Crilical Reviews in Food Science and NUlrilion, 31 (liZ): 103-163 (1992) Carotenoids and Retinoids in Human Nutrition E-Siong Tee Division of Human Nutrition, Institute for Medical Research, 50588 Kuala Lumpur, Malaysia Referee: C. Y. Lee, Ph.D., Department of Food Science and Technology, Cornell University, Geneva, New York 14456 ABSTRACT: Since the discovery of vitamin A as a fat-soluble growth factor in thl~ early part of the century. research into carotenoids and retinoids has attracted the attention of many scientists. These two groups of compounds are still being actively studied all over the world since many gaps in knowledge exist and new frontiers are being pursued. Recent developments in studies into the possible roles of carotl~noids and retinoids beyond their classical functions in vision have created a great deal of excitement in the biomedical community. This review covers a wide range of topics pertaining to these two closely related compounds. Particular emphasis is given to the functions of these compounds and their roles in human nutrition. V2,rious aspects of vitamin A deficiency and ,tudies on carotenoids and retmoids in cancer development and prevention are reviewed in some detail. KEY WORDS: carotenoids. retinoids, human nutrition, vitamin A deficiency, cancer development and prevention. I. INTRODUCTION chemical synthesis are all more recent achieve­ ments, accomplished during the 20th century. Some 75 years ago, vitamin A was discov-­ ered as a fat-soluble growth factor present in liver Vitamin A, or retinol, is an essential nutrient and recognized as an essential biochemical for for man and all mammalian species since it can­ normal vision in man and animals. It is, in fact.. not be synthesized within the body. Deficiency the first vitamin to be discovered. Today, after of the vitamin results in adverse effects on growth, several decades, very little is known about the reproduction, and resistance to infections. Var­ vitamin's biochemical mechanisms of action in ious mild to severe biochemical and clinical signs the different functions except for the process of develop, depending on the degree of severity of vision. 1 Vitamin A deficiency remains one of the the insufficiency. The most important manifes­ major public health nutritional problems in many tation of severe vitamin A deficiency is xeroph­ developing countries and is an important cause thalmia, and irreversible blindness may eventu­ of preventable blindness. Afflicting large num .. ally occur in one or both eyes. bers of pre-school children in southeast Asia, Xerophthalmia is not a condition of recent vitamin A deficiency is often associated with pro.. recognition. The ancient Papyrus Ebers, an tein-energy malnutrition, parasitic infestation, and Egyptian medical treatise of about 1500 B. C. , diarrheal disease. The interaction between vita .. and the Chinese at about the same time, had min A and infection has recently been given a already documented the occurrence of night great deal of attention. The synergistic effect be· blindness. 1.2 For the treatment of this early stage tween vitamin A deficiency and infection may of xerophthalmia, liver or liver extract was rec­ be responsible for excessi ve childhood morbidity ommended. However, the identification, isola­ and mortality in many developing regions of the tion, synthesis, and production of vitamin A by world. Recent studies on vitamin A supp1emen­ 1040-8398/92/$ .50 © 1992 by CRC Press, Inc. tation and child survival and mortality have cre­ ular attention to their importance to human nu­ ated a great deal of interest and debate in the trition. A detailed discussiOll of analytical meth­ international health and nutrition community. ods for retinoids and carotenoids is treated in a The major source of vitamin A in the diet of separate review by the author." most communities in developing countries is ca­ rotenoids. A review of vitamin A in human nu­ trition would thus be incomplete without due con­ II. HISTORICAL PERSPECTIVE sideration to these pigments of provitamin A activity. Carotenoids and retinoids have had a long Carotenoids are synthesized exclusively by and interesting history. Biologists, organic chem­ photosynthetic microorganisms and by members ists, and biochemists were fascinated by the of the plant kingdom where they play a funda­ brightly colored carotenoid pigments more than mental role in metabolism. Aside from providing a century ago. Studies on these pigments have aesthetic qualities as colorants in the plant and been traced to the beginning of the 19th century, the animal kingdoms, these pigments also take when the crystalline yellow pigment carotene was part in the photosynthetic process. Most impor­ first isolated in 1831 and the naming in 1837 of tantly, the carotenoids serve the animal kingdom the yellow pigments of autumn leaves as xan­ as sources of vitamin A activity. thophylls.7-9 In the early part of the 20th century, A large number of pigments in living organ­ it was clearly shown that there existed a whole isms - carotenoids, chlorophylls, anthocyanins, family of carotenoids, and that these were iso­ and porphyrins - provide the rich variety of prenoid derivatives. color in nature. The carotenoids, believed to have In 1913 McCollum and Davis 10 reported the derived their name from the fact that they con­ existence in certain foods of an essential Iipid­ stitute the major pigment in the carrot root, Dau­ soluble substance capable of promoting growth cus carata, are undoubtedly among the most in rats. They called this substance "fat-soluble widespread and important. This group of pig­ A" to distinguish it from essential water-soluble ments is found throughout the plant kingdom (al­ nutrients, which they called' . water-soluble B,', It though the~ir presence is often masked by chlo­ During the subsequent decade, further informa­ rophyll) and in insects, fish, birds, and other tion about the existence and properties of this animals. These pigments provide a whole range soluble essential nutrient was obtained from the of light yellow to dark red colorings, and when work of a number of investigators, including comp1exed with proteins, green and blue color­ McCollum and associates Osborne and Mendel, ations are achieved. Thus, a wide variety offoods Stepp, Steenbock, Moore, and others. It was and feeds - yellow vegetables, tomatoes, apri­ shown that • 'fat-soluble A" (now known as vi­ cots, oranges, egg yolk, chicken, butter, shrimp, tamin A) not only maintained growth in rats but lobsters, salmon, trout, yellow corn, etc. owe was capable of preventing night blindness and their color principally to carotenoids, as do cer­ xerophthalmia. Subsequently, the relationship tain food color extracts from natural sources such between vitamin A in animals and the provitamin as palm oil, paprika, annatto, and saffron. 3-5 carotene in plants was also clarified, particularly This review discusses these two large groups after Karrer and associat,~sI2 determined the of interrelated compounds, which are still being chemical structure of ~-carotene in 1930 and of actively studied all over the world. Many gaps retinol in 1931 using a highly purified vitamin A in knowledge exist, and new frontiers are being extract that they had obtained from shark liver pursued. Recent developments in studies into the oil. 13.14 Using such retinol preparations, the first possible roles of carotenoids and retinoids be­ oily retinol esters (e,g., retinyl acetate) were yond their classical functions have created a great prepared. 13 deal of excitement in the biomedical community. The structure of ~-carotene had been deter­ This is one of the few reviews on the subj(~ct that mined as early as 1930. 12 These two results made deals with the carotenoids and retinoids together. it possible to see from a chemical standpoint why A wide range of topics is discussed, with partic­ ~-car()tene is a natural precursor of vitamin A 104 compounds. This relationship was discovered be­ noic acid, but nevertheless retain many of the tween 1928 and 1930 in a large number of ammal biological activities of these substances. Ad­ experiments. 15.16 The elucidation of the vtamin vances in tracer chemistry now permit the syn­ A precursor function of these pigments has proved thesis of almost any desired retinoid in radioac­ to have great scientific and economic importance. tively labeled form.30 Remarkable progress has In 1937. Holmes and Corbet 17 were a.bIe to been made in the synthesis of carotl.~noids, par­ crystallize pure retinol from fish liver. Various ticularly to meet the needs of a wide range of crystalline esters of retinol were obtained from commercial uses. 31 fish liver oils by Baxter and Robeson. 18.19 These Major advances have occurred in understand­ pure compounds made possible the accurate deter­ ing the intermediary metabolism as well as the mination of a number of physicochemical c:harac­ transport systems of rctinoids, both extracellular teristics of carotenoids. Several years later. Arens and intracellular. The development of cell culture and Van Dorp20 and Isler and associates:~l suc­ techniques has facilitated study of the effects of ceeded in achieving the chemical synthesis of retinoids on cell differentiation and proliferation, pure retinoic acid and retinol. Shortly thereafter. one of the most basic problems of biology ..12 Fun­ the total synthesis of f3-carotene was also damental to these new studies is the realization reported. 22 that retinoids are highly potent agents for control Many studies were conducted in the first half of these processes_ In this regard, the retinoids of this century dealing with various aspects of have had a particularly striking role in helping to the physiology and metabolism of vitamin A. illuminate the problem of rnalignam cell differ­ Particularly noteworthy was the identification by entiation. There has thus been a thrust in the Wald,23 Morton,24 and Morton and Good"",in25 of development of new retinoids for prevention or the chromophore of the visual pigment a~, retin­ treatment of disease, particularly in the areas of aldehyde.