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,#,#
* Department of Nutrition, Harvard School of Public Health, Boston, MA;
Department of Food Science and Technology, The Ohio State University, Columbus, OH;
** Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD;
Division of Hematology and Oncology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH;
Division of Nutritional Sciences, University of Illinois, Urbana, IL;
Department of Epidemiology, Harvard School of Public Health, Boston, MA; and
# Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
2To whom correspondence should be addressed. E-mail: kana.wu{at}channing.harvard.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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67% of total lycopene (range 50–79%). At each time point, the various lycopene isomer concentrations were highly correlated with one another with Spearman correlation coefficients ranging from 0.90 to 0.99 (P < 0.001). Plasma concentrations of total lycopene and its most abundant isomers in samples taken 3–4 y apart were strongly correlated, indicating that dietary patterns and metabolic processes defining lycopene concentrations are stable over time. Because the patterns of lycopene isomers showed limited between-person variability, our results suggest that measuring specific lycopene isomers in epidemiologic studies may not provide additional information beyond that provided by total lycopene concentration. Single plasma samples quantitating plasma lycopene are a valid predictor of long-term exposure for epidemiologic studies.
KEY WORDS: • lycopene • isomers • reproducibility
Epidemiologic studies have suggested that higher intake of tomatoes and tomato products may protect against cardiovascular disease (1–5) and reduce the risk of several types of cancer, particularly those of the prostate, lung and digestive tract (2,3,6,7). The most abundant carotenoid in tomatoes is lycopene (8), which demonstrates a potent ability to quench reactive oxygen in vitro (9–12). Thus, lycopene has been hypothesized to mediate in part the potential health benefits of tomato products (3). However, knowledge gained from in vivo studies in experimental models or from clinical studies is insufficient to define the mechanisms through which lycopene may influence carcinogenesis or cardiovascular disease. Although much of the emphasis is directed toward antioxidant pathways (8,13–15), some in vitro data also suggest that lycopene may influence other cellular processes related to cancer or vascular damage (16–18).
In foods, lycopene occurs mainly in the all-trans form, which is the most thermodynamically stable form (19,20). However, in human and rodent plasma, the cis-form predominates and accounts for 50–70% of total lycopene (19,21). Although retaining their hydrophobic characteristics, the cis- and trans-isomers may distribute differently within lipoproteins and lipid bilayers of cell organelles and membranes, leading to unique biological effects (3,22). All-trans lycopene and a number of different cis-isomers have been measured in human plasma, but no information on the variability of plasma measures within individuals over time is available in the literature (19,23–26). Typically, plasma concentrations of lycopene are measured at one time point in nested case-control epidemiologic studies, which may or may not represent long-term dietary exposures. Thus, long-term within-person variation may be a source of measurement error and may weaken measures of association with risk or pathogenesis of disease. Information concerning lycopene isomer concentrations and their variability over time are therefore important for future epidemiologic studies investigating associations between specific lycopene isomers and human diseases (3). Furthermore, nested case-control studies also must consider possible associations of lycopene concentrations with certain lifestyle and demographic factors, such as age, body mass index (BMI) or alcohol intake, because these factors may be potential confounders (6,27). For cancers that vary by race, such as prostate cancer (27,28), information on possible variation in lycopene concentrations by race might also help to explain such variation in cancer risk.
Using blood samples taken 3 to 4 y apart in an ongoing large male cohort, the Health Professionals Follow-up Study, we investigated the variability of concentrations of lycopene and its major isomers in human plasma over time. We also examined whether certain lifestyle and demographic characteristics are associated with concentrations of total lycopene or specific isomers.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The Health Professionals Follow-Up Study (HPFS) was initiated in 1986 when 51,529 male U.S. health professionals returned a mailed questionnaire inquiring about lifestyle factors (including information on smoking status, ethnicity, weight and height) and medical history. A 131-item food-frequency questionnaire (FFQ) was also added to the questionnaire. Every 2 y, information on lifestyle factors and medical history was updated by follow-up questionnaires and every 4 y, another FFQ was added to the follow-up questionnaires (29). Between 1993 and 1995, we requested that surviving cohort members provide a blood specimen. Participants were mailed a blood collection kit and asked to return a blood sample, chilled in ice, by a prepaid overnight courier. Approximately 18,159 men returned EDTA-preserved blood samples. On receipt by our laboratory, the blood specimens were separated into buffy coats, plasma and RBC and frozen in liquid nitrogen. In 1997, 75 Caucasian, 75 Asian and 63 African-American men, who had donated blood earlier were asked to donate a second blood sample. Of those, 150 participants returned a second blood specimen resulting in 150 paired samples, which were analyzed for lycopene and specific isomers. Before blood donation, all participants were required to give written consent and this study was approved by the Human Subject Committee of the Harvard School of Public Health. For this analysis, we used information from the 1994 follow-up questionnaire and the 1994 FFQ.
