QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, C. M. Articles by Erdman, J. W. Search for Related Content PubMed PubMed Citation Articles by Lee, C. M. Articles by Erdman, J. W., Jr. Pubmed/NCBI databases Substance via MeSH

---

Review

Review of Animal Models in Carotenoid Research^{1 ,2}

Christine M. Lee^*, Amy C. Boileau, Thomas W. M. Boileau, Alexa W. Williams^*, Kelly S. Swanson, Kasey A. Heintz and John W. Erdman, Jr.^*,3

^* Department of Food Science and Human Nutrition and Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801

³To whom correspondence should be addressed.

ABSTRACT

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 ß-carotene (ßC) intact, but only gerbils and calves convert ßC to vitamin A with efficiency similar to that of humans. Mice and rats efficiently convert ßC 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.

KEY WORDS: • carotenoids • animal models • gerbils • ferrets • preruminant calves

The experimental evaluation of carotenoids is becoming increasingly common. Epidemiologic studies indicate that an increased intake of fruits and vegetables that contain carotenoids is associated with a decreased risk of many types of cancer including lung, breast and those affecting the gastrointestinal tract (Block et al. 1992 , Mayne 1996 , Steinmetz and Potter 1996 ), a decreased risk of cardiovascular disease (Kohlmeier and Hastings 1995 ), a decreased incidence of age-related macular degeneration (AMD)⁴ (Snodderly 1995 ) and a decreased incidence of xeropthalmia in areas with low preformed vitamin A (VA) intake (Fawzi et al. 1993 ). Consumption of certain fruits and vegetables has also been associated with a decreased risk of prostate cancer (Giovannucci et al. 1995 ), and ß-carotene (ßC) supplementation has been shown to enhance natural killer cell activity in elderly men (Santos et al. 1996 ). In contrast, it has been reported that supplementation of ßC either with or without VA to high risk populations may increase the risk of lung cancer (Albanes et al. 1996 , Omenn et al. 1996 ). These epidemiologic associations between carotenoid intake and risk of disease should be addressed to determine whether the carotenoids themselves are protective, or if carotenoids are markers for other protective factors in foods.

Figure 1 outlines the various steps required to release carotenoids from the food matrix, for carotenoid uptake by intestinal mucosal cells, and subsequent absorption, transport and metabolism. Mechanisms regulating the following processes are not well understood: 1) the release of carotenoids from the food matrix; 2) the solubilization of carotenoids into micelles; 3) the uptake of carotenoids into intestinal mucosal cells; 4) the absorption of intact carotenoids; 5) the cleavage of pro-VA carotenoids within the enterocyte or within other tissues to yield VA; and 6) the tissue distribution, metabolism and recycling of carotenoids (Boileau, T. et al. 1999 , Castenmiller and West 1998 ).

View larger version (37K): [in this window] [in a new window]   Figure 1. Digestion, absorption and metabolism of carotenoids. As a result of their lipophilic nature, carotenoids are often found complexed in the food matrix with protein, lipids and/or fiber. There are several steps (1-5) necessary for carotenoid absorption to occur: 1) the food matrix must be digested; 2) carotenoids must be released and combined with lipids and bile salts to form micelles; 3) the micelles must move to the intestinal brush border membrane so that carotenoids can be taken up and 4) transported into the enterocyte for subsequent processing; and 5) within the enterocyte, carotenoids can be metabolized, resecreted into the intestinal lumen when the cells turnover or be incorporated into chylomicrons and be secreted into the lymph. Chylomicrons then transport carotenoids to the liver. 6) The action of lipoprotein lipase of extrahepatic tissues may result in extrahepatic tissue uptake of carotenoids by these tissues before hepatic uptake. 7) Chylomicron remnants deliver the majority of absorbed carotenoid to the liver. 8) Carotenoids that are taken up by the liver may be stored there or resecreted in VLDL. 9) Carotenoids in LDL and HDL may also be taken up by extrahepatic tissues, where they may accumulate.

It would be ideal to study carotenoid absorption, metabolism and contribution to disease prevention in human subjects, but human studies are expensive and often difficult to coordinate. This necessitates the use of animal models, which offer many advantages (Van Vliet 1996 ), including the ability to use radiolabeled compounds and the ability to access tissues, neither of which is usually possible in humans. Mongolian gerbils (House et al. 1997 , Lee et al. 1998 , Moore et al. 1996 , Pollack et al. 1994 , Thatcher et al. 1998 ), ferrets (Gugger et al. 1992 , Ribaya-Mercado et al. 1989 , White et al. 1993b ), and preruminant calves (Bierer et al. 1995 , Chew et al. 1984 , Hoppe et al. 1996 , Poor et al. 1992 ) are relatively new models that are currently popular for such studies.

Choosing the most appropriate animal model for a study requires careful consideration. We know that humans absorb a variety of dietary carotenoids intact, and that some carotenoids such as ßC, ß-cryptoxanthin and -carotene can contribute to the VA status of the individual (de Pee et al. 1998a and 1998b , Olson 1999 ). Carotenoid involvement in cell-to-cell communication, immune response and reproduction has also been suggested, however the mechanisms involved and the physiologic relevance of these functions are unclear (Olson 1999 ). The limited knowledge about human carotenoid metabolism makes it especially difficult to choose an appropriate animal model. The ideal model would have the following characteristics: 1) absorb a variety of carotenoids intact at physiologic levels, similarly to humans; 2) have carotenoid distribution in tissues and serum similar to that of humans; 3) represent an appropriate model for the disease state of interest; 4) be readily available; 5) be easily manageable in a laboratory setting; and 6) be affordable. Unfortunately, no one model meets all of these criteria. This paper reviews recent progress in the development of animal models with which to study carotenoid absorption, metabolism and the potential health aspects of these compounds.

