Lycopene biodistribution is altered in 15,15'-carotenoid monooxygenase knockout mice.
ABSTRACT 15,15'-carotenoid monooxygenase (CMO I) is generally recognized as the central carotenoid cleavage enzyme responsible for converting provitamin A carotenoids to vitamin A, while having little affinity for nonprovitamin A carotenoids, such as lycopene. To investigate the role of CMO I in carotenoid metabolism, approximately 90-d-old C57BL/6 x 129/SvJ [CMO I wild-type (WT)] and B6;129S6-Bcmo1tm1Dnp [CMO I knockout (KO)] mice were fed a high-fat, moderate vitamin A, cholesterol-containing diet supplemented with 150 mg/kg diet of beta-carotene, lycopene, or placebo beadlets for 60 d (n = 12-14). CMO I KO mice fed lycopene (Lyc-KO) exhibited significant decreases in hepatic, spleen, and thymus lycopene concentrations and significant increases in prostate, seminal vesicles, testes, and brain lycopene concentrations compared with WT mice fed lycopene (Lyc-WT). Furthermore, in the serum and all tissues analyzed, excluding the testes, there was a significant increase in the percent lycopene cis isomers in Lyc-KO mice compared with Lyc-WT mice. CMO I KO mice fed beta-carotene (betaC-KO) had significantly lower hepatic vitamin A concentrations (17% of WT mice fed beta-carotene [betaC-WT]). Concordantly, betaC-KO mice had higher serum and tissue beta-carotene concentrations than betaC-WT mice. In addition, phenotypically CMO I KO mice had significantly higher final body weights and CMO I KO female mice had significantly lower uterus weights than CMO I WT mice. In conclusion, CMO I KO mice fed low levels of vitamin A have altered lycopene biodistribution and isomer patterns and do not cleave beta-carotene to vitamin A at appreciable levels.
- SourceAvailable from: John W Erdman Jr.[show abstract] [hide abstract]
ABSTRACT: An evaluation of the Health Professionals Follow-Up Study has detected a lower prostate cancer risk associated with the greater consumption of tomatoes and related food products. Tomatoes are the primary dietary source of lycopene, a non-provitamin A carotenoid with potent antioxidant activity. Our goal was to define the concentrations of lycopene, other carotenoids, and retinol in paired benign and malignant prostate tissue from 25 men, ages 53 to 74, undergoing prostatectomy for localized prostate cancer. The concentrations of specific carotenoids in the benign and malignant prostate tissue from the same subject are highly correlated. Lycopene and all-trans beta-carotene are the predominant carotenoids observed, with means +/- SE of 0.80 +/- 0.08 nmol/g and 0.54 +/- 0.09, respectively. Lycopene concentrations range from 0 to 2.58 nmol/g, and all-trans beta-carotene concentrations range from 0.09 to 1.70 nmol/g. The 9-cis beta-carotene isomer, alpha-carotene, lutein, alpha-cryptoxanthin, zeaxanthin, and beta-cryptoxanthin are consistently detectable in prostate tissue. No significant correlations between the concentration of lycopene and the concentrations of any other carotenoid are observed. In contrast, strong correlations between prostate beta-carotene and alpha-carotene are noted (correlation coefficient, 0.88; P < 0.0001), as are correlations between several other carotenoid pairs, which reflects their similar dietary origins. Mean vitamin A concentration in the prostate is 1.52 nmol/g, with a range of 0.71 to 3.30 nmol/g. We further evaluated tomato-based food products, serum, and prostate tissue for the presence of geometric lycopene isomers using high-performance liquid chromatography with a polymeric C30 reversed phase column. All-trans lycopene accounts for 79 to 91% and cis lycopene isomers for 9 to 21% of total lycopene in tomatoes, tomato paste, and tomato soup. Lycopene concentrations in the serum of men range between 0.60 and 1.9 nmol/ml, with 27 to 42% all-trans lycopene and 58 to 73% cis-isomers distributed among 12 to 13 peaks, depending upon their chromatographic resolution. In striking contrast with foods, all-trans lycopene accounts for only 12 to 21% and cis isomers for 79 to 88% of total lycopene in benign or malignant prostate tissues. cis Isomers of lycopene within the prostate are distributed among 14 to 18 peaks. We conclude that a diverse array of carotenoids are found in the human prostate with significant intra-individual