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HumanNutrition and Metabolism
Plasma Lycopene Concentrations in Humans Are Determined by Lycopene
Intake, Plasma Cholesterol Concentrations and Selected Demographic
Factors1,2
Susan T. Mayne,3 Brenda Cartmel, Fabricio Silva, Chi S. Kim, Barbara G. Fallon,
Kenneth Briskin, Tongzhang Zheng, Marianna Baum,* Gail Shor-Posner* and
W. Jarrard Goodwin Jr.*
Department of Epidemiology and Department of Otolaryngology, Yale University School of Medicine, New
Haven, CT, 06520 and the *Department of Otolaryngology and Department of Psychiatry and Behavioral Downloaded from
Science, University of Miami, Miami, FL, 33136.
ABSTRACT Higherplasmalycopeneconcentrationshavebeenassociatedwithareducedriskofseveralchronic
diseases. Determinants of lycopene concentrations in humans have received limited attention. We had blood
lycopene concentrations and lycopene consumption data available from 111 participants in a two-center cancer
prevention trial involving b-carotene and examined determinants of plasma lycopene levels cross-sectionally. The jn.nutrition.org
median plasma lycopene level was 0.59 mmol/L (range 0.07–1.79). Low plasma concentrations of lycopene were
associated with the following variables in univariate analyses: study site (Florida lower than Connecticut,
P 5 0.001), being nonmarried (P 5 0.02), having lower income (P 5 0.003), being nonwhite race/ethnicity (P
50.03), having lower dietary lycopene intake (r 5 0.29, P 5 0.002), having lower plasma cholesterol (r 5 0.43, P at UNIVERSITY OF CALIFORNIA DAVIS on August 26, 2015
50.0001)andtriglyceride levels (r 5 0.26, P 5 0.005), and consuming less vitamin C (r 5 0.20, P 5 0.03). Women
had slightly higher plasma lycopene levels than men (0.65 vs. 0.58 mmol/L; P 5 0.31), despite lower dietary intake
of lycopene (1,040 vs. 1,320 mg/d; P 5 0.50). Plasma lycopene levels did not differ in smokers and nonsmokers.
In stepwise regression analyses, the determinants of plasma lycopene were plasma cholesterol, dietary lycopene,
andmarital status; these three variables explained 26% of the variance in plasma lycopene. Relatively few lifestyle
anddemographicfactorswereimportantdeterminantsofplasmalycopenelevels,withplasmacholesterol, marital
status, and lycopene intake being of greatest importance. J. Nutr. 129: 849–854, 1999.
KEY WORDS: ● lycopene ● humans ● plasma ● determinants ● carotenoids
Lycopene is one of the major carotenoids in western diets, of the carotenoids, only adipose tissue lycopene remained
accounting for ;50% of carotenoids in human serum (Gerster signiﬁcantly associated with a lower risk of myocardial infarc-
1997). Lycopene is a nonprovitamin A carotenoid, concen- tion (odds ratio 5 0.52, 95% CI 0.33–0.82, comparing the
trated in tomatoes and tomato products. Interest in the com- 90th to the 10th percentile). As another example, Giovan-
pound lycopene has been generated based upon recent obser- nucci et al. (1995) reported that male health professionals who
vational epidemiologic studies indicating that persons who consumed higher levels of lycopene-rich foods (tomatoes, to-
ingest more lycopene, or who have higher concentrations of matosauce, tomato juice, pizza) were at signiﬁcantly lower risk
lycopene in plasma or in adipose tissue, are at reduced risk of for the subsequent development of prostate cancer (relative
certain chronic diseases, including cancer and coronary heart risk 5 0.65, 95% CI 5 0.44–0.95 comparing .10 vs. ,1.5
disease, as reviewed elsewhere (Gerster 1997, Hoffman and servings/wk).