MODEL SELECTION

There are several things that must be considered when choosing an animal model for any scientific study. Physiologic similarities of the model to humans with respect to the particular application being studied are very important, yet there are also practical considerations that should be addressed. Table 1 compares animal models used in carotenoid research with respect to some specific applications and their physiologic similarities to humans. Applications compared include the following: carotenoid absorption, carotenoid conversion and metabolism, vitamin A deficiency, and cardiovascular disease, immune function, AMD and cancer. The relative desirability of each model for the various applications was estimated, considering both their similarities to humans with respect to the application and their relative use as a model in current research. This table indicates that gerbils, ferrets and preruminant calves would be the best models with which to study carotenoid absorption and metabolism. However, these models are not well established for study of the disease states with epidemiologic correlations with carotenoids. Mice and/or rats are much more established for the study of cancer, immune function and VA deficiency, but these species do not absorb physiologic doses of carotenoids intact. When choosing a model with which to study carotenoids, the researcher must weigh the advantages and disadvantages of each model with respect to both their carotenoid metabolism and their appropriateness for the specific application to be studied.

Below are detailed descriptions of a few of the more desirable models currently being used in carotenoid research. Brief descriptions are also provided for some of the other models, which may not be considered as desirable.

Mongolian gerbils

When conducting any scientific study, it is necessary to have large enough sample groups to achieve statistical power. The Mongolian gerbil (Meriones unguiculatus) is a good model to choose in these situations because they are small, easily maintained in large numbers and readily available. Gerbils also possess several characteristics that make them an appropriate model for carotenoid research.

This laboratory was the first to demonstrate that gerbils absorb ßC intact when fed at physiologic levels (Pollack et al. 1994 ). We found that serum ßC peaked 4 h after a ßC dose and that ßC was found in the liver, spleen, kidney + adrenal, adipose and lung tissue of gerbils (Pollack et al. 1994 ). Recent work in our laboratory has also shown that Mongolian gerbils absorb dietary lycopene, resulting in accumulation in the liver, adrenal and spleen, and trace amounts in the kidney and heart (Heintz, unpublished data).

Intestinal absorption and tissue accumulation of ßC in gerbils has been studied extensively in our laboratory (Lee et al. 1998 , Thatcher et al. 1998 ), and by others (House et al. 1997 ). It has also been shown that ßC contributes to both hepatic and extrahepatic VA stores in Mongolian gerbils (House et al. 1997 , Lee et al. 1998 , Thatcher et al. 1998 ) and that gerbils convert dietary ßC to VA with efficiency similar to that currently estimated for humans (Lee et al. 1998 ). It has also been shown that substantial amounts of hepatic ßC that had accumulated when gerbils were fed a diet that contained ßC were rapidly depleted once ßC was removed from the diet, regardless of the VA status of the gerbils or the VA content of the diet (Thatcher et al. 1998 ). These data suggest that Mongolian gerbils are an appropriate animal model for studying carotenoid absorption, metabolism and the availability of VA from carotenoid precursors. However, knowledge about the VA requirement of this species is limited, thus comparing the VA value of a compound in this species to humans must be done with caution.

To our knowledge no one has used gerbils to study the consequences of VA deficiency. Studies from our laboratory have shown that it is difficult to produce clinical VA deficiency in this species. Weanling gerbils maintain liver stores of VA (120–138 nmol) even after 84 d of consuming a VA-free diet (Lee et al. 1998 , Thatcher et al. 1998 ). In contrast, hepatic VA stores in weanling rats are negligible after 28–33 d (Corey and Hayes 1972 , Gardner and Ross 1993 ), and rats exhibit clinical signs of VA deficiency after only 35 d of consuming a VA-free diet (Corey and Hayes 1972 ). Gerbils have the potential to be valuable models for evaluating VA deficiency, but it requires months to deplete hepatic VA stores. This time might be shortened by the development of a second generation, VA-deficiency model, as has been developed for the rat (Gardner and Ross 1993 , Roodenburg et al. 1995 ).

Mongolian gerbils are an established model for cholesterol and lipid metabolism because their serum lipid profile responds to dietary changes similarly to humans (DiFrancesco et al. 1990 , Nicolosi et al. 1981 , Pronczuk et al. 1994 , Sullivan et al. 1993 , Tasker and Potter 1993 ). Because gerbils also appear to metabolize ßC similarly to humans, they may be a promising model with which to evaluate any possible relationship between ßC intake and hyperlipidemia, a risk factor for developing coronary heart disease.

Overall, gerbils appear to be an appropriate model with which to study carotenoid absorption and metabolism, and they are a practical species for laboratory research.

Domestic ferrets

Gerbils may be a convenient model for many applications; however, they are small. If a study requires surgical manipulation, a larger model, such as the ferret, may be more appropriate. Ferrets may not be as practical as gerbils, due to their cost and housing requirements, but they are still easily managed in a research setting.

Ferrets are larger than gerbils (adult male ferrets weigh ~1200 g, and adult male gerbils 80 g), and carotenoid absorption can be measured directly by surgical cannulation of the lymphatics and the portal vein without extreme difficulty (Boileau, A. et al. 1999 , Wang et al. 1992 ). Ferrets are also resilient under halothane anesthesia and can be maintained easily in a surgical plane of anesthesia for several hours in terminal procedures (Boileau, A. et al. 1999 ).

Domestic ferrets are used in many areas of carotenoid research, including absorption and bioavailability, isomer metabolism and dietary interactions. Our laboratory has developed a pelleted, purified ferret diet containing adequate VA and negligible ßC (White et al. 1993b ). This diet has been used in our laboratory to standardize dietary treatment and deplete tissues of carotenoids.

Ferrets absorb dietary ßC intact and accumulate ßC in tissues and serum in a dose-dependent fashion (Ribaya-Mercado et al. 1989 ). Ferrets also absorb a variety of other carotenoids including -carotene, lycopene and canthaxanthin (Tang et al. 1993 , White et al. 1993a ). In addition, ferrets convert ßC to VA in the intestine (Wang et al. 1991 ) and in homogenates of liver, lung and adipose tissue (Wang et al. 1992 ); tissue distribution of carotenoids in ferrets is also similar to that of humans (Gugger et al. 1992 , Ribaya-Mercado et al. 1992 and 1989 ). Absorption and tissue distribution of ßC isomers, specifically 9-cis ßC, in ferrets also appear to be similar to what is reported in humans (Erdman et al. 1998 ).

