Some carotenoids are considered provitamins because they can be converted to:

A vast number of observational studies, including both case-control and cohort studies, of carotenoids and chronic disease risk have

Prospective blood carotenoid concentration studies may be particularly informative because blood samples are generally obtained several years prior to the clinical detection of disease. Thus, for the purposes of evaluating the association between quantitative carotenoid exposure and risk of chronic disease, the prospective blood concentration studies are most useful and are given the greatest weight in the analysis that follows. The studies in which food intakes were the basis for evaluating risk of disease are less useful due to the inherent problems in adequately estimating carotenoid intake. These studies, however, may give support to the overall evaluation of the role of carotenoids in chronic disease. The following section briefly summarizes some key research findings from observational studies of the relationship between carotenoids and chronic disease risk.

Mortality

Greenberg et al. (1996) obtained blood samples from 1,188 men and 532 women enrolled in a skin cancer prevention trial and examined the relationship between plasma β-carotene concentrations at entry and subsequent mortality over a median follow-up period of 8.2 years (). Persons in the lowest quartile of plasma β-carotene had a significant increase in their risk of dying compared to those with higher plasma concentrations of β-carotene. The adjusted relative risk was lowest for persons with plasma β-carotene concentrations in the range of 0.34 to 0.53 µmol/L (18 to 28 µg/dL) (quartile 3), with a risk reduction (compared to the lowest quartile) of 43 percent for total deaths, 43 percent for cardiovascular disease deaths, and 51 percent for cancer deaths. The relative risk for overall mortality was 38 percent lower for persons who had plasma β-carotene concentrations in the highest quartile compared to the lowest quartile (relative risk [RR] = 0.62; 95 percent confidence interval [CI] = 0.44−0.87). Thus, these results suggest that plasma β-carotene concentrations in the range of 0.34 to 0.53 µmol/L (18 to 28 µg/dL) are associated with the lowest risk of all-cause

mortality in U.S. adults. Note that these blood concentrations reflect levels in the absence of supplementation with β-carotene. Thus, this prospective study emphasizes the inverse association between β-carotene-rich foods and the risk of all-cause mortality.

TABLE 8-3

Concentrations of β-Carotene and Total Carotenoids in Plasma or Serum Associated with a Lower Risk of Various Health Outcomes in Selected Studies.

Another cohort study of carotenoids and mortality examined both dietary intake of total carotenoids and plasma concentrations of total carotenoids as predictors of mortality (Sahyoun et al., 1996). Results indicated that mortality from cancer and all causes other than coronary heart disease (CHD) was lowest at a plasma concentration of 3.13 µmol/L (168 µg/dL) total carotenoids or greater; mortality from CHD was lowest at plasma concentrations of 1.73 to 3.13 µmol/L (93 to 168 µg/dL). Overall mortality was lowest at dietary carotenoid intake levels of 8.6 mg/day (RR = 0.68 compared to those consuming 1.1 mg/day of carotenoids).

In the Western Electric cohort study, all-cause mortality was lowest for men who consumed the highest tertile of dietary β-carotene (RR = 0.80 for more than 4.1 mg/day of β-carotene versus less than 2.9 mg/day of β-carotene; p for trend = 0.01) (Pandey et al., 1995).

Cancer

Because there are literally hundreds of studies of carotenoids and cancer risk, this section emphasizes the results of epidemiological studies of all cancers combined, studies of carotenoids and lung cancer, and a few other selected tumor sites for which an inverse association with carotenoids is commonly seen.

Observational Epidemiological Studies. The Basel Prospective Study evaluated the relationship between plasma carotene concentrations in blood samples obtained in 1971–1973 and subsequent cancer mortality up to 1985 (Stahelin et al., 1991). Results showed that persons who went on to develop any cancer had significantly lower prediagnostic carotene concentrations than persons who remained alive and free of cancer in 1985 (mean plasma total carotenoid concentration 0.34 µmol/L [18 µg/dL] in those with cancer versus 0.43 µmol/L [23 µg/dL] in those free of cancer). The authors state that the reported carotene values represent approximately 80 percent β-carotene and 20 percent α-carotene; thus, plasma β-carotene concentrations of approximately 0.34 µmol/L (0.43 µmol/L × 0.8) (18 µg/dL [23 µg/dL × 0.8]) were typical for the survivors of this cohort. This concentration is within the range associated with lower risk elsewhere as shown in .