variation. The presence of lycopene in the prostate at concentrations that are biologically active in laboratory studies supports the hypothesis that lycopene may have direct effects within the prostate and contribute to the reduced prostate cancer risk associated with the reduced prostate cancer risk associated with the consumption of tomato-based foods. The future identification and characterization of geometric lycopene isomers may lead to the development of novel agents for chemoprevention studies.Cancer Epidemiology Biomarkers & Prevention 11/1996; 5(10):823-33. · 4.56 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Epidemiologic evidence suggests a possible role for lycopene-rich foods in the prevention of prostate cancer and cardiovascular disease. Despite active research in disease reduction, there is a paucity of information on the absorption, biodistribution and metabolism of lycopene. The aim of this study was to evaluate the biodistribution of 14C-lycopene (specific activity, 1.83 microCi/mg) and 14C-labeled products after an oral dose of 22 microCi of 14C-lycopene in male rats that had been prefed a lycopene-containing diet (0.25 g lycopene/ kg diet) for 30 d. The percentage of 14C excreted in feces and urine over the 168 h was 68%. Quantitatively, serum 14C levels were maintained between 3 and 24 h then decreased at 72 h (P < 0.05). At all time points the majority of tissue 14C was in the liver (approximately 72%), although total hepatic 14C decreased after 24 h. In a comparison of the extrahepatic tissue at 168 h, the 14C was greatest in adipose tissue followed by spleen and then adrenal; approximately 80% of the 14C in the liver was in the cis and all-trans configuration at all time points. At 3 h, the 14C in seminal vesicles was primarily in the all-trans plus 5-cis forms (70%), but by 168 h, 55% of 14C was present as 14C-polar products. Despite the presence of unlabeled lycopene in the prostate, the primary 14C form was in 14C-polar products (67-92%), even at 3 h. The percentage and amount of 14C-polar products in the dorsolateral prostate lobe increased from 3 to 24 h and then reached a plateau. The data suggest that lycopene may be metabolized differently among tissues in rats prefed lycopene.Journal of Nutrition 12/2003; 133(12):4189-95. · 4.20 Impact Factor
- Biochemical Journal 02/1929; 23(4):803-11. · 4.65 Impact Factor
The Journal of Nutrition
Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions
Lycopene Biodistribution Is Altered in
Brian L. Lindshield,4Jennifer L. King,4Adrian Wyss,6Regina Goralczyk,6Chi-Hua Lu,5Nikki A. Ford,4
and John W. Erdman Jr4,5*
4Division of Nutritional Sciences, and5Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL 61801;
and6DSM Nutritional Products, CH-4303 Kaiseraugst n. Basel, Switzerland
To investigate the role of CMO I in carotenoid metabolism, ;90-d-old C57BL/6 3 129/SvJ [CMO I wild-type (WT)] and
B6;129S6-Bcmo1tm1Dnp [CMO I knockout (KO)] mice were fed a high-fat, moderate vitamin A, cholesterol-containing diet
supplemented with 150 mg/kg diet of b-carotene, lycopene, or placebo beadlets for 60 d (n ¼ 12–14). CMO I KO mice fed
lycopene (Lyc-KO) exhibited significant decreases in hepatic, spleen, and thymus lycopene concentrations and significant
WT). Furthermore, in the serum and all tissues analyzed, excluding the testes, there was a significant increase in the percent
lycopene cis isomers in Lyc-KO mice compared with Lyc-WT mice. CMO I KO mice fed b-carotene (bC-KO) had significantly
lower hepatic vitamin A concentrations (17% of WT mice fed b-carotene [bC-WT]). Concordantly, bC-KO mice had higher
serum and tissue b-carotene concentrations than bC-WT mice. In addition, phenotypically CMO I KO mice had significantly
higher final body weights and CMO I KO female mice had significantly lower uterus weights than CMO I WT mice. In
conclusion, CMO I KO mice fed low levels of vitamin A have altered lycopene biodistribution and isomer patterns and do not
cleave b-carotene to vitamin A at appreciable levels. J. Nutr. 138: 2367–2371, 2008.
carotenoids, b-carotene and lycopene are the most prevalent in
human tissues (1). In 1929, Moore (2) showed that b-carotene
could be converted to vitamin A. Not until 1965 was a putative
enzyme identified that was responsible for this conversion (3,4).
