Transcriptomics does not show adverse effects of beta-carotene in A/J mice exposed to smoke for 2 weeks.

Beta-carotene (betaC) supplementation in smokers was unexpectedly associated with increased incidence of lung cancer versus smoking alone. We performed a study in A/J mice to explore possible betaC/cigarette smoke (CS) interactions potentially influencing lung cancer risk in smokers. A/J mice received a diet containing 120 or 600 ppm betaC for six weeks, and exposed to mainstream CS (140 mg total suspended particulates/m(3)) during the last two weeks. Lung transcriptomics analysis revealed that CS induced drug metabolism, oxidative stress, extracellular matrix (ECM) degradation, inflammation markers, and apoptosis. betaC reduced CS-induced inflammation markers and ECM degradation. betaC modulated the CS effect on apoptosis without a clear pro- or anti-apoptotic trend. betaC alone induced only minor changes of gene expression. In conclusion, betaC/CS interactions caused gene regulations in lungs. CS was the main effector. The gene regulations overall did not indicate that betaC exacerbated CS effects. Dose-dependency of betaC effects was minor and not detectable by genome-wide data mining.

beta-carotene-induced changes in RARbeta isoform mRNA expression patterns do not influence lung adenoma multiplicity in the NNK-initiated A/J mouse model.

A number of epidemiological studies have reported associations of beta-carotene plasma levels or intake with decreased lung cancer risk. However, intervention studies in smokers reported increased lung tumor rates after high long-term beta-carotene supplementation. For insight into these conflicting results, we studied the influence of beta-carotene on tobacco smoke carcinogen-induced lung cancer development in the A/J-mouse using 4-(N-Methyl-N-nitro samino)-1-(3-pyridyl)-1-butanone (NNK) as the initiator and lung adenoma multiplicity as the functional endpoint. Gene regulation of the putative tumor suppressor RARbeta in mouse lung was analyzed by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for its relevance in predicting the endpoint of lung cancer. A/J-mice achieved plasma beta-carotene levels of up to 3 micromol/L within 4 wk and up to 6 micromol/L after 6 mo of supplementation on a diet modified to enhance beta-carotene absorption. Despite high lung beta-carotene concentrations of up to 6 micromol/kg, tumor multiplicity was not significantly affected by the beta-carotene treatment, either in carcinogen-initiated or non-initiated mice, and was unrelated to beta-carotene dose and the time point of treatment during cancer formation. Tumor multiplicity did not correlate with beta-carotene plasma levels in NNK-treated animals. All RARbeta isoforms were significantly suppressed in the lungs of NNK- and NNK plus high dose beta-carotene-treated animals. However, the number of tumors per mouse did not correlate with the RARbeta-isoform expression levels. beta-carotene alone after 3 mo of supplementation mildly but significantly increased levels of RARbeta1, beta2, and beta4. This increase persisted for 6 mo for RARbeta2 and beta4. In summary, we found no effect of beta-carotene on tumor formation in the NNK-initiated A/J-mouse lung cancer model with respect to dose or time point of treatment. beta-Carotene-induced changes in RARbeta isoform gene expression levels were not predictive for the number of lung tumors but were indicative of intact beta-carotene metabolism and persistent sensitivity to retinoic acid in the mice. Down-regulation of RARbeta in NNK-induced adenoma-bearing lungs was similar to that observed in human lung cancer and further confirms the A/J-mouse as a valuable model for lung carcinogenesis.

Transformations of selected carotenoids in plasma, liver, and ocular tissues of humans and in nonprimate animal models.

PURPOSE: To determine the stereochemistry of carotenoids in human ocular tissues in comparison with plasma and liver and to elucidate the possible transformations of dietary (3R,3'R,6'R)-lutein and (3R,3'R)-zeaxanthin in the eye. Similarly, to characterize the carotenoid profiles in the eye tissues, plasma, and liver of quails and frogs to determine whether these can serve as appropriate nonprimate animal models for metabolic studies. METHODS: Configurational isomers of carotenoids and their nondietary by-products from pooled human plasma, liver, retinal pigment epithelium (RPE-choroid), ciliary body, iris, and lens were characterized and quantified by high-performance liquid chromatography (HPLC) on a chiral column. Carotenoids and their nondietary by-products in pooled extracts from quail and frog plasma, liver, retina, RPE-choroid, iris, and lens were similarly characterized and quantified. RESULTS: (3R,3'R,6'R)-lutein, (3R,3'R)-zeaxanthin, (3R,3'S; meso)-zeaxanthin, (3R,3'S,6'R)-lutein (3'-epilutein), 3-hydroxy-beta, epsilon -carotene-3'-one, and 5Z- and all-E-lycopene were detected in nearly all human ocular tissues examined. (3R,3'S; meso)-zeaxanthin was not detected in the human plasma and liver but was present in human macula, retina, and RPE-choroid. (3S,3'S)-zeaxanthin was detected in human macula in minute quantities. The carotenoid profiles in quail and frog ocular tissues were somewhat similar to those in humans, with the exception that lycopene was absent. Frog retina, plasma, and liver revealed the presence of (3S,3'S)-zeaxanthin. CONCLUSIONS: The most likely transformations of carotenoids in the human eye involve a series of oxidation-reduction and double-bond isomerization reactions. Quail and frog appear to possess the appropriate enzymes for conversion of dietary (3R,3'R,6'R)-lutein and (3R,3'R)-zeaxanthin to the same nondietary by-products observed in humans and thus may serve as excellent nonprimate animal models for metabolic studies.

Plasma concentration response to drinks containing beta-carotene as carrot juice or formulated as a water dispersible powder.

BACKGROUND: Bioavailability of beta-carotene is highly variable and depends on the source, the formulation and other nutritional factors. OBJECTIVE: It was the aim of the study to compare beta-carotene plasma response to b-carotene dosing with two commercially available drinks, containing beta-carotene from carrot juice or as water dispersible beta-carotene powder. Design In a randomized, parallel group study design, 4 volunteers per group received daily beta-carotene doses of 6-7 or 18-22 mg of either drink over 6 weeks. Blood samples for determination of carotenoid and vitamin A plasma concentrations were collected before supplementation and over the dosing period. RESULTS: Apparent steady-state beta-carotene concentrations were attained after 40 days of supplementation. Consumption of the beverage containing beta-carotene as a water dispersible powder resulted in a higher response of beta-carotene plasma concentrations with increments of 3.84 +/- 0.60 micromol/L (p < 0.05, dose: 7.2 mg/d) and 5.04 +/- 0.72 micromol/L (p < 0.05, dose: 21.6 mg/d), respectively, in comparison to the carrot juice-based drink with increments of 0.42 +/- 0.33 micromol/L (dose: 6 mg/d) and 1.71 +/- 0.55 micromol/L (dose: 18 mg/d), respectively. beta-carotene was cleared from the plasma with an apparent half-life of 6-11 days. Plasma concentrations of alpha-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene remained almost unchanged, whereas retinol plasma concentrations increased slightly. By contrast, with the exception of elevated 13-cis-retinoic acid in one group (21.6 mg/d, water dispersible powder), the concentrations of all-trans-retinoic acid, and the oxo-derivatives or retinoic acid were not significantly affected by b-carotene supplementation. CONCLUSIONS: The results confirm that the relative bioavailability of beta-carotene depends largely on the source of b-carotene and demonstrate the superior bioavailability of beta-carotene powder in comparison to that in carrot juice.