Numerous epidemiological studies have shown that individuals who consume a relatively large quantity of carotenoid-rich fruits and vegetables have a lower risk of cancer at several tumor sites (Block et al., 1992). The consistency of the results from observational studies is particularly striking for lung cancer, where carotenoid and fruit and vegetable intake has been associated with lower lung cancer risk in 8 of 8 prospective studies and 18 of 20 retrospective studies reviewed (Ziegler et al., 1996b).

Focusing on prospective blood analyses studies, the study with the largest number of cases (n = 99) was reported by Menkes et al. (1986) as part of the Washington County, Maryland, cohort. The risk of lung cancer increased in a linear fashion with decreasing serum concentrations of β-carotene, with the greatest risk at the lowest quintile (cutpoint not stated). The mean concentration of serum β-carotene in persons who subsequently developed lung cancer was 0.47 µmol/L (25 µg/dL), compared to 0.54 µmol/L (29 µg/dL) in persons who remained free of disease.

Nomura et al. (1985) conducted a prospective study of 6,860 men of Japanese ancestry in Hawaii; 74 men subsequently developed lung cancer. Men who later developed lung cancer had lower serum β-carotene concentrations (0.37 µmol/L [20 µg/dL]) than control subjects (0.54 µmol/L [29 µg/dL]). Similar results were reported in the Basel Prospective Study. Men who later developed lung cancer (n = 68) had α- plus β-carotene serum concentrations of 0.30 µmol/L (16 µg/dL) versus 0.43 µmol/L (23 µg/dL) in survivors (Stahelin et al., 1991). The Multiple Risk Factor Intervention Trial (MRFIT) cohort study had prediagnostic serologic data on 66 lung cancer cases and 131 control subjects (Connett et al., 1989). Lung cancer cases had lower serum β-carotene concentrations (mean of 0.17 µmol/L [9 µg/dL]) and total carotenoid concentrations (1.62 µmol/L [87 µg/dL]) compared to the control subjects (0.22 µmol/L [12 µg/dL] and 1.84 µmol/L [99 µg/dL]), respectively. The absolute carotenoid concentrations in this study are lower than those in the previous studies, which may be a consequence of long-term storage of the samples at −50°C, rather than at −70°C or colder as is recommended for carotenoids.

As for dietary studies, the majority of the studies of carotenoids and lung cancer risk have relied upon the U.S. Department of Agriculture (USDA) Nutrient Database for Standard Reference, Release 13, which does not contain estimates of the amount of carotenoids in various food items, but simply contains estimates of provitamin A activity. With the release of a new carotenoid database in 1993 (Mangels et al., 1993), quantitative studies relating consumption of individual carotenoids to lung cancer risk are now available. Le Marchand et al. (1993) found that higher dietary intake of α-carotene, β-carotene, and lutein was significantly associated with lower lung cancer risk in both men and women. Optimal levels of intake for each of these three carotenoids were as follows: β-carotene more than 4.0 mg/day for men and more than 4.4 mg/day for women; α-carotene more than 0.6 mg/day for men and more than 0.7 mg/day for women; and lutein more than 3.3 mg/day for both males and females. Ziegler et al. (1996a) also found significant inverse trends for dietary α- and β-carotene and a marginally significant effect for lutein and zeaxanthin with risk of lung cancer. Optimal levels in this study were as follows: β-carotene 2.5–5.9 mg/day; α-carotene more than 1.5 mg/day; and lutein and zeaxanthin more than 4.2 mg/day.

As reviewed elsewhere, retrospective and prospective epidemiological studies of diet and serum carotenoids strongly indicate that greater consumption of fruits, vegetables, and carotenoids is inversely associated with risk of cancers of the oral cavity, pharynx, and larynx (Mayne, 1996; Mayne and Goodwin, 1993). In a review (Block et al., 1992), 13 of 13 studies indicated that fruit and vegetable intake was associated with reduced risk of cancers of the oral cavity, pharynx, and larynx. As for prospective serologic studies, Zheng et al. (1993) conducted a nested case-control study of serum micronutrients and subsequent risk of oral and pharyngeal cancer. Blood samples were collected and stored in 1974 from a cohort of 25,802 adults in Maryland. Over the next 15 years, 28 individuals developed oral or pharyngeal cancer. Serum analyses indicated that prediagnostic serum concentrations of all the major individual carotenoids, particularly β-carotene, were lower among the case group than among control subjects selected from the same cohort. β-Carotene concentrations in persons who later developed these cancers were 0.21 µmol/L (11 µg/dL) versus 0.28 µmol/L (15 µg/dL) in control subjects (mean; p = 0.03). Adjustment for smoking, which is known to be associated with lower serum carotenoid concentrations, attenuated the protective association slightly. The unadjusted and adjusted relative odds of oral or pharyngeal cancer, comparing the upper tertile of serum β-carotene concentrations (cutpoints not given) versus the lower tertile, were 0.50 and 0.69, respectively.

