
, Giovannucci et al. 1995
,
Giovannucci 1999
). Additionally, lycopene is found in
the human prostate, suggesting the biological plausibility of a direct
effect of this carotenoid on prostate function and carcinogenesis.
Furthermore, our studies show that lycopene exists in the serum and
prostate as an array of 10–15 different isomers (Clinton et al. 1996
). The dietary and biological factors that influence the
pattern of cis-isomers found in blood and tissues or their
relevance to disease processes remain to be determined.
The mechanisms by which lycopene may alter prostate cancer risk remain
unknown. In vitro studies suggest that lycopene is a potent antioxidant
(Di Mascio et al. 1989
) and enhances expression of
gap-junction proteins involved in cell-cell communication
(Zhang et al. 1992
). Furthermore, little is known about
factors influencing lycopene absorption, metabolism and distribution to
tissues in humans and experimental animals. The laboratory rat is a
commonly used model for evaluation of dietary and endocrine effects on
transplantable and/or carcinogen-induced prostate carcinogenesis
(Clinton et al. 1988
and 1997
, McCormick et al. 1998
and 1999
, Mukherjee et al. 1999
, Rao et al. 1999
). To examine efficiently the epidemiologic
associations between lycopene and prostate cancer in rodent models, the
dietary lycopene content that provides tissue lycopene concentrations
and isomer patterns similar to humans must first be established.
Androgens are critical to normal prostate growth, differentiation and
function; they also contribute to prostate carcinogenesis. Interruption
of androgen metabolism by either surgical or pharmacologic means are
primary treatments for hormone-dependent prostate cancer in humans
(Aquilina et al. 1997
). Androgens also play a key role
in regulation of many metabolic systems (Gustafsson et al. 1983
) and therefore could potentially influence lycopene
metabolism.
The purpose of this study was to examine the effects of androgen status and dietary lycopene content as well as their interaction on tissue lycopene accumulation and isomer patterns in male F344 rats.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Intact male F344 rats (n = 44) and male F344 rats
(n = 44) castrated at 5 wk of age (before sexual
maturity) were obtained from Harlan (Indianapolis, IN). Four pelleted
experimental diets were prepared by Research Diets (New Brunswick, NJ)
using 10% water-dispersible lycopene beadlets and/or placebo
beadlets containing 0.0% lycopene (Hoffmann La Roche, Basel,
Switzerland) (Table 1
). The four diets contained the following dietary levels of lycopene:
0.00, 0.05, 0.50 and 5.00 g/kg. Rats consumed nonpurified diet (Teklad
22–5 MRH diet, Harlan Teklad, Madison, WI) until 14 wk of age, when 11
intact and 11 castrated rats were randomly assigned to each of the four
experimental diets and fed for 8 wk. Rats were provided fresh diet 3
times/wk to minimize carotenoid degradation. Diets were stored at 4°C
and in the dark. Rats were weighed weekly and food intakes measured.
After 8 wk of feeding, all rats were anesthetized with 0.1 mL/100 kg
body weight ketamine/xylazine (95:5) and blood was sampled by cardiac
puncture. Rats were killed by CO2 asphyxiation and the
liver, adrenals, kidneys, lungs and adipose tissue were collected from
all rats. Testes and prostates were also collected from intact rats.
Tissues were cooled rapidly on ice, protected from light and stored at
-20°C for lycopene analysis. Blood was allowed to coagulate for 30
min and then spun at 250 x g for 10 min to allow
for serum separation. Serum was stored at -20°C for analysis. All
animal procedures were approved by the University of Illinois Animal
Care Advisory Committee.
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Approximately 0.1 g of tissue was minced thoroughly, dissolved in 6 mL of a KOH/ethanol (1:5) solution containing 1 g/L BHT and vortexed. Tissues were saponified at 60°C for 30 min. Carotenoids were extracted twice under yellow lights using equal volumes of hexane (6 mL) plus 2 mL distilled water. Extracts were dried down in a Speedvac concentrator (Savant model AS160, Farmingdale, NY) and stored at -20°C for no longer than 2 d before HPLC analysis.
Serum cis-trans lycopene extraction.
Ethanol (0.5 mL) containing 100 g/L BHT was added to 0.5 mL serum and vortexed. Sera were extracted twice under yellow lights using 1.0 mL hexane. Extracts were dried and stored as described above.
