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* Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801 and Mass Spectrometry Center, School of Chemical Sciences, University of Illinois, Urbana, IL 61801
3 To whom correspondence should be addressed: E-mail: jwerdman{at}uiuc.edu.
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ABSTRACT |
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max = 473 nm and m/z = 417). The putative compound, apo-12'-lycopenal, was detected but no apo-10'-lycopenal was present. A number of other very polar, short-chain and/or short chromophore compounds with UV/VIS absorption <300 nm were present but were not characterized. These data show that lycopene is cleaved in vivo by rats at different positions to produce apo-12'-lycopenal, and other unidentified metabolites in addition to apo-8'-lycopenal. Apo-8'-lycopenal and the putative apo-12'-lycopenal are identified as lycopene metabolites in rat liver in vivo.
KEY WORDS: • lycopene • lycopene metabolites • apo-8'-lycopenal • apo-12'-lycopenal • rats
Lycopene, a nonprovitamin A carotenoid has attracted much attention for its possible role in disease prevention, especially cancer. A number of epidemiologic studies showed that higher serum lycopene concentrations are inversely related to prostate cancer risk (1–3), and lycopene was suggested to play a role in preventing cardiovascular disease (4–7). In vitro studies demonstrated that lycopene inhibited neoplastic cell growth in lung (8,9), prostate (10,11) endometrial (8), and HL-60 leukemic cells (12,13). Several hypotheses to explain the mechanisms of action were proposed. Lycopene is the most potent antioxidant in vitro among various carotenoids and can trap singlet oxygen and reduce mutagenesis (14). Lycopene was reported to suppress insulin-like growth factor (IGF)4-stimulated tumor cell proliferation (15), enhance gap junctional communication (16), and inhibit tumor cell growth by induction of cell cycle arrest and induction of apoptosis (17). However, the mechanism(s) by which lycopene exhibits its biological functions are not completely understood.
A number of studies investigated the in vivo metabolism and biotransformation of ß-carotene but little has been reported for lycopene. The first reported lycopene metabolites in humans were 5,6-dihydroxy-5',6'-dihydrolycopene (18) and 2,6-cyclolycopene-1,5-diol A and B (19). Apo-10'-lycopenoic acid was also found to be a lycopene metabolite in ferret lung tissue (20). Several in vitro chemical oxidation studies produced lycopene oxidation products to elucidate possible metabolites in vivo (21–23). A number of oxidative and cleavage products were formed, most of which were series of carbonyl homologs of different chain lengths.
In vivo and in vitro studies with ß-carotene established the plausibility for in vivo production of apolycopenals in biological systems. It was demonstrated that several ß-apocarotenals were formed from ß-carotene in the intestinal mucosal cells of rats and chickens in vivo (24,25). Incubation of ß-carotene with liver, kidney, lung, and fat homogenates from humans, monkeys, ferrets, and rats resulted in the appearance of ß-apocarotenals and retinoids (26). There is also an unresolved question whether lycopene is a substrate for carotenoid monoxygenase (CMO) I (27,28) or whether it is cleaved excentrically by CMO II. Kiefer et al. (29) cloned CMO II from mice and determined extensive cleavage of ß-carotene at the 9',10' double bond to yield a ß-apo-10'-carotenal and ß-ionone. They also transformed mouse CMO II into Escherichia coli genetically engineered to produce lycopene and found production of lycopenals. The identification of lycopene metabolites in vivo will provide evidence to resolve whether lycopene may be a substrate for CMO I or CMO II.
Our laboratory previously studied rats that were prefed lycopene and then intubated with a singe oral dose of 14C-lycopene (30). The livers from these rats were extracted and analyzed for the presence of lycopene metabolites. The goal of this work was to determine whether apolycopenals are in vivo metabolites of lycopene in rat liver, as predicted from the in vitro studies (29).
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MATERIALS AND METHODS |
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8 mg/d of lycopene. The dose provided 0.152 mg lycopene (both 14C-lycopene and nonradioactive lycopene) which was 2% of the daily lycopene intake in the lycopene-fed group. Rats and study design. The same rats and study design as described earlier (30) were used for this study.
Hepatic lycopene. Livers of the rats that were lycopene-prefed and killed at 5 and 24 h after the dose were used for analysis of lycopene metabolites because of the expected highest lycopene concentration (31). The samples were extracted as described previously (30,31).