Conversion of dietary ßC to VA in ferrets requires a weight ratio of ßC/VA >15:1 (Lederman et al. 1998 ), much higher than the estimated 6:1 ratio required for humans (NRC 1989 ). Therefore, ferrets are not an ideal model with which to evaluate the conversion of dietary ßC to VA. Ferrets also have high concentrations of retinyl esters in their serum (Lederman et al. 1998 , Ribaya-Mercado et al. 1992 ). Under normal dietary conditions, humans have negligible concentrations of serum retinyl esters. This suggests differences between ferret and human VA metabolism (Bankson et al. 1986 ). Despite these differences, ferrets do absorb ßC intact and accumulate it in their tissues; they should be an appropriate animal model for studying the biological effects of tissue ßC.

The association between ßC and lung cancer is currently an active area of carotenoid research. Recently, a smoke-exposed ferret model was used to evaluate the effects of smoke exposure and/or ßC supplementation on lung tissue morphology, and plasma ßC and retinoid concentrations (Wang et al. 1999 ). These researchers found increased proliferation of alveolar cells and macrophages, elevated activator protein-1 expression (AP-1 is a transcription factor usually associated with increased lung carcinogenesis), and down-regulation of retinoic acid receptor-ß in the lungs of ßC-supplemented, smoke-exposed ferrets. These data indicate that ferrets are a good model with which to study the relationship between ßC, smoking, and lung cancer, and the specific mechanisms.

Ferrets may also be a suitable model with which to evaluate the possible relationship between carotenoids and stomach cancer. High intakes of fruits and vegetables, which contain carotenoids, have been associated with a decreased risk of stomach cancer (Block et al. 1992 , Mayne 1996 , Steinmetz and Potter 1996 ), and a number of studies have suggested that ferrets are a good model with which to study certain types of stomach cancer (Erdman et al. 1997 , Fox et al. 1997 ).

Preruminant calves

It is often necessary to obtain larger quantities of tissue and/or multiple samples from the same animal. For these situations, preruminant calves may be a more realistic model. Preruminant calves are monogastric and, like humans, absorb ßC intact. It is possible to obtain multiple blood samples, and a liver biopsy procedure that allows multiple sampling of hepatic tissue from this species has been developed recently in our laboratory (Swanson, unpublished data).

It has been demonstrated the preruminant calf is an appropriate animal model for carotenoid research (Bierer et al. 1995 , Hoppe and Schoner 1987 , Poor et al. 1992 ). Following a ßC-containing meal, preruminant calves demonstrate carotenoid absorption kinetics similar to what has been reported for human infants (Poor et al. 1992 ). The following characteristics have been demonstrated by preruminant calves: 1) they absorb other carotenoids such as canthaxanthin, lutein, lycopene and -carotene (Bierer et al. 1995 ), although ßC is preferentially absorbed; 2) dietary ßC can be used as a source of VA (Hoppe et al. 1996 ); and 3) the serum appearance and tissue distribution of 9-cis ßC are similar to what has been reported in humans (Bierer et al., unpublished data). Preruminant calves have also been used to evaluate the role of ß-carotene in reproductive function (Chew et al. 1984 , Wang et al. 1988 ). Our laboratory is currently in the process of defining the VA requirement of calves (Swanson et al., unpublished data). This information should prove valuable in formulating diets for carotenoid studies.

Preruminant calves are ideal for absorption studies because of the availability of multiple blood and liver samples. However, they are not readily available, they are more expensive than many other models, they are not easily maintained in a laboratory setting because they require special facilities for housing, and they are difficult to obtain in large numbers (sample size), thus creating a challenge in achieving statistical power.

Rats and mice

Rats and mice are used in many areas of scientific research, including the study of carotenoids. Specific applications for these species include cancer studies (Sato et al. 1997 , Thompson et al. 1993 ) and studies evaluating immune function (Bendich and Shapiro 1986 , Jyonouchi et al. 1994 ). These rodents are well characterized and there are many strains, including knock-outs and transgenics available that have been established as models for many of the diseases epidemiologically associated with carotenoid intake. However, rats and mice absorb carotenoids differently than humans; thus extrapolation of data to humans must be done with caution.

Rats have been used extensively (Biesalski and Weiser 1993 , Grolier et al. 1995 , Mittal 1983 ) to evaluate the efficiency of ßC conversion to VA by monitoring changes in liver VA stores. Rats are high efficiency converters of ßC to VA at the level of the enterocyte (Fig. 1 , step 4). Therefore, they do not readily absorb carotenoids intact (Fig. 1 , step 5).

If fed diets containing supraphysiologic levels of carotenoids (0.02% of diet), rats can absorb a variety of carotenoids including ßC (Krinsky et al. 1990 , Ribaya-Mercado et al. 1989 , Warmer et al. 1985 ), canthaxanthin and lycopene (Mathews-Roth et al. 1990 ), and accumulate ßC in tissues in a dose-dependent manner (Shapiro et al. 1984 ). (When normalized for body weight, feeding ßC at 0.02% of diet is equivalent to a 70-kg person eating 163 carrots per day.) This is in contrast to humans, who absorb small, physiologic doses of a variety of carotenoids, including ßC, intact.

Rats and mice may not be the most appropriate models for studying carotenoid absorption and bioavailability, but rats are a desirable model with which to study the effects of VA deficiency. Dietary restriction of VA and ßC in rats causes a rapid depletion of hepatic VA stores (28–33 d) and the onset of clinical VA deficiency (35 d) (Corey and Hayes 1972 , Gardner and Ross 1993 ). A second-generation model has also been developed in this species, resulting in more rapid development of VA deficiency, (Gardner and Ross 1993 , Roodenburg et al. 1995 ).