Laboratory analysis.
Specimens were divided into aliquots under dim light and arranged in pairs. Paired quality control samples (n = 10), obtained from pooled plasma samples were interspersed randomly among the 150 paired samples. Lycopene analysis was conducted in the laboratory of Dr. Steven Schwartz at the Department of Food Science and Technology at The Ohio State University, Columbus, OH. Aliquots (100 µL) of blood plasma were deproteinated with incorporation of 100 µL ethanol containing a mass fraction of 0.1% BHT. Carotenoids were then extracted with two 500-µL portions of acetone/hexane (volume fraction 1:1) containing a mass fraction of 0.02% BHT. Each portion was mixed using a vortex for 30 s, after which the hexane layers were removed and combined. Individual extracts were dried under a stream of nitrogen at ambient temperature and analyzed immediately by reversed-phase HPLC using a C30 column (prepared at the National Institute of Standards and Technology, Gaithersburg, MD; commercially available from Waters, Milford, MA) with an electrochemical detector (ESA Coularray, Chelmsford, MA) following the methodology of Ferruzzi et al. (30). Because lycopene is transported in the plasma via lipoproteins (31), we also measured plasma cholesterol concentrations at the laboratory of Dr. Steven Clinton at The Ohio State University using an Infinity Total Cholesterol enzymatic assay kit (Sigma Diagnostics, St. Louis, MO) according to the manufacturer’s recommendations. The mean intrapair CV for plasma cholesterol measurements based on 10 quality control samples was 7.5%.
Statistical analysis.
Lycopene concentrations were right skewed; therefore nonparametric tests were employed. Differences between time 1 and time 2 concentrations were assessed using the Wilcoxon sign rank test, and correlations between paired lycopene and isomer concentrations were examined by calculating Spearman partial correlation coefficients. We adjusted for factors that might influence lycopene concentrations at time 1 and time 2 such as age, race, month of blood sampling, BMI and cholesterol concentrations. We assessed differences in lycopene concentrations by lifestyle and demographic characteristics using the Wilcoxon rank-sum test (2 categories) or the Kruskal-Wallis test (3 or more categories). Because age, BMI, hours since last meal and alcohol intake (information on these variables was obtained from the 1994 questionnaire) are continuous variables, we also performed a trend test by regressing these variables on lycopene concentrations. Six paired samples were excluded from our final analysis because of technical problems when analyzing the samples. Mean intrapair CV were calculated on the basis of the 10 paired quality control samples. P-values are reported for two-sided tests. A P-value of <0.05 was considered significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Correlations between total lycopene and the major isomers for the two blood sampling times ranged from 0.55 to 0.70 (P < 0.01) (Table 3). Total lycopene concentrations and the major isomers were also strongly correlated with one another (r = 0.90 to 0.99) (P < 0.01) (Table 4).
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67% (range 50–79%) to total lycopene (Fig. 2). These proportions did not vary by race or other demographic variables (data not shown). In addition, we also investigated whether the contribution of total cis-and all-trans-isomers to total lycopene changed over time by calculating differences in proportions of total cis-lycopene and all-trans lycopene to total lycopene between times 2 and 1. The differences in the all trans/total lycopene ratio between times 2 and 1 did not exceed 10% (Fig. 3) for 84% of participants. All reported results were similar after we excluded the 5 current smokers from the analysis.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Although the sample size was small, our study did not suggest strong relationships between lycopene isomer concentrations and certain lifestyle and demographic characteristics, such as age, race, BMI or alcohol intake. We did observe a significant inverse trend between hours since last meal and lycopene concentrations. Lipoprotein clearance after overnight fasting is expected and because no other known plasma transport mechanisms exist for lycopene transport, this finding illustrates that standardizing sampling to a specific time point postfasting is one way to reduce variability in lycopene blood concentrations, thereby improving the precision of epidemiologic studies.