HPLC analysis of cis-trans lycopene.
HPLC analysis was performed on a Rainin Dynamax gradient pump system
model SD-200 (Woburn, MA) using a C-30 "carotenoid column" (YMC,
Wilmington, NC) and a Rainin Dynamax UV-visible dual wavelength
detector (model UV-DII, Walnut Creek, CA), monitoring at 472 nm.
The gradient and mobile phases were used as previously described
(Yeum 1996
). Briefly, mobile phase A (A)
consisted of an 83:15:2 mixture of methanol:tert-butyl-methyl-ether:15
g ammonia acetate/L water. Mobile phase B (B) consisted of an 8:90:2
mixture of methanol:tert-butyl-methyl-ether:15 g ammonia acetate/L
water. Pumps were programmed to perform the following gradient with a
flow rate of 1 mL/min: 5 min at 90% A, 10% B, a 12-min linear
gradient to 55% A, 45% B, 12-min linear gradient to 95% B, 5% A, a
5-min hold at 95% B, 5% A, and a 2-min gradient back to 90% A, 10%
B. Standard curves were prepared using crystalline lycopene extracted
from a tomato oleoresin (Lycored, Natural Industries, Beer Sheva,
Israel) and purified on a YMC C-30 column. Lycopene was quantitated
using an external standard curve, plotting lycopene peak area vs.
nanograms lycopene injected into the HPLC machine. This laboratory
participates quarterly in the National Institutes of Standards in
Technology micronutrient measurement proficiency testing program. The
CV for lycopene analysis is <12%.
Statistics.
Differences in mean tissue lycopene levels and
cis-trans lycopene isomer ratios between
groups were analyzed by two-way ANOVA with main effects of
androgens status and dietary lycopene level and their interaction. When
significant tests were found (P < 0.05), group
differences were analyzed further by the post-hoc Fisher’s
Protected Least Squares Difference (PLSD) test (Carmer and Swanson 1973
) (Statview, Brain Power, Calabasas, CA). Data with
unequal variances were log transformed and reanalyzed by ANOVA and
Fisher’s PLSD. All data are expressed as the original untransformed
values for ease of interpretation.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All rats gained weight throughout the study (Fig. 1
). At the time of assignment to lycopene-containing diets, castrated
rats weighed 19 ± 2% less than intact rats (P < 0.001). Weight gain during the lycopene feeding period (8 wk) was 35
± 5 g for castrated rats and 59 ± 6 g for intact
rats. Food intake during that period was 10 ± 3 g/d for castrated
rats and 13 ± 3 g/d for intact rats (P < 0.05).
However, when expressed relative to body weight, castrated [5.6
± 1.2 g food/(100 g body weight · d)] and intact rats
[5.4 ± 1.1 g food/(100 g body weight · d)] were not
different. Food intake of rats consuming lycopene-containing diets
did not differ from that of rats consuming placebo beadlet diets.
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The three lycopene-containing diets did not differ in trans-cis lycopene isomer profiles or ratios (all diets contained 56–57% cis lycopene isomers). Beadlets contained 32% cis-lycopene, whereas diets contained 57% cis-lycopene, with the two major isomers in beadlets and diet being all-trans lycopene and 5-cis lycopene. Two to four other cis-lycopene isomers were detected in beadlets and diet and were grouped as "other cis." Diet preparation from beadlets results in an increase in the relative amount of the 5-cis lycopene isomer.
Tissue lycopene.
Lycopene was not detected in any tissue from rats fed the diet without
lycopene. Lycopene (trans- + cis-lycopene
isomers) concentration significantly (ANOVA P < 0.01;
main effect of dietary lycopene concentration) increased in liver of
both intact and castrated rats as dietary lycopene concentration
increased from 0 to 0.50 g/kg (Table 2
). Liver lycopene did not differ between rats fed 0.50 and 5.00 g/kg
lycopene. The increase in hepatic total lycopene was due primarily to
an increase in the 5-cis isomer (Table 3
). Representative HPLC chromatograms of livers from rats fed the three
different dietary lycopene concentrations are shown in Figure 2
. The two major lycopene isomers detected were 5-cis and
all-trans lycopene. Three to five additional
cis-lycopene isomers were also detected and grouped as
"other cis." Liver total cis-lycopene (mean
± SD of castrated and intact rats combined) was 66
± 2% for rats fed 0.05 g/kg, 71 ± 2% for rats fed 0.50
g/kg and 83 ± 2% for those fed 5.00 g/kg. This increase in liver
cis-lycopene with the increase in dietary lycopene was
observed in both intact and castrated rats. Adrenal, lung, adipose,
kidney, testes, prostate and serum all exhibited similar
dose-dependent accumulations of lycopene (Table 4
) (ANOVA P < 0.01; main effect of dietary lycopene
concentration). Liver of both castrated and intact rats accumulated
greater quantities of lycopene than other tissues. Adrenal accumulated
~90% less than liver, but 100-fold more than other extrahepatic
tissues (Table 4)
.