Weisburger 1997). For example, Kohlmeier et al. (1997) con- Whereas much is known about the determinants of the
ducted a multi-center case-control study of antioxidant nutri- carotenoid b-carotene in human plasma, far less is known
ents in adipose tissue and risk of myocardial infarction in about the determinants of plasma lycopene. The limited data
Europe, and found that cases had lower levels of three caro- that do exist suggest that determinants of blood lycopene
tenoids, a-carotene, b-carotene, and lycopene, compared to levels differ from those of blood b-carotene levels. For exam-
their matched controls. In multivariate models containing all ple, numerous studies have found that smokers have signiﬁ-
cantly lower blood levels of b-carotene than nonsmokers
1 Results based on interim analyses of these data presented at Experimental (Brady et al. 1996, Fukao et al. 1996, Margetts and Jackson
Biology 1996, Washington D.C. [S. T. Mayne, B. Cartmel, B. G. Fallon, C. Fried- 1996, Pamuk et al. 1994, Stryker et al. 1988); this does not
man, K. Briskin, F. Silva, M. Baum, G. Shor-Posner & W. J. Goodwin Jr. (1996) seemtobethecaseforlycopene(Bradyetal. 1996, Peng et al.
Determinants of lycopene levels in human plasma. FASEB J. 10: A240.(abs.)] 1995, Ross et al. 1995, Tsubono et al. 1996). Also, consump-
2 Supported by grants #R01 CA 42101 and CA 64567.
3 To whom correspondence and reprint requests should be addressed. tion of alcoholic beverages was inversely associated with blood
0022-3166/99 $3.00 © 1999 American Society for Nutritional Sciences.
Manuscript received 5 September 1998. Initial review completed 21 October 1998. Revision accepted 21 December 1998.
849
850 MAYNE ET AL.
concentrations of b-carotene (Brady et al. 1996, Fukao et al. questionnaire by the National Cancer Institute. Nutrient calculations
1996, Stryker et al. 1988); an inverse association with alcohol are based upon USDAfoodcompositiondatabases.Subjectswerealso
was observed in some studies of lycopene (Buiatti et al. 1996, asked about smoking and drinking habits. Questionnaires were ex-
Forman et al., 1995), but not others (Ascherio et al. 1992, cluded if 10 or more food items were missing, if energy intake was
Brady et al. 1996, Tsubono et al. 1996). Women generally implausible (.20.9 MJ/d, excluding alcohol) or if the questionnaire
have higher concentrations of many carotenoids, including a- was missing data on key lycopene-containing foods, such as tomatoes
and b-carotene (National Center for Health Statistics 1996), and tomato juice.
but this relationship was also not observed consistently with Phlebotomy and biochemical analyses. The interviewers, who
werealsotrainedinphlebotomy,obtainedbloodsamplesatthe12mo
lycopene (Ascherio et al. 1992, Brady et al. 1996, Michaud et interview. Blood was collected into two 10 mL heparinized evacuated
al. 1998). Several studies suggest that lycopene levels are tubes. Bloods were kept cold in the dark until the plasma could be
inversely associated with age (Ascherio et al. 1992, Brady et al. separated. Plasma was aliquotted and stored at 270°C pending anal-
1996, Campbell et al. 1994, Michaud et al. 1998, Peng et al. ysis. Samples from the Miami recruitment site were stored temporarily
1995, Vogel et al. 1997), and positively associated with plasma at 270°C, then shipped frozen to the clinical trial laboratory at Yale,
cholesterol (Ascherio et al. 1992, Brady et al. 1996, Campbell where all samples were analyzed.
et al. 1994, Michaud et al. 1998, Vogel et al. 1997). Plasma lycopene was analyzed by reverse-phase high pressure
The observation that smokers tend to have lower b-caro- liquid chromatography as described previously (Mayne et al. 1998).