Despite shortcomings, rodents are used extensively to evaluate the effect of dietary carotenoids on the development of cancer (Moon 1989 , Nagasawa et al. 1995 , Narisawa et al. 1996 and 1998 , Schwartz and Shklar 1987 , Youping et al. 1997 ) and immune function (Bendich 1989 , Bendich and Shapiro 1986 , Jyonouchi et al. 1994 , Lingen et al. 1959 , Rosales and Ross 1998 ). Generally, high levels of dietary carotenoids are fed in these studies to achieve adequate tissue levels. Therefore, relevance to humans must be considered with caution.

Nonhuman primates

Nonhuman primates have been used to evaluate carotenoid accumulation in the macula of the eye (especially lutein and zeaxanthin) to study age-related macular degeneration because they have a macula lutea similar to that of humans (Handelman et al. 1992 , Snodderly et al. 1991 ). These species have also been used to study many aspects of cardiovascular disease (Bond et al. 1980 , Williams et al. 1991 ), making nonhuman primates a possible model with which to study the association between carotenoids and cardiovascular disease. However, there are differences in carotenoid absorption between different species of nonhuman primates compared with humans. Primate species include both high and low absorbers of carotenoids (Krinsky et al. 1990 , Slifka et al. 1999 , Snodderly et al. 1990 ). Thus, care must be taken when choosing the species of nonhuman primate to be used.

Advantages to using these species include the following: 1) they are more closely related to humans than other models from an evolutionary standpoint; and 2) it is possible to obtain multiple blood samples from the same animal.

Despite their close relationship with humans, nonhuman primates are not commonly used because they are extremely expensive, they are not easily managed in a laboratory setting, they require special facilities and their availability is limited.

Other species

Many other animal species have been, or are currently being used in carotenoid research. Pigs have been used to evaluate ßC absorption and uptake (Chew et al. 1991 ) and the role of ßC on reproductive function (Chew 1993 ). However, it has also been reported that this species does not absorb appreciable quantities of intact ßC and is not a good model with which to study postabsorptive metabolism of ßC (Poor et al. 1987 ). Hamsters have been used for carotenoid studies investigating cancer (Schwartz and Shklar 1987 ) and toxicology (Beems et al. 1987 ). Chicks have been evaluated as a carotenoid bioavailability model (Erdman et al. 1986 , Poor et al. 1987 ), and have been used for absorption studies (Tyczkowski and Hamilton 1986 ). Rabbits have been used to evaluate carotenoid absorption and distribution (Yap et al. 1997 ), and the effect of ßC on the development of athersclerotic lesions (Sun et al. 1997 ). Dogs are currently being used to study carotenoids and immune function (Chew et al. 1998 , Kim et al. 1998 ). Quail, a relatively new model, have been used to study carotenoids and AMD because the quail retina is similar to the human macula. Because this species ages rapidly, disease progression is accelerated (Dorey et al. 1998 , Kunert et al. 1997 , Toyoda et al. 1996 ).

SUMMARY

Choosing the most appropriate animal model for a specific application can be challenging. No one animal model completely mimics human absorption and metabolism of carotenoids. The best model must be chosen considering the specific application, characteristics of the individual models, and the available funding and facilities. It may also be desirable to verify findings in more than one species to increase confidence in extrapolating the results of animal studies to humans.

FOOTNOTES

¹ Presented at Experimental Biology 98, April 1998, San Francisco, CA [Lee, C. M., Moore, A. C., Boileau, T.W.M., Williams, A. W., Thatcher. A. J. & Erdman, J. W., Jr. (1998) Comparative utility of various animal models for the evaluation of carotenoid absorption, metabolism and impact on progression of chronic diseases. FASEB J. 12: A966 (abs.)].

² Supported by NRI/U.S. Department of Agriculture Competitive Grants Program agreement # 95–37206-1685.

⁴ Abbreviations used: AMD, age-related macular degeneration; ßC, ß-carotene; VA, vitamin A.

Manuscript received March 22, 1999. Initial review completed April 30, 1999. Revision accepted August 23, 1999.

REFERENCES

1. Albanes D., Heinined O. P., Taylor P. R., Vitamo J., Edwards B. K., Rautalahti M., Hartman A. M., Palmgren J., Freedman L. S., Haapakoske J., Barrett M. J., Pietinen P., Malila N., Tala E., Liippo K., Salomaa E.-R., Tangrea J. A., Teppo L., Askin F. B., Taskinen E., Erozoan Y., Greenwald P., Huttunen J. K. -Tocopherol and ß-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: Effects of base-line characteristics and study compliance. J. Nat. Cancer Inst. 1996;88:1560-1570[Abstract/Free Full Text]

2. Bankson D. D., Russell R. M., Sadowski J. A. Determination of retinyl esters and retinol in serum or plasma by normal-phase liquid chromatography: method and applications. Clin. Chem. 1986;32:35-40[Abstract/Free Full Text]

3. Beems R. B., Beek L. v., Rutten A.A.J.J.L., Speek A. J. Subchronic (106-day) toxicology and nutrition studies with vitamin A and ß-carotene in Syrian hamsters. Nutr. Rep. Int. 1987;35:765-770

4. Bendich A. Carotenoids and the immune response. J. Nutr. 1989;119:112-115

5. Bendich A., Shapiro S. S. Effect of ß-carotene and canthaxanthin on the immune responses of the rat. J. Nutr. 1986;116:2254-2262

6. Bierer T. L., Merchen N. R., Erdman J. W., Jr Comparative absorption and transport of five common carotenoids in preruminant calves. J. Nutr. 1995;125:1569-1577

7. Biesalski H. K., Weiser H. ß-Carotene Supplements Cannot Meet All Vitamin A Requirements of Vitamin A-Deficient Rats 1993 New York Academy of Science New York, NY.