HPLC analyses on C30 column. Lycopene and metabolites were analyzed using reverse-phase HPLC. The system consisted of a 2-pump system, a Rainin Dynamics gradient pump, model SD-200) and a Varian Prostar pump, model 210, a C30 4.6 x 150 mm YMC "carotenoid column" (YMC), an HPLC Column Cooler (Model 250; Thomson Instrument Company), a Waters 991 photodiode array detector (Millipore), and Waters Millennium software. A ß-ram online radioactive detector was placed in series with HPLC-photodiode array (PDA) for monitoring of the 14C radioactivity. A modified method described by Yeum et al. (32) was used. The same mobile phases with a modified gradient method were utilized for tissue analysis. The gradient procedure at a flow rate of 1 mL/min was as follows: 90% solvent A and 10% solvent B for 5 min followed by a 12-min linear gradient to 35% A and 65% B, a 12-min linear gradient to 95% B and 5% A, a 5-min hold at 95% B and 5% A, a 2-min gradient back to 90% solvent A and 10% solvent B and a 2-min hold at 90% A and 10% B. The column temperature was set at 18°C for tissue analysis. The detector was set at 340, 450, and 472 nm so that both shorter and/or more polar as well as longer and/or less polar lycopene metabolites could be observed. Compounds of interest were isolated by first collecting the appropriate fraction of HPLC eluate from several liver extracts. Fractions were then combined, dried under the stream of nitrogen, flushed with argon and stored at –20°C overnight. The next day, the samples were reconstituted in 150 µL of ethanol and analyzed by MS.
ESI-MS analysis of standards and lycopene metabolites. Mass spectrometry characterization of the standards and compounds of interest from liver extracts was performed by ionization/ion trap electrospray (ESI)-MS. An LCQ Deca XP (2001, Thermo Electron) mass spectrometer with ESI source and ion trap was used for analyses. ESI was performed in the positive mode. The system was optimized for the maximum signal intensity of molecular ions. High-purity nitrogen was used as the sheath and auxiliary gas. The other main parameter settings were: sheath flow gas, 50 L/min; auxiliary gas flow, 20 L/min; ESI capillary temperature, 250°C; ion spray voltage, 5 kV; and capillary voltage, 37 V. All spectra were obtained in the positive ion mode over a mass range of m/z 150–2000.
HPLC analysis on C18 column. To obtain further separation of compounds eluting from the C30 HPLC column, 4 eluate fractions from the C30 column were collected: fraction I (0–5 min), fraction II (5–10 min), fraction III (10–15 min) and fraction IV (15–20 min). Fractions from 5 HPLC runs (from a total liver sample of 1.5 g), were collected, combined, and dried under a stream of nitrogen, parafilmed, and stored overnight at –20°C. A Pecosphere-3 C18 0.46 x 8.3 cm cartridge column (Perkin-Elmer) was used for further separation of fractions I–IV. HPLC analyses were accomplished using a method described by dos Anjos Ferreira et al. (23).
LC/ESI-MS analysis of C30 fractions. For the LC/ESI-MS analysis of the C30 fractions, livers were extracted and analyzed by HPLC analysis on a C30 column as described above. The 4 fractions as for HPLC analysis on a C18 column were collected. The samples were dried under nitrogen, parafilmed, and stored at –20°C overnight. Fractions were redissolved in 150 µL of ethanol, and a 20-µL aliquot was analyzed by ESI/LC-MS the next day. The same C18 column and gradient method were used as described above for the C18 column. The mobile phase was ACN:H2O:formic acid (5:95:0.1, by vol, solvent A) and ACN:H2O:formic acid (95:5:0.1, by vol, solvent B). The mass spectrometer and conditions for the LC-MS were the same as for the MS analysis.
FD-MS analysis of all-trans plus 5-cis lycopene peak.
For the MS analysis of the all-trans plus 5-cis lycopene peak, 5 liver samples (1.5 g of tissue total) were extracted and analyzed by C30 HPLC (described above). The 29–31 min fraction from each sample was collected; the fractions were combined together and analyzed by MS using the field desorption technique (FD). A Micromass 70-VSE double focusing mass spectrometer (Waters) was used. Experimental conditions were as follows: extraction element temperature was 110°C, extraction voltage = 4 kV, accelerator voltage = 8 kV, emitter current of 15–20 mA.