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tene levels but not lower lycopene levels than nonsmokers The laboratory participated in the National Institute of Standards
may reﬂect a speciﬁc effect of smoking on b-carotene, may be and Technology micronutrient measurement proﬁciency testing pro-
gram. The coefﬁcients of variation for the lycopene assay aver-
a consequence of dietary patterns of smokers and nonsmokers aged ,10%.
with regard to b-carotene versus lycopene, or may reﬂect both Plasma cholesterol and plasma triglycerides were analyzed in du-
factors. Therefore, studies of determinants of plasma lycopene plicate by enzymatic assays (Sigma diagnostics, methods #352 and
levels must also consider dietary intake of lycopene. The 339, respectively, Sigma, St. Louis, MO).
jn.nutrition.org
purpose of this study was to perform a cross-sectional evalua- Data analysis. Data were analyzed using PC-SAS software
tion of a large number of potentially important determinants (SAS/STAT version 6; SAS Institute, Cary, NC). For descriptive
of blood lycopene levels, including age, gender, smoking, statistics, median plasma and dietary lycopene were calculated, strat-
drinking, dietary intake, plasma cholesterol, body mass index, iﬁed by several variables. Medians were used because the distribution
race/ethnicity, seasonality, and marital status, in participants of plasma lycopene was skewed, and the sample size was relatively
at UNIVERSITY OF CALIFORNIA DAVIS on August 26, 2015
small. Wilcoxon rank sum tests and a median test were used to test
in a cancer prevention intervention trial. statistical signiﬁcance. Pearson’s correlation coefﬁcients were calcu-
lated for continuous variables. As the plasma lycopene distribution
SUBJECTS AND METHODS was not normally distributed, concentrations were also log trans-
formed. Forward stepwise regression analysis, and multiple regression
Subjects. The study population for this cross-sectional analysis analysis, was used to determine the predictors of plasma lycopene
included participants who were part of a randomized, double-blind, concentrations. Variables evaluated in these models included several
placebo-controlled trial. The goal of the trial was to determine dietary variables (i.e., consumption of individual carotenoids; fat;
whether supplemental b-carotene reduces the incidence of second cholesterol; carbohydrate; energy; vitamins A, C, E), serologic vari-
primary tumors and local recurrences in patients curatively treated for ables (i.e., plasma cholesterol, triglycerides, plasma carotenoids, sea-
early stage cancers of the oral cavity, pharynx, or larynx. Patients son when blood was drawn), and demographic variables (i.e. sex, site,
were recruited from two recruitment sites, one based at Yale Univer- education, smoking status, income, drinking, race/ethnicity, age,
sity and recruiting from the entire state of Connecticut, and the body mass index, religious afﬁliation, previous cancer site). A P
second based at the University of Miami and recruiting from south value # 0.05 was considered signiﬁcant.
Florida.
Participants in the clinical trial were recruited from 35 hospitals in RESULTS
Connecticut and from 14 hospitals in south Florida. Institutional
Review Board approval was obtained from all hospitals from which Atotal of 138 persons in the clinical trial were interviewed
patients were recruited (49 total hospitals). To be eligible, patients at the 12-mo time point and blood successfully obtained by
had to have a recently diagnosed Stage I or Stage II squamous cell venipuncture. One blood sample was not successfully analyzed
carcinoma of one of the following sites: tongue, gum or mouth, for lycopene because of an insufﬁcient sample. Of the 137
oropharynx, hypopharynx, pharynx, or larynx. Patients with carci-
noma in situ at the above sites were also eligible. Patients had to be persons with plasma lycopene data, a total of 111 (81%) had
between 20 and 75 y of age, have completed their treatments for the adequate dietary questionnaires available for analysis.
