Testosterone and food restriction modulate hepatic lycopene isomer concentrations in male F344 rats.

We previously demonstrated that the castration of male rats profoundly increases hepatic lycopene compared with intact controls. Here we further characterized the role of testosterone in modulating hepatic lycopene accumulation and isomer patterns in male rats. Furthermore, because castration significantly decreases ad libitum food consumption, we investigated the influence of food restriction on lycopene metabolism. Forty male F344 rats 8 wk of age were randomly assigned to one of four treatments (n = 10/group): 1) intact, free access to food, 2) castration, free access to food, 3) castration plus testosterone implants, free access to food and 4) intact, 20% food restricted. All rats were fed an AIN-based diet with 0.25 g lycopene (as 10% water-soluble beadlets)/kg diet for 3 wk. Serum testosterone was 5.31 +/- 1.46 nmol/L in intact controls allowed free access to food, reduced in castrated animals (0.52 +/- 0.10, P < 0.0001 versus controls) and intact, food-restricted rats (1.53 +/- 0.49 nmol/L, P < 0.0001 versus controls) and greater (17.23 +/- 3.09 nmol/L) in castrated rats administered testosterone (P < 0.0001 versus controls). Castrated rats accumulated approximately twice as much liver lycopene (74.5 +/- 8.5 nmol/g; P < 0.01 versus controls) as intact rats allowed free access to food (39.5 +/- 5.0) despite 13% lower dietary lycopene intake (P < 0.001; 3.38 +/- 0.07 versus 3.95 +/- 0.06 mg lycopene/d). Testosterone replacement in castrated rats returned liver lycopene concentrations (32.5 +/- 5.5 nmol lycopene/g with 3.76 +/- 0.05 mg dietary lycopene/d) to those observed in intact rats. Food restriction resulted in a 20% decrease in lycopene intake but significantly increased liver lycopene by 68% (66.3 +/- 7.9 nmol lycopene/g with 3.38 +/- 0.00 mg lycopene/d) compared with controls and castrated rats administered testosterone. These results suggest that androgen depletion and 20% food restriction increase hepatic lycopene accumulation. We hypothesize an endocrine and dietary interaction, where higher androgen concentrations and greater energy intake may stimulate lycopene metabolism and degradation.

beta-Carotene stability and uptake by prostate cancer cells are dependent on delivery vehicle.

Cell culture systems provide an opportunity to evaluate the effects of carotenoids on molecular and cellular processes involved in proliferation and differentiation of prostate cancer cells. The stability and cellular uptake of beta-carotene (BC) by prostate cancer cells were investigated in vitro by use of various delivery methods and three human prostate adenocarcinoma cell lines: PC-3, DU 145, and LNCaP. Recovery of BC from the media (prepared from water-dispersible BC beadlets) significantly (p < 0.05) decreased after 12 hours in culture and continued to significantly decrease (p < 0.05) after 24, 48, 72, and 96 hours, an observation primarily attributed to BC degradation rather than isomerization, metabolism, or cellular uptake. The uptake of BC by prostate cancer cells was compared when delivered by tetrahydrofuran, BC-enriched bovine serum, water-dispersible BC beadlets, and artificial liposomes. Recovery of BC after three days in culture from enriched bovine serum medium was significantly (p < 0.05) greater than recovery from medium prepared by beadlets, tetrahydrofuran, or artificial liposomes. We conclude that BC is relatively unstable in vitro and that degradation products may contribute to biological responses. Furthermore, our studies indicate that enriched bovine serum provides a stable and physiological approach to carotenoid treatment of cells in culture.

Tissue lycopene concentrations and isomer patterns are affected by androgen status and dietary lycopene concentration in male F344 rats.