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RESULTS |
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2% of the mean daily nonradioactive lycopene intake. As a result, for the MS analysis, we looked for the metabolites with a predominant peak that corresponded to the nonradioactive molecular weight. HPLC and radioactivity profile. The identification of lycopene metabolites was accomplished by separation of HPLC followed by radioactivity detection and either ESI-MS or ESI/LC-MS analysis. Peaks obtained by HPLC analysis were compared with the apolycopenal and apolycopenoic acid standards. In addition, we synthesized several apolycopenol standards by reduction of apolycopenals with sodium borohydride (NaBH4) into corresponding alcohols, i.e., apo-8'-lycopenol, apo-10'-lycopenol, apo-12'-lycopenol, and acycloretinol. We obtained a C30 reverse-phase HPLC analysis of the typical liver extract from a lycopene-prefed rat that was dosed with radioactive-labeled lycopene [Fig. 3B) (472 nm) and C (340 nm)]. The radioactivity profile of 14C-labeled lycopene and its metabolites of the same liver extract is shown in Figure 3D. The all-trans and 5-cis isomer of lycopene eluted at 29–32 min and other cis isomers of lycopene elute between 20 and 29 min (Figs. 3A-C). The radioactivity profile of the same liver shows all-trans and 5-cis lycopene eluting at 32–35 min and other cis isomers of lycopene emerging at 23–32 min (Fig. 3D). The 3-min shift of the retention times in the radioactive profile is due to the time required for the eluant to travel from the PDA detector through the ß-ram detector. The majority of lycopene metabolites eluted at 1–6 min when monitored on a PDA detector (Fig. 3B and C) or at 4–9 min when monitored on the ß-ram detector (Fig. 3D). These most polar metabolites absorbed strongly at <300 nm and were present in substantial amounts in the liver 24 h after the dose. Other, less polar products eluted at 6–20 min (PDA detector, Fig. 3B) or 9–23 min (ß-ram detector, Fig. 3D). Unidentified polar products could not be separated completely and clear UV/VIS spectra could not be resolved. We collected the fraction I (0–5 min), attempted to further separate peaks on a C18 column, but were unable to obtain clearly resolved peaks; thus, mass spectra could not be obtained.
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Peak identification by HPLC. One of the peaks eluting from the C30 column showed the retention time and a UV spectrum with absorption essentially identical to that of apo-8'-lycopenal. Retention time of the apo-8'-lycopenal standard was 17.7 min on the C30 column, whereas the unknown peak had a retention time of 17.6 min on the same column. UV/VIS spectra for apo-8-lycopenal standard and the unknown lycopene metabolite are shown in Figure 4A and B. To obtain molecular mass of an unknown peak, that particular fraction from the HPLC chromatogram was collected and dried under N2 and analyzed using MS.
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No apo-10'-lycopenal, apo-10'-lycopenol, or apo-10'-lycopenoic acid was detected in the liver of rats prefed diets containing lycopene. In addition, no apo-8'-lycopenol and no apo-12'-lycopenol was detected in rat livers. It is possible, based on the retention times of the standards, that acycloretinol and acycloretoinic acid were present in the first polar fraction (0–5 min) that could not be completely separated.
Identification of apo-8'-lycopenal by ESI-MS. Mass detection was performed using low-resolution ESI as described above. The molecular weight of the apo-8'-lycopenal standard is 416 and the ESI-MS analysis showed a dominant pseudomolecular ion [M+H]+ at m/z 417 (Supplemental Figure 1). ESI-MS analysis of the collected fraction of an unknown compound generated 3 pseudomolecular ions; the most abundant peak (100%) was at m/z 539.4, the second most abundant peak (90% of the most abundant peak 539.4) was at m/z 417.3, and the third most abundant peak (87% of the most abundant peak 539.4) was at m/z 298.9 (data not shown). It was obvious even from the C30 HPLC chromatogram that the compound with the retention time and UV/VIS spectra similar to the apo-8'-lycopenal standard was not completely pure and that there were other compounds eluting at the same time; thus it was expected that other contaminants were present. To substantiate the presence of apo-8'-lycopenal in liver, we further separated that portion of the chromatogram. Liver samples were again subjected to reverse-phase HPLC analysis in which 4 fractions were collected (as described above) and analyzed by ESI-LC/MS. Putative apo-8'-lycopenal, RT = 17.7, was collected in fraction IV (15–20 min on C30 column).
Identification of apo-8'-lycopenal using UV/VIS and ESI-LC/MS.