ﬁrst cancer, be considered free of cancer at any site at entry into the Table 1 shows the demographic characteristics of the 111
trial, have no signiﬁcant co-morbidities, and not have taken supple- participants who had complete dietary questionnaires and
ments of retinol, b-carotene, vitamin E, or selenium other than blood samples available at year 1 and also the median plasma
multivitamins within the past year. lycopene level and median dietary lycopene intake in this
Physician consent was obtained prior to contacting potential population, stratiﬁed by key demographic factors. The study
participants. Participants were approached for participation by letter population was primarily made up of male Caucasians, al-
and then by phone; those who agreed were subsequently visited though the Miami recruitment site provided some ethnic
in-person by a trained nurse- or physician-interviewer/phlebotomist
(usually in the participant’s home), who obtained consent prior to diversity to the study population. Despite a prior diagnosis of
proceeding. Participants were randomized to receive either supple- oral, pharynx, or larynx cancer (all tobacco-related cancers),
mental b-carotene (50 mg/d; Lurotin, BASF, Parsippany, NJ) or a one fourth of the participants were still smoking at the one-
corresponding placebo. year time point. The median age of the study population was
Dietary data collection. One year after randomization, trained 65 y (range 40–76 y); the median body mass index was 25
interviewers assisted subjects in completing the Block Health Habits/ 2 2
History Questionnaire v.2.1 (long form), which is a food frequency kg/m (range 15–41 kg/m ); and 68% of the participants had
questionnaire consisting of a list of 98 food items, plus additional a prior laryngeal cancer, 23% a prior oral cancer, and 9% a
questions regarding dietary behaviors (Block et al. 1986). Participants prior pharyngeal cancer. Fifty-eight percent of patients had
were asked to report on their usual dietary patterns over the past 12 been treated previously with radiation therapy, 34% with
mo. Nutrient intake was computed from the questionnaires using the surgery, and 8% with the combination of radiation plus sur-
HHHQ software package (version 3.4, 1995), provided with the gery.
PLASMA LYCOPENE DETERMINANTS 851
TABLE 1
Median, 25th and 75th percentiles of plasma and dietary lycopene levels in study participants, by sex, site, marital status,
1
smoking, income, intervention, drinking, and race/ethnicity
n Plasma lycopene (mmol/L) P-value Dietary lycopene (mg/d) P-value
Overall 111 0.59 (0.30, 0.86) 1290(775, 2300)
Sex
Male 91 0.58 (0.28, 0.88) 1320(765, 2355)
Female 20 0.65 (0.45, 0.85) 0.31 1040(805, 2110) 0.50
Study Site
Connecticut 90 0.64 (0.39, 0.89) 1470(945, 2490)
Florida 21 0.28 (0.21, 0.52) 0.001*** 750(220, 1090) 0.0002***
Marital Status
Married 74 0.64 (0.39, 0.88) 1305(835, 2490)
Not married 37 0.37 (0.20, 0.79) 0.02* 1250(595, 2055) 0.19
Smoking Status Downloaded from
Smoker 29 0.52 (0.25, 1.00) 1410(945, 2355)
Former/Never 82 0.59 (0.32, 0.79) 0.75 1210(775, 2235) 0.41
Income
Lower 40 0.36 (0.24, 0.73) 985(590, 2305)
Higher 71 0.69 (0.39, 0.91) 0.003** 1380(945, 2300) 0.08
Intervention
b-carotene 62 0.59 (0.32, 0.88) 1270(685, 2330)
Placebo 49 0.54 (0.30, 0.85) 0.81 1320(865, 2135) 0.92 jn.nutrition.org
Drinking
Current 70 0.63 (0.29, 0.89) 1270(825, 2255)
Ex/Never 41 0.58 (0.32, 0.73) 0.43 1320(690, 2300) 0.96
Race/Ethnicity
White Non-Hispanic 100 0.60 (0.34, 0.88) 1390(870, 2345) at UNIVERSITY OF CALIFORNIA DAVIS on August 26, 2015
Other 11 0.28 (0.21, 0.70) 0.03* 690(185, 950) 0.0002***
1 th th
Values are medians with 25 and 75 percentiles in parentheses.
* P # 0.05, **P # 0.01, ***P # 0.001
The median plasma lycopene level and median dietary and vitamin C intake, were identiﬁed as potential determi-
lycopene intake in this population were 0.59 mmol/L and nants using backward elimination; however, incorporating
1,290 mg/d, respectively (Table 1). In this stratiﬁed, univariate eachintothemodelincreasedtheR-squaredonlyslightlyfrom
analysis, plasma lycopene concentrations were signiﬁcantly 0.26 to 0.269 for site and from 0.269 to 0.274 for site plus
lower in Florida participants compared to Connecticut partic- vitamin C intake. Therefore, the most parsimonious model
ipants (P 5 0.001), in those not married (P 5 0.02), in those includes only the three variables shown in Table 3. A model
with lower incomes (P 5 0.003), and in nonwhites compared incorporating 10 variables (log plasma cholesterol, marital
to whites (P 5 0.03). The subgroups with signiﬁcantly lower status, log dietary lycopene, age, energy intake, study site,
plasma lycopene levels also had signiﬁcantly lower lycopene race/ethnicity, sex, income, and body mass index) explained
intake, with the exception of the nonmarried group (P 5 0.19) only 28% of the variance in plasma lycopene levels.