8. Block G., Patterson B., Subar A. Fruit, vegetable, and cancer prevention: a review of the epidemiological evidence. Nutr. Cancer 1992;18:1-29[Medline]

9. Boileau A. C., Merchen N. R., Wasson K., Atkinson C. A., Erdman J. W., Jr cis-Lycopene is more bioavailable than trans-lycopene in vitro and also in vivo in the lymph-cannulated ferret. J. Nutr. 1999;129:1176-1181[Abstract/Free Full Text]

10. Boileau T.W.M., Moore A. C., Erdman J. W., Jr Carotenoids and Vitamin A in Human Health. Papas A. M. eds. Antioxidant Status, Diet, Nutrition, and Health 1999:133-158 CRC Press Boca Raton, FL.

11. Bond M. G., Bullock B. C., Belinger D. A., Hamm T. E. Myocardial infarction in a large colony of nonhuman primates with coronary artery athersclerosis. Am. J. Pathol. 1980;101:675-692[Abstract]

12. Castenmiller J.J.M., West C. E. Bioavailability and bioconversion of carotenoids. Annu. Rev. Nutr. 1998;18:19-38[Medline]

13. Chew B. P. Effects of supplemental ß-carotene and vitamin A on reproduction in swine. J. Anim. Sci. 1993;71:247-252[Abstract]

14. Chew B. P., Holpuch D. M., O’Fallon J. V. Vitamin A and ß-Carotene in bovine and porcine plasma, liver, corpora lutea, and follicular fluid. J. Dairy Sci. 1984;67:1316-1322

15. Chew B. P., Park J. S., Wong T. S., Weng B. C., Kim H. W., Byrne K. M., Hayek M. G., Reinhart G. A. Role of dietary ß-carotene in modulating cell-mediated and humoral immune response in dogs. FASEB J 1998;12:A967(abs.)

16. Chew B. P., Wong T. S., Michal J. J., Standaert F. E., Heirman L. R. Kinetic characteristics of ß-carotene uptake after an injection of ß-carotene in pigs. J. Anim. Sci. 1991;69:4883-4891[Abstract]

17. Corey J. E., Hayes K. C. Cerebrospinal fluid pressure, growth, and hematology in relation to retinol status of the rat in acute vitamin A deficiency. J. Nutr. 1972;102:1585-1594

18. de Pee S., Bloen M. W., Gorstein J., Sari M., Satoto , Yip R., Shrimpton R., Muhilal Reappraisal of the role of vegetables in the vitamin A status of mothers in Central Java, Indonesia. Am. J. Clin. Nutr. 1998;68:1068-1074[Abstract]

19. de Pee S., West C. E., Permaesih D., Martuti S., Muhilal & Hautvast J. G. Orange fruit is more effective than are dark-green, leafy vegetables in increasing serum concentrations of retinol and ß-carotene in school children in Indonesia. Am. J. Clin. Nutr. 1998;68:1058-1067[Abstract]

20. DiFrancesco L., Allen O. B., Mercer N. H. Long-term feeding of casein or soy protein with or without cholesterol in Mongolian gerbils. Acta Cardiol 1990;45:273-290[Medline]

21. Dorey C. K., Thomson L., Kinert K., Finger M., Nichols C., Cheng K., Craft N. Effect of dietary zeaxanthin on age related changes in quail retinas. Ophthalmol. Vis. Sci. 1998;39:164(abs.)[Abstract/Free Full Text]

22. Erdman J. W., Jr, Fahey G. C., Jr, White C. B. Effects of purified dietary fiber sources on ß-carotene utilization by the chick. J. Nutr. 1986;116:2415-2423

23. Erdman J. W., Jr, Thatcher A. J., Hofmann N. E., Lederman J. D., Block S. S., Lee C. M., Mokady S. All-trans ß-carotene is absorbed preferentially to 9-cis ß-Carotene, but the latter accumulates in the tissues of domestic ferrets (Mustela purotius furo). J. Nutr. 1998;128:2009-2013[Abstract/Free Full Text]

24. Erdman S. E., Correa P., Coleman L. A., Schrenzel M. D., Li X., Fox J. G. Helicobacter mustelae-associated gastric MALT lymphoma in ferrets. Am. J. Pathol. 1997;151:273-280[Abstract]

25. Fawzi W. W., Herrera M. G., Willett W. C., Amin A. E., Nestel P., Lipsitz S., Spiegelman D., Mohamed K. A. Vitamin A supplementation and dietary vitamin A in relation to the risk of xerophthalmia. Am. J. Clin. Nutr. 1993;58:385-391[Abstract/Free Full Text]

26. Fox J. G., Dangler C. A., Sager W., Borkowski R., Gliatto J. M. Helicobacter mustelea-associated gastric adenocarcinoma in ferrets (Mustela putorius furo). Vet. Pathol. 1997;34:225-229[Abstract]

27. Gardner E. M., Ross A. C. Dietary vitamin A restriction produces marginal vitamin A status in young rats. J. Nutr. 1993;123:1435-1443

28. Giovannucci E., Ascherio A., Rimm E. B., Stampfer M. J., Colditz G. A., Willett W. C. Intake of carotenoids and retinol in relation to risk of prostate cancer. J. Natl. Cancer Inst. 1995;87:1767-1776[Abstract/Free Full Text]

29. Grolier P., Agoudave S., Azais-Braesco V. Comparative bioavailability of diet-, oil- and emulsion-based preparations of vitamin A and ß-carotene in rats. Nutr. Res. 1995;15:1507-1516

30. Gugger E. T., Bierer T. L., Henze T. M., White W. S., Erdman J. W., Jr ß-Carotene uptake and tissue distribution in ferrets (Mustela putorius furo). J. Nutr. 1992;122:115-119

31. Handelman G. J., Snodderly D. M., Adler A. J., Russett M. D., Dratz E. A. Measurement of carotenoids in human and monkey retinas. Methods Enzymol 1992;213:220-230[Medline]

32. Hoppe, D. P. & Schoner, F. J. (1987) Application of Carotenoids to Animal Nutrition and Bioavailibility of Synthetic ß-Carotene in Laboratory Animals and Calves. 8th International Symposium on Carotenoids, Boston, MA (abs. 53).