Apo-8'-lycopenal standard and fractions collected from the C30 column were analyzed using positive ion ESI-LC/MS. In this system set-up, the complete separation of the compounds eluting at the same time as putative apo-8'-lycopenal in fraction IV was obtained. Structural assignment of the unknown compound was confirmed by comparison of the retention times, mass spectra of the apo-8'-lycopenal standard and of an unknown peak and was supported by the information obtained from the photodiode array spectra collected before the mass spectrometer. The ESI-LC/MS analysis of fraction IV produced numerous peaks. The MS and UV/VIS spectra of the compound in fraction IV, with the same retention time as the apo-8'-lycopenal standard, is shown in Supplemental Figure 2. The parameters for the apo-8'-lycopenal standard and putative apo-8'-lycopenal were as follows: apo-8'-lycopenal standard: retention time = 26.9 min, max = 465 nm and m/z = 417 (data not shown). Putative apo-8-lycopenal: retention time = 26.8 min, max = 465 nm and m/z = 417 (Supplemental Figure 2).
14C radioactivity analysis of the collected and purified putative apo-8'-lycopenal fraction from the C30 column (Fig. 3B) showed that this compound was radioactive (data not shown). We estimated from the radioactivity profile (Fig. 3D) that identified apo-8'-lycopenal accounts for 2% of all lycopene metabolites and 0.75% of the total radioactivity in the liver extract.
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DISCUSSION |
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It was shown that there is an inverse relation between the intake of lycopene-rich food and prostate cancer (1–3) and the risk of cardiovascular disease (4–6,37). The mechanisms by which lycopene influences health have not yet been elucidated. It is possible that lycopene metabolite products, rather than the intact molecule, may act at the gene level to modulate the expression of relevant genes and function as anticancer agents. It was reported that a mixture of oxidation products of lycopene induced apoptosis in HL-60 cells during incubation for 24 h (38). Acyclo-retinoic acid, the centrally cleaved metabolite of lycopene, reduced cell viability by inducing apoptosis in human prostate cancer cells (39). A lycopene oxidation product (2,7,11-trimethyl-tetradecahexaene-1,14-dial) enhanced gap junctional communication in rat liver epithelial WB-F344 cells (40).
In this paper, we examined whether apolycopenals are the in vivo metabolic products of lycopene as predicted from the in vitro studies (29). A number of lycopene metabolites were present in the F344 rat liver. We identified and characterized apo-8'-lycopenal and the putative apo-12'-lycopenal as in vivo metabolic products of lycopene in rat liver.
The metabolites present in the greatest quantities in the liver of lycopene prefed rats were very polar, short-chain and/or short-chromophore compounds. The radioactivity profile (Fig. 3D) showed the highest radioactivity (in addition to radioactive lycopene and its isomers) eluting between 4 and 9 min, which would correspond with the most polar compounds. The PDA profile of this peak (Fig. 3A) showed that it contained a mixture of compounds and had UV/VIS absorbance <300 nm, suggesting that the lycopene chromophore had either been very shortened by the cleavage of the molecule or had been disrupted by hydrogenation or some other atom addition. It is noteworthy that when apo-8'-lycopenal or apo-12'-lycopenal are produced from (6, 7, 6', 7')-14C-radioactive labeled lycopene, short compounds with two 14C-atoms (6' and 7' position) are the expected cleavage products. These compounds may contribute to the early eluting polar fraction. Further separation and identification of these short, polar lycopene metabolites is required and will clearly contribute to better understanding of lycopene metabolism in vivo.
A lycopene metabolite, associated with radioactivity eluted at 17.7 min from the C30 column, was identified as apo-8'-lycopenal. The retention time matched and the UV/VIS spectrum was very similar to that of the apo-8'-lycopenal standard. The 7.3-nm difference in maximum absorptions of UV/VIS spectra of metabolite and apo-8'-lycopenal standard may be explained by the presence of small amounts of several other compounds with similar UV/VIS spectra, thus shifting the peak apex. When the same peak was collected and further purified on a C18 column, complete separation was achieved and the retention time and UV/VIS spectrum of the major metabolite precisely matched that of the apo-8'-lycopenal standard (data not shown). ESI-LC/MS analysis of that particular fraction of the eluate confirmed that it was indeed apo-8'-lycopenal. Further confirmation that identified apo-8'-lycopenal as a lycopene metabolite product came from radioactivity analysis of the collected apo-8'-lycopenal fraction from the HPLC. 14C-radioactivity was detected in the HPLC eluent of the apo-8'-lycopenal from 0.9 g of liver tissue. The radioactivity of the collected apo-8'-lycopenal was >2 times higher than the radioactivity of the background (data not shown).