Because prostate cancer risk is greater in African American men and reduced in Asian American men compared with Caucasians (27,28), some of the differences in risk might be related to differences in tomato product intake or perhaps differences in carotenoid/lycopene metabolism. Ethnic variation in dietary intake of carotenoid containing fruits and vegetables and differences in plasma carotenoids have been reported (32–35). Our study showed no major differences between plasma lycopene concentrations or patterns and concentrations of major lycopene isomers. This study is limited to health professionals with similar education and socioeconomic status, and strongly suggests that there are no major ethnic determinants of lycopene metabolism. However, our study does not eliminate the possibility that the larger spectrum of socioeconomic status may contribute to ethnic differences in dietary patterns involving tomato products and lycopene, which in turn may mediate overall prostate cancer risk.
The majority of published studies that have examined the relationships between demographic factors and plasma lycopene concentrations found significant inverse associations between total lycopene concentration and age (36–41). These observations may be due to age-related changes in dietary patterns or a decrease in total food intake in addition to changes in metabolism associated with aging, age-related diseases and medications (36–41). However, in this cohort of relatively healthy professional men, we did not observe any age-related trends. Although alcohol is hypothesized to modulate lycopene absorption or metabolism (37), we did not observe any associations with lycopene concentrations or isomer patterns in our study.
This study is the largest one to examine the variation in concentrations of plasma lycopene and its major isomers over time. We observed significant moderate correlations of 0.55–0.70 for total lycopene and major isomers in blood samples taken 3–4 y apart. Several previous studies examined total lycopene concentrations at different time points but within a period 
1 y (38,42,43). In a study by Peng et al. (38), an intraclass correlation of 0.85 was found in 96 healthy Caucasians based on 3 lycopene measurements over a 1-mo period. A correlation of 0.57 between lycopene concentrations among 29 healthy volunteers over an interval of 1 y was observed in another study (43). Interestingly, in a group of 42 British women, mean total lycopene concentrations differed significantly by the season in which the sample was obtained. In that study, higher total lycopene concentrations were found in summer and autumn than in winter and spring (44). On the other hand, another study (42) reported slightly higher lycopene levels in the winter, but differences were not significant. Neither total lycopene concentrations nor all-trans or total cis-lycopene concentrations differed significantly by month of blood sampling in our group of U.S. health professionals.
Finally, we found that lycopene isomer concentrations at each time of blood sampling were highly correlated with one another and that the proportion of total cis-lycopene and all-trans lycopene to total lycopene did not vary substantially among most subjects. In our study, total cis-lycopene contributed 60–80% to total lycopene concentrations. These proportions are consistent with some recent studies published using the advanced HPLC technology that allows the separation and quantitation of the lycopene isomers (19,23,25,45).
Our findings do not provide insight into the mechanisms underlying the formation, interconversion or biological roles of various lycopene isomers. Tomato products contain lycopene primarily in the all-trans form (19,20), a thermodynamically stable isomer, and we have again documented that the cis-form predominates in plasma. Although harsh cooking methods may contribute to cis-isomer formation, it appears that the majority of isomerization occurs in vivo (19–21). For cis-isomers ingested or formed during digestion, it appears that the structural change enhances the bioavailability, perhaps through improving solubility into micelles (21,46). In rodents, androgen status and energy intake modulate lycopene isomer metabolism (47,48). The limited within-person and between-person variability in lycopene isomer patterns suggests the activity of undefined biologic processes that maintain stability in this equilibrium (21). Future efforts will be directed toward elucidating details of lycopene isomer formation and biological function, issues that remain enigmatic (3,22).
In summary, reasonably high correlations between plasma concentrations of total lycopene and its most common isomers in plasma samples drawn 3–4 y apart were observed in mostly nonsmoking health professionals. Much additional laboratory and clinical research is required to define the mechanisms leading to cis-isomer formation and the biological functions of the various isomers. However, the very strong correlations among these lycopene isomers and the limited between-person variability in the proportions of total cis-lycopene and all-trans lycopene to total lycopene, suggest that it will be difficult to separate the independent effects of each of the isomers in the course of epidemiologic studies. At the present time, the additional effort and costs of measuring different lycopene isomers in epidemiologic studies are not likely to provide predictive information beyond that provided by total lycopene.
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FOOTNOTES |
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Manuscript received 18 December 2002. Initial review completed 13 January 2003. Revision accepted 18 February 2003.
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LITERATURE CITED |
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