33. Hoppe P. P., Chew B. P., Safer A., Stegemann I., Biesalski H. K. Dietary ß-carotene elevates plasma steady-state and tissue concentrations of ß-carotene and enhances vitamin A balance in preruminant calves. J. Nutr. 1996;126:202-208

34. House W. A., Apgar J., Smith J. C. The gerbil: a model for studying the metabolism of beta-carotene and minerals. Nutr. Res. 1997;17:1293-1302

35. Humphrey J. H., West K. P., Jr, Sommer A. Vitamin A deficiency and attributable mortality among under-5-year olds. Bull. WHO 1992;70:225-232[Medline]

36. Jyonouchi H., Zhang L., Gross M., Tomita Y. Immunomodulating actions of carotenoids: enhancement of in vivo and in vitro antibody production to T-dependent antigens. Nutr. Cancer 1994;21:47-58[Medline]

37. Kim H. W., Chew B. P., Wong T. S., Park J. S., Weng B. C., Byrne K. M., Hayek B. G. Modulation of cell-mediated immunity by dietary lutein in dogs. FASEB J 1998;12:A966(abs.)

38. Kohlmeier L., Hastings S. B. Epidemiologic evidence of a role of carotenoids in cardiovascular disease prevention. Am. J. Clin. Nutr. 1995;62:1370S-1376S[Abstract/Free Full Text]

39. Krinsky N. I., Mathews-Roth M. M., Welankiwar S., Sehgal K., Lausen N.C.G., Russett M. The metabolism of ¹⁴C-ß-carotene and the presence of other carotenoids in rats and monkeys. J. Nutr. 1990;120:81-87

40. Kunert K., Fitzgerald M.E.C., Thomson L., Cheng K., Dorey C. K. Activated microglia among the photoreceptors in aging birds. Investig. Ophthalmol 1997;39:561(abs.)

41. Lederman J. D., Overton K. M., Hofmann N. E., Moore B. J., Thornton J., Erdman J. W., Jr Ferrets (Mustela putoius furo) inefficiently convert ß-carotene to vitamin A. J. Nutr. 1998;128:271-279[Abstract/Free Full Text]

42. Lee C. M., Lederman J. D., Hofmann N. E., Erdman J. W., Jr The Mongolian gerbil (Meriones unguiculatus) is an appropriate animal for evaluation of the conversion of ß-carotene to vitamin A. J. Nutr. 1998;128:280-286[Abstract/Free Full Text]

43. Lingen C., Ernster L., Lindberg O. The promoting effect of lycopene on the non-specific resistance of animals. Exp. Cell Res. 1959;16:384-393

44. Mathews-Roth M. M., Welankiwar S., Sehgal P. K., Lausen N.C.G., Russett M., Krinsky N. I. Distribution of ¹⁴C-canthaxanthin and ¹⁴C-lycopene in rats and monkeys. J. Nutr. 1990;120:1205-1213

45. Mayne S. T. Beta-carotene, carotenoids, and disease prevention in humans. FASEB J 1996;10:690-701[Abstract]

46. Mittal P. C. ß-Carotene utilization in rats fed either vitamin A or carotene in early life. Nutr. Rep. Int. 1983;28:181-188

47. Moon R. C. Comparative aspects of carotenoids and retinoids as chemopreventive agents for cancer. J. Nutr. 1989;119:127-134

48. Moore A. C., Gugger E. T., Erdman J. W., Jr Brush border membrane vesicles from rats and gerbils can be used to study uptake of all-trans and 9-cis ß-carotene. J. Nutr. 1996;126:2904-2912

49. Nagasawa H., Mitamura T., Sakamoto S., Yamamoto K. Effects of lycopene on spontaneous mammary tumor development in SHN virgin mice. Anticancer Res 1995;15:1173-1178[Medline]

50. Narisawa T., Fukaura Y., Hasebe M., Ito M., Aizawa R., Murakoshi M., Uemura S., Khachik F., Nishino H. Inhibitory effects of natural carotenoids, -carotene, ß-carotene, lycopene and lutein, on colonic aberrant crypt foci formation in rats. Cancer Lett 1996;107:137-142[Medline]

51. Narisawa T., Fukaura Y, Haseve M., Nomura S., Oshima S., Sakamoto H., Inakuma T., Ishiguro Y., Takayasu J., Nishino H. Prevention of N-methylnitrosourea-induced colon carcinogenesis in F344 rats by lycopene and tomato juice rich in lycopene. Jpn. J. Cancer Res. 1998;89:1003-1008[Medline]

52. National Research Council Recommended Dietary Allowances 10th ed. 1989 National Academy Press Washington, DC.

53. Nicolosi R. J., Marlett J. A., Morrello A. M., Flanagan S. A., Hegsted D. M. Influence of dietary unsaturated and saturated fat on the plasma lipoproteins of Mongolian gerbils. Atherosclerosis 1981;38:359-371[Medline]

54. Olson J. A. Carotenoids. Shils M. E. Olson J. A. Shike M. Ross A. C. eds. Modern Nutrition in Health and Disease 1999:525-541 Williams and Wilkins Baltimore, MD.

55. Omenn G. S., Goodman G. E., Thornquist M. D. Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease. N. Eng. J. Med. 1996;334:1150-1155[Abstract/Free Full Text]

56. Pollack J., Campbell J. M., Potter S. M., Erdman J. W., Jr Mongolian gerbils (Meriones unguiculatus) absorb ß-carotene intact from a test meal. J. Nutr. 1994;124:869-873

57. Poor C. L., Bierer T. L., Merchen N. R., Fahey G. C., Jr, Murphy M. R., Erdman J. W., Jr Evaluation of the preruminant calf as a model for the study of human carotenoid metabolism. J. Nutr. 1992;122:262-268

58. Poor C. L., Miller S. D., Fahey G. C., Jr, Easter R. A., Erdman J. W., Jr Animal models for carotenoid utilization studies: evaluation of the chick and the pig. Nutr. Rep. Int. 1987;36:229-234