Evidence is provided that apo-12'-lycopenal was also present in the rat liver. Comparison of the UV/VIS spectra of identified apo-8'-lycopenal and putative apo-12'-lycopenal in the same liver extract showed that the putative apo-12'-lycopenal was present in the same or even greater quantities than apo-8'-lycopenal. We estimated that 250 ng of apo-8'-lycopenal was present in 1 g of liver tissue, which is 235-fold less than the concentration of lycopene.
A number of studies showed that lycopene undergoes degradation under oxidative conditions in vitro (21–23). Many oxidative products were formed, most of which were apolycopenals. These authors hypothesized that lycopene can be unselectively cleaved at any double bond position in nonenzymatic manner when organisms are subjected to oxidative stress.
It is likely that apo-8'-lycopenal and apo-12'-lycopenal are produced by a carotenoid cleavage enzyme. It is not yet clear whether lycopene is a substrate for carotene 15,15'-oxygenase (CMO I). Some in vitro studies reported that lycopene was not a substrate for CMO I (28), whereas other studies showed that it can be cleaved by CMO I in vitro when lycopene is present in higher concentrations than ß-carotene (27). It was shown in studies on ß-carotene metabolism that the apocarotenals present in the animal's liver undergo both oxidation and reduction to the corresponding acids and alcohols (41), and the presence of small quantities of apo-8'-lycopenol and apo-12'-lycopenol might be expected. If present, those compounds were in very low concentrations and we could not detect them. The results of our study showed that, in addition to apo-8'-lycopenal and apo-12'-lycopenal, the majority of lycopene metabolites were short, polar products, some of which were likely residues after apo-8'-lycopenal and apo-12'-lycopenal cleavage from lycopene; they could also possibly be secondary lycopene metabolites. It is possible that the turnover rate of apo-8'-lycopenal and apo-12'-lycopenal to secondary metabolites (corresponding acids/alcohols and shorter-chain metabolites) is very high, which would explain the small amounts of apolycopenals present in rat liver. Although low, these concentrations of apolycopenals may be meaningful as possibly bioactive components because these are similar to concentrations found for vitamin A in extrahepatic human tissues (42).
In vitro studies suggested that lycopene is a substrate for carotene-9',10'-oxygenase (CMO II) (20,29). The metabolic product of cleavage of lycopene with this enzyme would be apo-10'-lycopenal. In the current study, however, we could not detect apo-10'-lycopenal [or its oxidized (apo-10'-lycopenoic acid) and reduced (apo-10'-lycopenol) homologs]. The exact position at which CMO II cleaves carotenoids is still controversial. Kiefer et al. (29) reported that substantial amounts of ß-apo-10'-carotenol and ß-ionone were formed when ß-carotene was provided as a substrate for mouse cloned CMO II in ß-carotene producing strain of E. coli. They did not state which apolycopenals were formed when lycopene was presented as a substrate for the same enzyme in the lycopene-producing strain of E. coli. Wang et al. (26) showed that ß-apo-8'-carotenal, ß-apo-10'-carotenal, and ß-apo-12'-carotenal were the products of the excentric cleavage of ß-carotene in ferret lung.
The current results suggest that apo-8'-lycopenal and perhaps apo-12'-lycopenal but not apo-10'-lycopenal are lycopene metabolic cleavage products of CMO II or of some other carotenoid cleavage enzyme in rat liver. The more polar unidentified cleavage products of lycopene may result directly from lycopene cleavage or as a result of apo-8'-lycopenal and apo-12'-lycopenal metabolism to form secondary metabolic products. The detection and identification of further metabolic oxidation products of lycopene in vivo are required to clarify their possible contributions to the health effects attributed to lycopene.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supplemental Figures 1 and 2 are available with the online posting of this paper at www.nutrition.org.
4 Abbreviations used: 14C-lycopene, (6,7,6',7')-14C-radioactive labeled lycopene; CMO, carotenoid monoxygenase; ESI-MS, electrospray ionization-MS; FD-MS, field desorption-MS; IGF-1, insulin-like growth factor-1; lyc, lycopene; PDA, photodiode array.
Manuscript received 23 December 2005. Initial review completed 22 January 2006. Revision accepted 16 March 2006.
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