More recently, 2 animal carotenoid cleavage enzymes have been
identified; the central cleavage enzyme, 15,15’-carotenoid
monooxygenase (CMO I),7and the eccentric cleavage enzyme,
carotenoid monooxygenase-II (CMO II) (1,5–11). CMO I is
responsible for the central cleavage of the provitamin A carot-
enoids b-carotene, a-carotene, and b-cryptoxanthin to vitamin
position and the resulting b-apocarotenals undergo chain short-
ening and oxidation to form retinal or retinoic acid (12–14).
Hessel et al. (15) recently published the first paper character-
izing CMO I knockout (KO) mice. Hepatic vitamin A concen-
trations were not altered in CMO I KO mice fed b-carotene and
low vitamin A-containing diets. This suggests that CMO I is the
primary enzyme that converts b-carotene to vitamin A in mice.
This finding has recently been validated in another laboratory
(16). In addition to the alterations in carotenoid metabolism,
Hessel et al. (15) noted a surprising finding that CMO I KO mice
had alterations in lipid metabolism, including liver steatosis, in-
creased serum FFA, and increased body weights in older female
mice fed a high-fat diet.
The primary purpose of this study was to determine whether
tissue lycopene biodistribution was altered in CMO I KO mice
validate that CMO I KO mice do not convert b-carotene to vita-
1Supported by NIH grant R01CA125384, and by a Jonathan Baldwin Turner
Fellowship from the College of Agricultural, Consumer and Environmental
Sciences at the University of Illinois (B. L. L.).
2Author disclosures: B. L. Lindshield, J. L. King, A. Wyss, R. Goralcyk, C-H. Lu,
N. A. Ford, and J. W. Erdman Jr, no conflicts of interest.
3Supplemental Figure 1 and Supplemental Table 1 are available with the online
posting of this paper at jn.nutrition.org.
7Abbreviations used: bC-KO, knockout mice fed b-carotene; bC-WT, wild-type
mice fed b-carotene; CMO I, 15,15’-carotenoid monooxygenase; CMO II,
carotenoid monooxygenase-II; KO, knockout; Lyc-KO, knockout mice fed
lycopene; Lyc-WT, wild-type mice fed lycopene; Pl-KO, placebo knockout group;
Pl-WT, placebo wild-type group; WT, wild-type.
* To whom correspondence should be addressed. E-mail: jwerdman@illinois.
0022-3166/08 $8.00 ª 2008 American Society for Nutrition.
Manuscript received 15 September 2008. Initial review completed 22 September 2008. Revision accepted 3 October 2008.
been found in CMO I KO mice (15), we investigated whether
there are alterations in serum or hepatic lipids in CMO I KO and
CMO I WT mice fed high-fat, cholesterol-containing diets con-
taining b-carotene, lycopene, or placebo beadlets.
Materials and Methods
Mice. C57BL/6 3 129/SvJ (CMO I WT, n ¼ 41) and B6;129S6-
Bcmo1tm1Dnp (CMO I KO, n ¼ 37) were provided courtesy of DSM
Nutritional Products. Generation of these mice has been described
previously (15). Mice were bred at RCC Ltd Laboratory Animal Services
and fed a low-vitamin A (450 mg retinol/kg diet in the form of retinol
palmitate) diet prior to shipment to the University of Illinois where they
were individually housed in shoebox cages with free access to water. For
3 wk after receipt, mice consumed ad libitum a standard AIN-93G diet
(17) that was adjusted to contain 825 mg retinol palmitate/kg.
After 3 wk, mice were assigned to 1 of 3 experimental diets sup-
plemented with placebo, b-carotene, or lycopene beadlets (gift from
DSM) to provide 150 mg/kg diet of b-carotene or lycopene using a
randomized complete block design (blocked variables; strain, sex, and
shipment date). The study groups were as follows: placebo WT (Pl-WT),
placebo KO (Pl-KO), b-carotene wild-type (bC-WT), b-carotene KO
(bC-KO), lycopene wild-type (Lyc-WT), and lycopene KO (Lyc-KO).