59. Pronczuk A., Khosla P., Hayes K. C. Dietary myristic, palmitic, and linoleic acids modulate cholesterolemia in gerbils. FASEB J 1994;8:191-200

60. Ribaya-Mercado J. D., Fox J. G., Rosenblad W. D., Blanco M. C., Russell R. M. ß-Carotene, retinol and retinyl ester concentrations in serum and selected tissues of ferrets fed ß-carotene. J. Nutr. 1992;122:1898-1903

61. Ribaya-Mercado J. D., Holmgren S. C., Fox J. G., Russell R. M. Dietary ß-carotene absorption and metabolism in ferrets and rats. J. Nutr. 1989;119:665-668

62. Roodenburg A.J.C., West C. E., Hovenier R., Beynen A. C. Evaluation of a two-generation model for vitamin A deficiency and the interrelationship with iron metabolism. Br. J. Nutr. 1995;74:689-700[Medline]

63. Rosales F. J., Ross A. C. Acute inflammation induces hyopretinemia and modifies the plasma and tissue response to vitamin A supplememtation in marginally vitamin A–deficient rats. J. Nutr. 1998;128:960-966[Abstract/Free Full Text]

64. Santos M. S., Meydani S. N., Leka L., Wu D., Fotouhi N., Meydani M., Hennekens C. H., Gaziano J. M. Natural killer cell activity in elderly men is enhanced by ß-carotene supplementation. Am. J. Clin. Nutr. 1996;64:772-777[Abstract/Free Full Text]

65. Sato N., Gleave M. E., Burchovsky N., Rennie P. S., Beralde E., Sullivan L. D. A metastatic and androgen-sensitive human prostate cancer model using intraprostatic inoculation of LNCaP cells in SCID mice. Cancer Res 1997;57:1584-1589[Abstract/Free Full Text]

66. Schwartz J., Shklar G. Regression of experimental hamster cancer by beta carotene and algae extracts. J. Oral Maxillofac. Surg. 1987;45:510-515[Medline]

67. Shapiro S. S., Mott D. J., Machlin L. J. Kinetic characteristics of ß-carotene uptake and depletion in rat tissue. J. Nutr. 1984;114:1924-1933

68. Slifka K. A., Bowen P. E., Stacewicz-Sapontzakis M., Crissey S. D. A survey of serum and dietary carotenoids in captive wild animals. J. Nutr. 1999;129:380-390[Abstract/Free Full Text]

69. Snodderly D. M. Evidence for protection against age-related macular degeneration by carotenoids and antioxidant vitamins. Am. J. Clin. Nutr. 1995;62:1448S-1461S[Abstract/Free Full Text]

70. Snodderly D. M., Handelman G. J., Adler A. J. Distribution on individual macular pigment carotenoids in central retina of macaque and squirrel monkeys. Investig. Ophthalmol. Vis. Sci. 1991;32:268-279[Abstract/Free Full Text]

71. Snodderly D. M., Russett M. D., Land R. I., Krinsky N. I. Plasma carotenoids of monkeys (Macaca fascicularis and Saimiri sciureus) fed a nonpurified diet. J. Nutr. 1990;120:1663-1671

72. Sommer A., West K. P., Jr Vitamin A Deficiency: Health, Survival, and Vision 1996:438 Oxford University Press New York, NY.

73. Steinmetz K. A., Potter J. D. Vegetables, fruit, and cancer prevention: a review. J. Am. Diet. Assoc. 1996;96:1027-1039[Medline]

74. Sullivan M. P., Cerda J. J., Robbins F. L., Burgin C. W., Beatty R. J. The gerbil, hamster, and guinea pig as rodent modles of hyperlipidemia. Lab. Anim. Sci. 1993;43:575-578[Medline]

75. Sun J., Giraud D. W., Moxley R. A., Driskell J. A. ß-Carotene and -tocopherol inhibit the development of atherosclerotic lesions in hypercholesterolemic rabbits. Int. J. Vitam. Nutr. Res. 1997;67:155-163[Medline]

76. Tang G., Dolnikowski G. G., Blanco M. C., Fox J. G., Russell R. M. Serum carotenoids and retinoids in ferrets fed canthaxanthin. J. Nutr. Biochem. 1993;4:58-63

77. Tasker T. E., Potter S. M. Effects of dietary protein source on plasma lipids, HMG CoA reductase activity, and hepatic glutathione levels in gerbils. J. Nutr. Biochem. 1993;4:458-462

78. Thatcher A. J., Lee C. M., Erdman J. W., Jr Tissue stores of ß-carotene are not conserved for later use as a source of vitamin A during compromised vitamin A status in Mongolian gerbils (Meriones unguiculatus). J. Nutr. 1998;128:1179-1185[Abstract/Free Full Text]

79. Thompson T. C., Truong L. D., Timme T. L., McCune D.K.B.K., Flanders K. C., Scardino P. T., Park S. H. Transgenic models for the study of prostate cancer. Cancer 1993;71:1165-1171[Medline]

80. Toyoda, Y., Sapunzatkis, M., Nichols, C., Cheng, K. & Dorey, C. K. (1996) Carotenoids in the quail retina. an animal for retinal carotenoids. Investig. Ophthalmol. Vis. Sci. 36: (abs.).