and the lower-income group (P 5 0.08). Consistent with our
ownwork(Mayneetal. 1998) and that of others (Nierenberg
et al. 1997, Ribaya-Mercado et al. 1995), b-carotene supple- TABLE 2
mentation had no effect on plasma lycopene concentrations
(P 5 0.81). Females tended to have slightly higher plasma Correlation between selected continuous variables and
lycopene levels than males (P 5 0.31). Plasma lycopene levels 1,2
did not vary signiﬁcantly by season when blood was drawn plasma lycopene levels
(data restricted to Connecticut site only; November–February, Log plasma
March–June, July–October) or education (above versus below Plasma lycopene lycopene
median; data not shown).
The following variables were signiﬁcantly correlated with rP-value rP-value
plasma lycopene concentrations, with and without log trans- Plasma cholesterol 0.43 0.0001 0.37 0.0001
formation, in univariate analyses: plasma cholesterol, dietary Log plasma cholesterol 0.42 0.0001 0.37 0.0001
lycopene, plasma triglyceride, and daily vitamin C intake Dietary lycopene 0.29 0.002 0.25 0.007
(Table 2). None of the other dietary, serologic, or demo- Log dietary lycopene 0.32 0.0007 0.32 0.0007
graphic variables were signiﬁcantly correlated with plasma Plasma triglyceride 0.26 0.005 0.25 0.01
lycopene concentrations. Dietary vitamin C 0.20 0.03 0.21 0.03
Determinants of plasma lycopene levels based upon step- Age 20.10 0.28 20.07 0.46
wise regression analyses are shown in Table 3. Three variables, 1 n 5 111
log plasma cholesterol, marital status, and log dietary lycopene 2 Body mass index, energy intake, dietary b-carotene, dietary cho-
intake, were selected in a forward stepwise regression model, lesterol, energy from alcohol, dietary retinol, and dietary a-carotene
and these three variables explained 26% of the variance in were not correlated with plasma lycopene levels (20.10 , r , 0.10;
plasma lycopene levels. Two additional variables, study site P $ 0.30).
852 MAYNE ET AL.
TABLE 3
1
Determinants of plasma lycopene levels: Stepwise regression analyses
Variable
b SE(b) Partial r2 Model r2 P-value
Forward Stepwise
Log plasma cholesterol 0.92 0.24 0.14 0.14 0.0001
Marital status 20.33 0.12 0.08 0.22 0.002
Log dietary lycopene 0.16 0.06 0.05 0.26 0.01
1 Dependent variable 5 log lycopene levels
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Weanalyzed the foods that contributed the most to lyco- of the fact that lycopene is predominantly transported in low
pene intake in this population. Relatively few foods were density lipoproteins; these lipoproteins carry the bulk of cho-
important contributors: spaghetti/lasagna/other pasta (grouped lesterol in the plasma. We also found that subjects who were
together in the Block food frequency questionnaire) were the married had signiﬁcantly higher lycopene levels than nonmar-
top food source for 54% of the population, and tomatoes/ ried subjects, even after adjusting for dietary intake of lyco-
tomato juice (also grouped in the questionnaire) were the top pene and plasma cholesterol concentrations. Married subjects
food source for 42% of the population. Other food items had slightly higher proportions of several of the variables that
jn.nutrition.org
contributed only minor amounts to the overall dietary lyco- were associated with higher lycopene levels in the univariate
peneintake(e.g., salsa, red chili sauce were the top food source analysis, for example, those with higher incomes were more
for 2% of the population, the remaining 2% came from various likely to be married (72% of married had high incomes versus
other foods). 49% of nonmarried subjects), 82% of Connecticut residents
Lycopene bioavailability has been noted to be somewhat were married compared to 78% of Florida residents, and 77%
at UNIVERSITY OF CALIFORNIA DAVIS on August 26, 2015
greater for heat-processed versus unprocessed tomato products of married subjects were former/never smokers versus 68% of
(Stahl and Sies 1992); therefore, we ran additional regression nonmarriedsubjects. Thus, the marital status variable seems to
models to look at the inﬂuence of different food sources of be capturing many other variables that are associated with
lycopene on plasma lycopene levels. In a regression model higher plasma lycopene levels.