Diets rich in lycopene from tomato products as well as greater concentrations of blood lycopene have been associated with a decreased risk for prostate cancer in epidemiologic studies. However, little is known about factors modulating lycopene absorption, metabolism and tissue distribution in humans and animal models of prostate cancer. A 2 x 4 factorial design was used to measure the effects of androgen status (castrated vs. intact), dietary lycopene concentration (0.00-5.00 g/kg lycopene) and their interaction on tissue lycopene accumulation and isomer patterns in male F344 rats. Male F344 rats ( 14 wk old; 44 castrated, 44 intact) were randomly assigned to one of four diets containing total lycopene concentrations of 0.00, 0.05, 0.50 or 5.00 g/kg as beadlets and fed for 8 wk. Tissue total lycopene and cis/trans lycopene profiles were determined by HPLC. Tissue and serum lycopene concentrations increased significantly (P < 0.01) as dietary lycopene levels increased between 0.00 and 0.50 g/kg. No further increases in serum or tissue concentrations were seen in rats fed dietary lycopene between 0.50 and 5.00 g/kg. As dietary lycopene increased, so did the percentage of cis lycopene in the liver (P < 0.05), due primarily to an increase in the 5-cis isomer. Castrated rats accumulated twice (P < 0.01) the liver lycopene as compared to intact controls, with no effect of castration on serum lycopene or adrenal, kidney, adipose, or lung tissue concentration. Livers from castrated rats had a greater proportion of cis-lycopene than those of intact rats (P < 0.05). A significant interaction between dietary lycopene concentration and androgen status was seen for liver lycopene concentration (P < 0.01). We conclude that serum and tissue lycopene reaches a plateau between 0.05 and 0.50 g/kg dietary lycopene, the tissue cis/trans lycopene ratio increases with greater dietary lycopene and androgens modulate hepatic lycopene metabolism.

Beta-carotene modulates human prostate cancer cell growth and may undergo intracellular metabolism to retinol.

Epidemiologic and animal studies provide support for a relationship between high intakes of carotenoids from fruits and vegetables with reduced risk of several malignancies including prostate cancer. The highly controlled environments of in vitro systems provide an opportunity to investigate the cellular and molecular effects of carotenoids. The effects of beta-carotene (BC) on in vitro growth rates, p21(WAF1) and p53 gene expression, as well as the conversion of BC to retinol were investigated in three human prostate adenocarcinoma cell lines: PC-3, DU 145 and LNCaP. In these experiments, media concentrations of 30 micromol BC/L for 72 h significantly (P < 0.05) slowed in vitro growth rates in all three cell lines, independently of p53 or p21(WAF1) status or expression. (14)C-labeled retinol was detected in prostate tumor cells incubated with (14)C-labeled BC, suggesting metabolic conversion of BC to retinol. Conversely, no (14)C-labeled retinol was detected in media incubated without prostate cancer cells. These studies support a hypothesis that in vitro biological effects of BC on prostate cells may result in part from the conversion of BC to retinol or other metabolites. The possibility that prostate cancer cells in vivo locally metabolize provitamin A carotenoids to retinol and other related metabolites may have implications for our understanding of prostate cancer etiology and the design of future prevention studies.

Review of animal models in carotenoid research.

Foods containing provitamin A carotenoids are the primary source of vitamin A in many countries, despite the poor bioavailability of carotenoids. In addition, epidemiologic studies suggest that dietary intake of carotenoids influences the risk for certain types of cancer, cardiovascular disease and other chronic diseases. Although it would be ideal to use humans directly to answer critical questions regarding carotenoid absorption, metabolism and effects on disease progression, appropriate animal models offer many advantages. This paper will review recent progress in the development of animal models with which to study this class of nutrients. Each potential model has strengths and weaknesses. Like humans, gerbils, ferrets and preruminant calves all absorb beta-carotene (betaC) intact, but only gerbils and calves convert betaC to vitamin A with efficiency similar to that of humans. Mice and rats efficiently convert betaC to vitamin A but absorb carotenoids intact only when they are provided in the diet at supraphysiologic levels. Mice, rats and ferrets can be used to study cancer, whereas primates and gerbils are probably more appropriate for studies on biomarkers of heart disease. No one animal model completely mimics human absorption and metabolism of carotenoids; thus the best model must be chosen with consideration of the specific application being studied, characteristics of the model, and the available funding and facilities.