81. Tyczkowski J. K., Hamilton P. B. Evidence for differential absorption of zeacarotene, cryptoxanthin, and lutein in young broiler chickens. Poult. Sci. 1986;65:1137-1140[Medline]

82. Van Vliet T. Absorption of ß-carotene and other carotenoids in humans and animal models. Eur. J. Clin. Nutr. 1996;50:S32-S37

83. Wang J. Y., Owen F. G., Larson L. L. Effect of beta-carotene supplementation on reproductive performance of lactating Holstein cows. J. Dairy Sci. 1988;71:181-186

84. Wang X.-D., Krinsky N. I., Marini R. P., Tang G.-W., Yu J., Hurley R., Fox J. G., Russell R. M. Intestinal uptake and lymphatic absorption of ß-carotene in ferrets: a model for human ß-carotene metabolism. Am. J. Physiol. 1992;263:G480-G486[Abstract/Free Full Text]

85. Wang X.-D., Liu C., Bronson R. T., Smith D. E., Krinsky N. I., Russell R. M. Retiniod signaling and activator protein-1 expression in ferrets given ß-carotene supplements and exposed to tobacco smoke. J. Natl. Cancer Inst. 1999;91:60-66[Abstract/Free Full Text]

86. Wang X.-D., Tang G.-W., Fox J. G., Krinsky N. I., Russell R. M. Enzymatic conversion of ß-carotene into ß-apocarotenals and retinoids by human, monkey, ferret, and rat tissues. Arch. Biochem. Biophys. 1991;285:8-16[Medline]

87. Warmer W., Giles A., Jr, Kornhauser A. Accumulation of dietary ß-carotene in the rat. Nutr. Rep. Int. 1985;32:295-301

88. White W. S., Peck K. M., Bierer T. L., Gugger E. T., Erdman J. W., Jr Interactions of oral ß-carotene and canthaxanthin in ferrets. J. Nutr. 1993;123:1405-1413

89. White W. S., Peck K. M., Ulman E. A., Erdman J. W., Jr The ferret as a model for evaluation of the bioavailabilities of all-trans ß-carotene and its isomers. J. Nutr. 1993;123:1129-1139

90. Williams J. K., Anthony M. S., Clarkson T. B. Coronary heart disease in rhesus monkeys with diet-induced coronary artery atherosclerosis. Arch. Pathol. Lab. Med. 1991;115:784-790[Medline]

91. Yap S. C., Choo Y. M., Hew N. F., Goh S. H. Distribution of dietary palm carotenes and their metabolites in the rabbit. Nutr. Res. 1997;17:1721-1731

92. Youping G., Root M. M., Parker R. S., Campbell T. C. Effects of carotenoid-rich food extracts on the development of preneoplastic lesions in rat liver and in in vivo and in vitro antioxidant status. Nutr. Cancer 1997;27:238-244[Medline]

This article has been cited by other articles:

				S. Blanquet-Diot, M. Soufi, M. Rambeau, E. Rock, and M. Alric Digestive Stability of Xanthophylls Exceeds That of Carotenes As Studied in a Dynamic in Vitro Gastrointestinal System J. Nutr., May 1, 2009; 139(5): 876 - 883. [Abstract] [Full Text] [PDF]

				D. H. Baker Animal Models in Nutrition Research J. Nutr., February 1, 2008; 138(2): 391 - 396. [Abstract] [Full Text] [PDF]

				J. P. Mills, P. W. Simon, and S. A. Tanumihardjo {beta}-Carotene from Red Carrot Maintains Vitamin A Status, but Lycopene Bioavailability Is Lower Relative to Tomato Paste in Mongolian Gerbils J. Nutr., June 1, 2007; 137(6): 1395 - 1400. [Abstract] [Full Text] [PDF]

				J. A. Howe and S. A. Tanumihardjo Carotenoid-Biofortified Maize Maintains Adequate Vitamin A Status in Mongolian Gerbils J. Nutr., October 1, 2006; 136(10): 2562 - 2567. [Abstract] [Full Text] [PDF]

				T. Sicilia, A. Bub, G. Rechkemmer, K. Kraemer, P. P. Hoppe, and S. E. Kulling Novel Lycopene Metabolites Are Detectable in Plasma of Preruminant Calves after Lycopene Supplementation J. Nutr., November 1, 2005; 135(11): 2616 - 2621. [Abstract] [Full Text] [PDF]

				S. A. Tanumihardjo and J. A. Howe Twice the Amount of {alpha}-Carotene Isolated from Carrots Is as Effective as {beta}-Carotene in Maintaining the Vitamin A Status of Mongolian Gerbils J. Nutr., November 1, 2005; 135(11): 2622 - 2626. [Abstract] [Full Text] [PDF]

				S. Zaripheh, T. W.-M. Boileau, M. A. Lila, and J. W. Erdman Jr [14C]-Lycopene and [14C]-Labeled Polar Products Are Differentially Distributed in Tissues of F344 Rats Prefed Lycopene J. Nutr., December 1, 2003; 133(12): 4189 - 4195. [Abstract] [Full Text] [PDF]

				M. van Lieshout, C. E West, and R. B van Breemen Isotopic tracer techniques for studying the bioavailability and bioefficacy of dietary carotenoids, particularly {beta}-carotene, in humans: a review Am. J. Clinical Nutrition, January 1, 2003; 77(1): 12 - 28. [Abstract] [Full Text] [PDF]

				B. C. Goswami, K. D. Ivanoff, and A. B. Barua Absorption and Conversion of 11,12-3H-{beta}-Carotene to Vitamin A in Sprague-Dawley Rats of Different Vitamin A Status J. Nutr., January 1, 2003; 133(1): 148 - 153. [Abstract] [Full Text] [PDF]

				T. W.-M. Boileau, A. C. Boileau, and J. W. Erdman Jr Bioavailability of all-trans and cis-Isomers of Lycopene Experimental Biology and Medicine, November 1, 2002; 227(10): 914 - 919. [Abstract] [Full Text] [PDF]

				J. Raila, C. Gomez, and F. J. Schweigert The Ferret as a Model for Vitamin A Metabolism in Carnivores J. Nutr., June 1, 2002; 132(6): 1787S - 1789. [Abstract] [Full Text] [PDF]

				T. W. M. Boileau, S. K. Clinton, and J. W. Erdman Jr. Tissue Lycopene Concentrations and Isomer Patterns Are Affected by Androgen Status and Dietary Lycopene Concentration in Male F344 Rats J. Nutr., June 1, 2000; 130(6): 1613 - 1618. [Abstract] [Full Text]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, C. M. Articles by Erdman, J. W. Search for Related Content PubMed PubMed Citation Articles by Lee, C. M. Articles by Erdman, J. W., Jr. Pubmed/NCBI databases Substance via MeSH