The carotenoid level consumed is roughly equivalent to humans con-
suming 230 mg/d of one of these carotenoids. Placebo beadlets were
added at equivalent concentrations to placebo diet. Table 1 shows the
number of males and females assigned to the study diet groups. Diets
were adapted from Kirk et al. (18) and were high fat (16.7%), contained
0.1% cholesterol, and lower vitamin E and A levels (22.5 mg of
a-tocopherol and 825 mg retinol palmitate/kg of diet; TD.04070 Harlan
Tekland; Table 2). New batches of experimental diets were made every
3 wk by adding new beadlets to the basal diet and stored in the dark at
4?C. Individual feed intake was monitored when fresh feed was provided
every 48 h and mice were weighed weekly. All animal procedures were
approved by the University of Illinois Institutional Animal Care and Use
After 60 d of receiving their experimental diets, mice were anesthe-
tized with 200:10.5 mg/kg ketamine: xylazine. The thoracic cavity was
opened and blood was taken via cardiac puncture, after which mice were
killed by heart removal. Tissues were removed and snap-frozen in liquid
nitrogen and stored at 280?C until analysis.
Carotenoid and retinoid extraction. Carotenoids and retinoids were
extracted as previously described (19) with minor modifications de-
scribed below. For hepatic tissue, 0.2 g was minced in a 50-mL test tube
containing 6 mL of ethanol containing 0.1% butylated hydroxytoluene.
Echinenone (a gift from DSM), the internal standard for carotenoids,
and3 mL of saturated potassium hydroxidewas then added andvortexed
before saponifying for 30 min at 60?C. The test tubes were removed,
placed on ice, and 3 mL of deionized water was added. The samples were
ethanol with 0.1% butylated hydroxytoluene, 1 mL of saturated po-
tassium hydroxide, and 1 mL of deionized water were utilized.
For diet analysis, ;10 mL of ethanol with 0.1% butylated hydroxy-
ltoluene and 4 mL of saturatedpotassiumhydroxide were addedto 1 g of
diet. The samples were then vortexed and saponified at 70?C for 30 min.
The test tubes were removed, placed on ice, and 8 mL of deionized water
was added. The samples were extracted initially with 14 mL of hexane
and then twice with 7 mL of hexane. Echinenone was then added as an
internal standard. All extracts were dried down in a Speedvac concen-
trator (model AES1010; Savant), flushed with argon and stored at
220?C for ,48 h before HPLC analysis.
HPLC analysis. Retinol (20) and carotenoids (21,22) were analyzed
SD-200 Dynamax pumps, a C30 column (4.5 3 150 mm, 3 mm; YMC)
or C18 column (4.6 3 250 mm, 5 mm; Supelco), a UV-1 or UV-DII De-
tector, and a Dynamax HPLC Methods Manager integrator (Rainin
Instrument). Our laboratory routinely participates in the National In-
stitutes of Standards in Technology micronutrient proficiency testing
programfor carotenoids andretinoidsandourcarotenoidvaluesare nor-
mally within 1 SD of the median.
Cholesterol and lipid analysis. Serum total cholesterol was measured
in triplicate using kit instructions and an enzymatic colorimetric assay
(Thermo DMA catalogue no. 2350–500). Serum triglycerides were
measured per kit instructions using an enzymatic assay (Wako catalogue
no. 998–40391, 998–40491). Liver lipids were extracted using a
modification of the Folch method (23). The sample (0.5 g) was placed
in chloroform:methanol (1:1), homogenized, and filtered by gravity. The
interface was washed twice with 0.29% sodium chloride solution,
centrifuged at 183 3 g for 4 min at 25?C, and the top layer was
discarded. The remaining solution was evaporated, placed to dry in a
desiccator for at least 48 h, and weighed to determine total lipids. PBS
was then added to the dried lipid fraction of the liver, heated to 37?C,
and vortexed. Dissolved liver fractions were then quantified for total
cholesterol content using the same method as described above for serum.