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. In extrahepatic tissues and serum, the percentage
of lycopene present as cis-isomers was higher in rats fed
5.00 g/kg lycopene compared with rats fed 0.05 or 0.50 g/kg in both
intact and castrated rats (Table 5
).
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Castrated rats accumulated twice the (ANOVA P < 0.01;
significant main effect of androgen status) hepatic lycopene as
compared to intact controls (Table 2)
. No differences in the lycopene
concentration were observed in extrahepatic tissues (prostate and
testes not examined) between intact and castrated rats (Table 4)
.
Castrated rats had a higher proportion (P < 0.05) of
hepatic total cis-lycopene isomers than intact rats at all
dietary levels. Significant interactions between dietary lycopene
concentration and androgen status were observed for hepatic lycopene
concentration (ANOVA P < 0.01; interaction of androgen
status and dietary lycopene content). No significant interactions were
seen for any variables measured in extrahepatic tissues or serum.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animal studies to elucidate biological effects of lycopene are limited
in part due to a lack of knowledge concerning the absorption,
metabolism and tissue distribution of lycopene. Because rats absorb
carotenoids less efficiently than humans (Lee et al. 1999
), it is necessary to determine the amount of dietary
lycopene required to achieve tissue concentrations similar to those of
humans. A clear dose-response for tissue lycopene concentration was
observed as dietary lycopene increased from 0 to 0.05 to 0.50 g/kg
(P < 0.01) lycopene in both intact and castrated rats.
However, no difference in lycopene concentration was seen between rats
fed 0.50 and 5.00 g/kg lycopene. These data suggest that tissue
lycopene reaches a plateau between 0.05 and 0.50 g/kg dietary lycopene
when incorporated into the diet as 10% water-dispersible lycopene
beadlets. Similarly, serum lycopene increased as dietary lycopene
increased from 0 to 0.50 g/kg. No further increase in serum lycopene
was observed in rats fed 5.00 g/kg, suggesting that the plateau in
serum lycopene is accompanied by a similar plateau in tissue lycopene.
Other studies examining the accumulation of lycopene in rat tissues are
similar to this study. Mathews-Roth et al. (1990)
have
shown the liver to be the major site of lycopene accumulation in rats
after a single dose of 14C lycopene. Zhao and co-workers (1998)
demonstrated that lycopene
accumulated in liver and extrahepatic tissues of male and female F344
rats in a dose-response manner when incorporated into the diet as a
tomato oleoresin. When lycopene (0.48 g/kg) was fed to female F344 rats
for 10 wk, rats accumulated 119 nmol lycopene/g liver as measured by
HPLC. This is similar to the concentrations of lycopene (146 nmol/g)
found in livers of castrated male rats fed 0.50 g/kg lycopene in this
study. No data were reported for liver lycopene in male rats. Lycopene
concentration of the prostate (0.18 nmol/g) and lung (0.39 nmol/g) of
intact male rats fed the 0.48 g/kg lycopene diet in the study of
Zhao et al. (1998)
were also very similar to prostate
(0.22 nmol/g) and lung (0.37 nmol/g) lycopene levels of intact rats in
this study.