containing variables for lycopene from spaghetti/lasagna/other The rather striking observation that the participants from
pasta and lycopene from tomatoes/tomato juice, the b-coefﬁ- Florida consumed half as much lycopene as participants from
cient for the former was 1.7-fold the magnitude of the coefﬁ- Connecticut may be a consequence of regional differences in
cient for the latter (P values 5 0.06 and 0.1, respectively). food preferences or might also reﬂect racial and ethnic differ-
Thus, lycopene from heat-processed tomato products was ap- ences in food preferences, as the black and Hispanic partici-
parently more bioavailable than lycopene from unprocessed pants in the study were mostly from Florida. The difference in
tomato products. intakes is not likely to be due to measurement error of the
The relationship between dietary lycopene intake versus dietary instrument because blood levels of lycopene were also
plasma lycopene concentration, by study site, is shown in signiﬁcantly lower in the study subjects from Florida, despite
Figure.1. Study subjects from Florida had notably lower lyco- the fact that all bloods were analyzed in one laboratory in
pene intakes (P 5 0.0002) and plasma concentrations (P Connecticut. Others have reported that lycopene intakes are
50.001) compared to participants from Connecticut. There lower in African-American men than in Caucasian men, and
was considerable variability in this relationship, with some
subjects having relatively high plasma lycopene levels (.0.9
mmol/L) despite relatively low intake (,1,500 mg/d), and
others having relatively low plasma lycopene levels (,0.2
mmol/L) despite high intake levels (.2,000 mg/d). The b-co-
efﬁcient for residents of Florida was somewhat greater than
that for residents of Connecticut, suggesting a greater efﬁ-
ciency of carotenoid absorption in Florida residents, possibly
due to lower overall intake levels of lycopene (Fig. 1).
DISCUSSION
These results indicate that relatively few variables, plasma
cholesterol, marital status, and dietary lycopene intake, were
important determinants of plasma lycopene levels in our study
population. The ﬁnding that dietary lycopene intake was sig-
niﬁcantly associated with plasma lycopene concentrations was
expected, although some studies have not found a signiﬁcant
association between dietary lycopene intake and plasma con-
centrations (Coates et al. 1991). The strong association with FIGURE 1 Lycopene intake (mg/d) versus plasma lycopene con-
plasma cholesterol was reported in other studies (Ascherio et centrations (mmol/L) in 111 persons from Connecticut and south Flor-
al. 1992, Brady et al. 1996, Campbell et al. 1994, Michaud et ida. b-coefﬁcient, P value by site are as follows: Connecticut only: b
al. 1998, Vogel et al. 1997), and most likely is a consequence 50.00006, P 5 0.11; Florida only: b 5 0.0002, P 5 0.006.

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...Humannutrition and metabolism plasma lycopene concentrations in humans are determined by intake cholesterol selected demographic factors susan t mayne brenda cartmel fabricio silva chi s kim barbara g fallon kenneth briskin tongzhang zheng marianna baum gail shor posner w jarrard goodwin jr department of epidemiology otolaryngology yale university school medicine new haven ct the psychiatry behavioral downloaded from science miami fl abstract higherplasmalycopeneconcentrationshavebeenassociatedwithareducedriskofseveralchronic diseases determinants have received limited attention we had blood consumption data available participants a two center cancer prevention trial involving b carotene examined levels cross sectionally jn nutrition org median level was mmol l range low were associated with following variables univariate analyses study site florida lower than connecticut p being nonmarried having income nonwhite race ethnicity dietary r at california davis on august andtriglyceride co...

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