Statistics. Initial body weights, final body weights, serum cholesterol,
serum triglycerides, liver weights, liver lipids, and liver cholesterol con-
centrations were analyzed using dummy coded multiple linear regression
used to determine whether covariate interaction terms and treatment
interaction terms accounted for a significant amount of the variance; if
model assumptions the natural logs of initial body weights, final body
used for statistical analysis. Lycopene concentrations, percent all-trans
lycopene, and b-carotene concentrations were analyzed by 2-sample
for assumption violations. When this transformation did not correct
assumption violations, we used the Wilcoxon’s Rank Exact Sum test (26)
Gender distribution of CMO I WT and CMO I KO
131214 1314 12
Basal diet composition1
AIN-93 vitamin mixa
Mineral mix, Ca-P deficient (TD 79055)
Calcium phosphate, dibasic CaHPO4
Calcium carbonate CaCO3
1Adjusted to provided 22.5 mg of RRR-a-tocopherol (as a-tocopherol acetate) and 450 mg
retinol (as retinol palmitate)/kg diet.
2368Lindshield et al.
to analyze the data. Serum and hepatic vitamin A concentrations were
P , 0.05 was considered significant.
concentrations (3.5- to 22-fold of bC-WT; Table 3). Concor-
A concentrations (Table 4; P , 0.05). However, there was no
difference in serum vitamin A concentrations between bC-KO
and bC-WT mice (Table 4).
Lyc-KO mice exhibited significant decreases in hepatic,
spleen, and thymus lycopene concentrations (Table 3) compared
with Lyc-WT. At the same time, there were significant increases
in prostate, seminal vesicles, testes, and brain lycopene concen-
trations in Lyc-KO compared with Lyc-WT mice. In addition,
serum, liver, spleen, adrenals, kidney, lungs, prostate, and semi-
nal vesicles of Lyc-KO mice exhibited significant decreases in the
percent of lycopene that was in the all-trans isomer form com-
pared with Lyc-WT mice. Instead, the tissues contained a higher
percentage of cis lycopene isomers (Supplemental Fig. 1).
however, CMO I KO mice weighed more at the end of the study
(Supplemental Table 1; P ¼ 0.04). Experimental diets did not
affect final body weights. We also found that CMO I KO female
mice had lower uterus weights (0.10 6 0.05 g) than the CMO I
as a percent of body weight did not differ (data not shown).
Given that we fed an atherogenic diet and reported alter-
ations in CMO I KO mice (15), we also evaluated whether
carotenoid feeding or genotype altered various lipid parameters
(Supplemental Table 1). Neither diet nor genotype significantly
affected liver lipids or liver cholesterol concentrations; however,
there was a significant gender 3 genotype interaction, where
male KO mice had smaller livers as a percent of body weight and
females hadlarger liversas a percent of body weight(P ¼ 0.009).
Lycopene consumption led to a significant increase in serum
tween lycopene and genotype (P ¼ 0.0003). Serum cholesterol
concentrations were decreased in Lyc-KO mice and increased in
Lyc-WT mice compared with the placebo groups. Diet did not
affect serum triglycerides, but CMO I KO mice had higher (P ¼
0.03) serum triglyceride concentrations than CMO I WT mice.