Tissue lycopene concentrations achieved in this study are in the range
of those reported for humans. For example, analyses of human liver at
autopsy have reported lycopene concentrations ranging from 0.2 to 4.5
nmol/g (Kaplan et al. 1990
), from 0.0 to 20.7 nmol/g
(Schmitz et al. 1991
) and from 0.1 to 4.1 nmol/g
(Stahl et al. 1992
) in three independent studies. In
this study, intact rats consuming 0.05 and 0.50 g/kg dietary lycopene
for 8 wk accumulated hepatic lycopene within the ranges reported for
humans. Human prostate lycopene concentrations range from 0.0 to 1.7
nmol/g (Clinton et al. 1996
). Intact rats consuming 0.05
to 0.50 g/kg dietary lycopene had prostate lycopene within the range
observed in human prostate. Similarly, the concentration of lycopene
achieved in rat lung (0.32 nmol/g) is similar to that in humans (0.6
nmol/g) (Schmitz et al. 1991
). These data suggest that
tissue lycopene concentrations in rats fed lycopene beadlets are
similar to those reported in humans. The rat may be a useful model to
study lycopene metabolism in vivo and mechanisms by which lycopene may
modify biological outcomes. However, relatively high dietary
concentrations have been fed to rats in this study to achieve tissue
concentrations similar to those of humans. Lycopene intakes in human
populations have been estimated to be ~2.0 mg/d (Nebeling 1997
). Rats in this study fed 0.5 g lycopene/kg diet were
consuming ~10 mg/d, but weigh only 0.200 kg compared with the average
human weighing ~75 kg. Therefore, rats appear to achieve tissue
concentrations in the range of what is observed in humans when lycopene
is fed at relatively high concentrations.
Androgen status and lycopene metabolism.
In this study, castrated rats accumulated approximately two times as
much (P < 0.01) liver lycopene as compared to intact
controls at all dietary lycopene concentrations. This occurred even
with lower total lycopene intake (20 ± 5% less food per day) by
castrated rats. Interestingly, the effect of castration was not
significant in serum or extrahepatic tissues. This finding suggests
that androgens alter hepatic lycopene metabolism. Castration decreases
the activities of several liver enzymes via the pituitary-growth
hormone axis (Gustafsson et al. 1983
). However, at this
point, no liver enzymes for which lycopene is thought to be a substrate
have been characterized. Other possible explanations for the effect of
castration include the following: alterations in lipoprotein metabolism
and hepatic LDL receptor activity, effects on lycopene absorption
and hepatic uptake of chylomicrons, alterations of lipoprotein
lipase activity and uptake of lycopene by extrahepatic tissues on first
pass, and reduced hepatic lycopene catabolism and excretion.
Interestingly, extrahepatic tissue and serum lycopene concentrations
were not altered significantly by castration in this short-term
study. However, it is possible that androgens may influence blood and
extrahepatic tissue concentrations under conditions in which dietary
intake is variable (such as human populations), unlike this study in
which intake was stable. If dietary intake is variable, perhaps liver
stores have a more profound influence on serum lycopene levels and
hence accumulation of lycopene by extrahepatic tissues. Because
androgens are critically involved in prostate carcinogenesis, it is of
etiologic interest that androgens may modulate lycopene metabolism and
tissue accumulation. Our work suggests that lycopene and androgens
should be examined together in epidemiologic, clinical and rodent
studies on prostate carcinogenesis.
Lycopene isomers.
Serum and tissue cis-lycopene isomers existed as an array of
5–7 different isomers as measured by our HPLC methodology. Both intact
and castrated rats accumulated significantly (P < 0.01) more liver cis-lycopene as total dietary lycopene
concentration increased. This occurred despite the fact that diets did
not differ in cis- and trans-lycopene isomer
profiles. In serum and extrahepatic tissues, cis-lycopene
was significantly higher (P < 0.01) in the groups fed
5.00 and 0.50 g/kg than in those fed 0.05 g/kg lycopene. Castration
increased the proportion (P < 0.05) of
cis-lycopene isomers in liver. It has been hypothesized that
cis-lycopene isomers are more bioavailable than the
all-trans form. This hypothesis was supported recently using
lymph-cannulated ferrets. When ferrets were fed lycopene (<10%
was cis-lycopene), lymph contained nearly 80%
cis-isomers of lycopene (Boileau et al. 1999
), suggesting that cis-lycopene isomers are more
soluble in mixed micelles compared with the all-trans form
and are therefore taken up more easily by the intestine and absorbed
into the circulation. This observation may be related to work showing
that cis-isomers of carotenoids are less likely to form
crystals than their all-trans counterparts (Britton 1995
).
The biological relevance of specific lycopene isomers is not known at
this time. However, humans tend to accumulate a wide array of
cis-lycopene isomers in both serum and tissues even though
dietary lycopene is mainly in the all-trans configuration
(Clinton 1998
). The possibility that isomers represent
participation in specific antioxidant reactions requires investigation.