In this study, we fed CMO I KO and CMO I WT mice diets con-
taining placebo, b-carotene, or lycopene beadlets and discovered
converting b-carotene to vitamin A in mice. This was clear from
the substantial increases in tissue b-carotene concentrations in
vitamin A concentrations (17% of bC-WT). Apparently, CMO II
or other murine enzymes failed to cleave b-carotene to vitamin A
to any great extent when mice are fed low-vitamin A diets as
Awas fed, the mice were not vitamin A deficient, as indicated by
hepatic vitamin A concentrations in excess of 100 nmol/g in all
groups and normal serum vitamin A concentrations, which are
homeostatically controlled and are reduced only when mice
One novel finding was the substantially altered lycopene bio-
distribution in Lyc-KO mice. Lycopene concentrations were sig-
nificantly lower in liver, spleen, and thymus but significantly
higherin theprostate,seminalvesicles,testes,andbrainin Lyc-KO
mice than in Lyc-WT mice. We hypothesize that the difference
between the genotypes is partly due to the relative tissue-specific
expression levels of CMO II (27). Previous evidence suggests
that CMO I has little cleaving activity toward lycopene (9,10),
Serum and tissue b-carotene and lycopene concentrations and percent all-trans lycopene isomer in CMO I WT
and CMO I KO mice fed b-carotene or lycopene diets for 60 d1
bC-KOLyc-WT Lyc-KOLyc-WT Lyc-KO
Serum0.76 6 0.20 (6) 10.31 6 0.99 (6)**0.59 6 0.11 (4) 0.61 6 0.078 (6)19.0 6 2.1 (4)8.5 6 1.3 (6)*
18.0 6 2.2 (6)
25.0 6 6.6 (7)
20.2 6 1.5 (7)
1.53 6 0.16 (6)
2.05 6 0.17 (8)
0.072 6 0.019 (6)
3.74 6 0.39 (4)
2.08 6 0.99 (6)
3.67 6 0.58 (4)
1.32 6 0.07 (3)
3.56 6 0.37 (6)
0.28 6 0.10 (6)
246 6 61 (6)*
89.4 6 15.9 (6)**
266.7 6 8.7 (7)**
22.5 6 1.5 (6)**
22.7 6 2.4 (8)**
1.44 6 0.18 (5)*
37.4 6 3.6 (4)**
45.6 6 10.8 (6)**
31.3 6 4.6 (3)**
22.7 6 5.6 (3)**
37.4 6 3.8 (6)**
3.56 6 0.50 (5)*
469 6 107 (6)
270 6 41 (7)
48.8 6 15.3 (7)
2.60 6 0.21 (12)
1.94 6 0.38 (7)
0.019 6 0.005 (6)
4.71 6 1.03 (5)
3.06 6 0.79 (5)
4.43 6 0.81 (4)
0.81 6 0.08 (3)
2.12 6 0.14 (6)
0.04 6 0.01 (6)
100 6 18 (6)**
29.8 6 6.5 (6)**
37.9 6 14.4 (4)
3.75 6 0.51 (12)
1.38 6 0.21 (6)
0.048 6 0.006 (5)*
2.24 6 0.47 (4)*
4.90 6 1.16 (5)
3.29 6 1.85 (2)
3.24 6 0.79 (3)*
5.11 6 0.80 (6)*
0.15 6 0.05 (5)*
51.3 6 2.8 (5)
58.9 6 1.0 (5)
32.0 6 2.3 (7)
47.5 6 2.8 (5)
41.1 6 2.7 (7)
33.1 6 1.3 (3)
25.6 6 2.9 (6)
31.2 6 3.3 (6)
27.6 6 1.1 (5)**
45.9 6 1.6 (5)**
17.9 6 1.6 (4)**
30.2 6 2.1 (5)**
18.7 6 1.2 (6)**
20.5 6 1.3 (3)*
20.3 6 1.5 (6)
18.4 6 0.9 (5)*
1Values are means 6 SEM, (n). Asterisks indicate different from corresponding WT, *P , 0.05, **P , 0.001.
2b-Carotene was not detected in mice fed placebo or lycopene beadlet-containing diets.
3Lycopene was not detected in mice fed placebo or b-carotene beadlet-containing diets.
4Pooled from 2–3 mice.
5ND, Not determined.
Altered lycopene biodistribution in mice2369
but work with Escherichia coli suggests that CMO II may cleave
this compound (8). It has been reported that cis lycopene isomers
of lycopene are preferential substrates for CMO II in vitro com-
pared with all-trans lycopene (28). In food, lycopene is primarily
found in the all-trans form; however, tissues such as the prostate
accumulate higher concentrations of cis isomers (29). We and
others have shown previously that cis isomers are more bio-
available than the all-trans parent (30,31). It is not clear if there
is a difference in antioxidant or other biological activity of cis
isomers as compared with all-trans lycopene in vivo.