Levin and co-workers (1997)
have shown
9-cis ß-carotene to be a more effective antioxidant than
its all-trans counterpart, suggesting that
cis-isomers of carotenoids may indeed be better
antioxidants. It is also possible that isomerization is nonspecific and
secondary only to chemical instability at body temperature.
In summary, we report that feeding lycopene incorporated into the diet as water-dispersible beadlets over the range of 0 to 0.50 g/kg results in dose-dependent serum and tissue lycopene concentrations in male F344 rats. Tissue concentrations achieved are similar to those reported for humans. The percentage of lycopene as cis-isomers in serum and tissues increased as dietary lycopene increased. Furthermore, the removal of testicular androgens by castration increased hepatic lycopene concentration and the percentage of liver lycopene present as cis-isomers. The effects of androgens on lycopene metabolism and tissue accumulation warrant further investigation relative to prostate cancer etiology and prevention.
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FOOTNOTES |
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Manuscript received October 8, 1999. Initial review completed December 20, 1999. Revision accepted February 18, 2000.
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 H. L. Hantz, L. F. Young, and K. R. Martin Physiologically Attainable Concentrations of Lycopene Induce Mitochondrial Apoptosis in LNCaP Human Prostate Cancer Cells Experimental Biology and Medicine, March 1, 2005; 230(3): 171 - 179. [Abstract] [Full Text] [PDF]
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S. Zaripheh, T. W.-M. Boileau, M. A. Lila, and J. W. Erdman Jr [14C]-Lycopene and [14C]-Labeled Polar Products Are Differentially Distributed in Tissues of F344 Rats Prefed Lycopene J. Nutr., December 1, 2003; 133(12): 4189 - 4195. [Abstract] [Full Text] [PDF]
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 T. W.-M. Boileau, Z. Liao, S. Kim, S. Lemeshow, J. W. Erdman Jr., and S. K. Clinton Prostate Carcinogenesis in N-methyl-N-nitrosourea (NMU)-Testosterone-Treated Rats Fed Tomato Powder, Lycopene, or Energy-Restricted Diets J Natl Cancer Inst, November 5, 2003; 95(21): 1578 - 1586. [Abstract] [Full Text] [PDF]
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K. Wu, S. J. Schwartz, E. A. Platz, S. K. Clinton, J. W. Erdman Jr., M. G. Ferruzzi, W. C. Willett, and E. L. Giovannucci Variations in Plasma Lycopene and Specific Isomers over Time in a Cohort of U.S. Men J. Nutr., June 1, 2003; 133(6): 1930 - 1936. [Abstract] [Full Text] [PDF]
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L. A. Cohen A Review of Animal Model Studies of Tomato Carotenoids, Lycopene, and Cancer Chemoprevention Experimental Biology and Medicine, November 1, 2002; 227(10): 864 - 868. [Abstract] [Full Text] [PDF]
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C. W. Hadley, E. C. Miller, S. J. Schwartz, and S. K. Clinton Tomatoes, Lycopene, and Prostate Cancer: Progress and Promise Experimental Biology and Medicine, November 1, 2002; 227(10): 869 - 880. [Abstract] [Full Text] [PDF]
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T. W.-M. Boileau, A. C. Boileau, and J. W. Erdman Jr Bioavailability of all-trans and cis-Isomers of Lycopene Experimental Biology and Medicine, November 1, 2002; 227(10): 914 - 919. [Abstract] [Full Text] [PDF]
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L. Chen, M. Stacewicz-Sapuntzakis, C. Duncan, R. Sharifi, L. Ghosh, R. v. Breemen, D. Ashton, and P. E. Bowen Oxidative DNA Damage in Prostate Cancer Patients Consuming Tomato Sauce-Based Entrees as a Whole-Food Intervention J Natl Cancer Inst, December 19, 2001; 93(24): 1872 - 1879. [Abstract] [Full Text] [PDF]
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T. W.-M. Boileau, S. K. Clinton, S. Zaripheh, M. H. Monaco, S. M. Donovan, and J. W. Erdman Jr. Testosterone and Food Restriction Modulate Hepatic Lycopene Isomer Concentrations in Male F344 Rats J. Nutr., June 1, 2001; 131(6): 1746 - 1752. [Abstract] [Full Text]
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