However, all tissues examined, except the testes, exhibited
significantly lower percentages of all-trans lycopene and thus a
greater proportion of cis isomers in CMO I KO mice than in
CMO I WT mice. If cis isomers were indeed a preferred substrate
for CMO II, we would have expected to find the opposite out-
come. It is also possible that other unidentified enzyme(s) may
cleave lycopene in CMO I KO mice. If so, it would seem likely
that this uncharacterized enzyme either prefers all-trans lyco-
pene as a substrate or that there is a lycopene isomerase present,
which would explain the high cis concentrations in CMO I KO
tissues. Another possibility is a binding protein that preferen-
tially binds to cis forms of lycopene and facilitates tissue uptake
and/or prevents their degradation and excretion.
Recently, Vogel et al. (32) evaluated eccentric carotenoid
cleavage of lycopene and other carotenoids in maize, Arabidop-
sis, and tomatoes. Interestingly, the plant eccentric cleavage
enzyme (carotenoid cleavage diooxygenase 1) cleaved lycopene
but not its more saturated precursor phytoene. The authors note
‘‘carotenoid cleavage enzymes are an ancient and highly con-
served family, with members present in plants, animals, and
bacteria (32).’’ Further work is needed to determine whether the
Additional studies are needed to characterize tissue CMO II
mRNA expression and protein levels and determine whether
CMO II levels are responsible for the altered lycopene biodis-
entirely responsible for the altered lycopene biodistribution or
exhibit alterations in CMO II protein or enzyme activity levels
KO mice may have differences in lipid transporters such as
scavenge receptor class B, type 1, which is involved in carotenoid
transport (33,34). The mechanism(s) responsible for the altered
lycopene biodistribution is currently under investigation.
In addition to alterations in carotenoid metabolism, Hessel
et al. (15) also reported a significant increase in weight gain in
pared with CMO I WT mice. Hessel et al. (15) also reported in-
creases in serum FFA, hepatic total lipids, cholesterol esters, and
higher serum triglyceride concentrations but no differences in
serum cholesterol, hepatic lipids, or hepatic cholesterol concen-
trations. These different outcomes may be due to the age of the
mice (21.5 wk vs. 28 wk at the end of the respective studies) and/
or the fact that we fed high-fat, cholesterol-containing diets.
We did not find evidence to suggest that either b-carotene or
significant diet 3 genotype interaction; serum cholesterol con-
centrations were increased in Lyc-WT mice but decreased in Lyc-
KO mice. More research is needed to clarify the relationship
less than one-half the size of CMO I WT mice. It is possible that
there may be an alteration in estrogen status in CMO I KO mice.
We did not collect other estrogen-responsive tissues nor have
remaining tissue for analysis. We are pursuing this currently with
Alterations in CMO I have been reported in humans. For in-
stance,a CMOImutationresulted indrastically reducedenzyme
Thus, it is clear that CMO I function is critical to the production
not be important for understanding the reported health benefits
of tomatoes and lycopene (27).
that CMO I is the primary central cleavage enzyme responsible
for conversion of b-carotene to vitamin A. Furthermore, CMO I
weights, higher serum triglyceride concentrations, and smaller
uterus sizes. It ispossible thatCMOII and/or another carotenoid
cleavage enzyme is/are responsible for differential lycopene
metabolism. Additional work is currently underway to further
clarify these novel findings in these mice.
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Olson JA, Hayaishi O. The enzymatic cleavage of beta-carotene into
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Goodman DS, Huang HS. Biosynthesis of vitamin A with rat intestinal
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Yan W, Jang GF, Haeseleer F, Esumi N, Chang J, Kerrigan M,
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Serum and liver vitamin A concentrations in CMO I WT and CMO I KO mice following consumption
of placebo, b-carotene, or lycopene diets for 60 d1
1.35 6 0.13 (11)
144 6 24 (6)a
1.56 6 0.08 (11)
130 6 14 (6)a
1.37 6 0.09 (10)
876 6 94 (6)b
1.38 6 0.06 (10)
148 6 14 (6)a
1.33 6 0.15 (11)
190 6 36 (6)a
1.46 6 0.09 (11)
166 6 16 (6)a
1Values are means 6 SEM, (n). Labeled means in a row with superscripts without a common letter differ, P , 0.05.
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Altered lycopene biodistribution in mice2371