One recent prospective cohort study (Giovannucci et al., 1995) evaluated 47,894 participants in the Health Professionals Follow-up Study, 812 of whom were diagnosed with prostate cancer during the 6-year follow-up. Intake of tomato-based foods (tomato sauce, tomatoes, and pizza—but not tomato juice) and lycopene, which is found predominantly in tomato products, was associated with significantly lower prostate cancer risk. Risk was lowest for those who were estimated to consume more than 6.46 mg/day of lycopene. The lack of association for tomato juice may reflect the fact that lycopene is more bioavailable from processed tomato products than from fresh tomatoes (Gartner et al., 1997).

A prospective study of serum micronutrients and prostate cancer in Japanese men in Hawaii, however, found no difference in prediagnostic serum lycopene concentrations in 142 cases versus 142 matched control subjects (Nomura et al., 1997). The lack of effect seen in this study could possibly relate to the fact that serum lycopene concentrations were relatively low in this population (median 0.25 µmol/L [13 µg/dL]). This is likely a consequence of the fact that tomato products are not widely consumed in the Asian diet (thus the range of exposure may have been limited). Comprehensive reviews of the relationship between lycopene and prostate cancer have been published elsewhere (Clinton, 1998; Giovannucci, 1999).

Consumption of fruits and vegetables also has been reported to be inversely associated with cervical cancer risk in a number of studies. Batieha et al. (1993) conducted a nested case-control study, analyzing a variety of carotenoids in sera stored from 50 women who had developed either invasive cervical cancer or carcinoma in situ during a 15-year follow-up and in 99 control women pair-matched to the cases. The risk of cervical cancer was significantly higher among women with the lowest prediagnostic serum concentrations of total carotenoids (odds ratio [OR] = 2.7; 95 percent CI = 1.1−6.4), α-carotene (OR = 3.1; 95 percent CI = 1.3−7.6), and β-carotene (OR = 3.1; 95 percent CI = 1.2−8.1) compared to women in the upper tertiles. Mean serum concentrations of β-cryptoxanthin were also lower among cases relative to control subjects (p = 0.03). Optimal concentrations of these carotenoids for reducing the risk of cervical cancer were as follows: total carotenoids greater than 1.88 µmol/L (101 µg/dL); α-carotene greater than 0.05 µmol/L (2.7 µg/dL); β-carotene greater than 0.26 µmol/L (14 µg/dL); and cryptoxanthin greater than 0.17 µmol/L (9 µg/dL).

Intervention Trials. Three major double-blind, randomized intervention trials have been conducted using high-dose β-carotene supplements, either alone or in combination with other agents, in an attempt to evaluate any protective role in the development of lung or total cancers. In none of these studies was there any evidence of a protective role for supplementary β-carotene.

In current smokers participating in the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study, supplementation with 20 mg/day of β-carotene (with or without 50 mg of α-tocopherol) for 5 to 8 years led to a higher incidence in lung cancer but had no effect on the incidence of other major cancers occurring in this population (prostate, bladder, colon or rectum, or stomach) (ATBC Cancer Prevention Study Group, 1994). In addition, the Carotene and Retinol Efficacy Trial (CARET) used a nutrient combination of β-carotene (30 mg/day) plus retinyl palmitate (25,000 international units [IU]/day) versus placebo in asbestos workers and smokers (Omenn et al., 1996a, 1996b). This study reported more lung cancer cases in the supplemented group. The Physicians' Health Study (PHS) of supplemental β-carotene versus placebo in 22,071 male U.S. physicians reported no significant effect of 12 years of supplementation of β-carotene (50 mg every other day) on cancer or total mortality (Hennekens et al., 1996).

Summary. Higher consumption of carotenoid-containing fruits and vegetables and higher plasma concentrations of several carotenoids, including β-carotene, are associated with a lower risk of many different cancers, especially lung, oral cavity, pharyngeal, laryngeal, and cervical cancers. These prospective blood concentration studies show that β-carotene concentrations in the range of 0.28 µmol/L (15 µg/dL) or less are associated with higher risk of many cancers (), whereas concentrations greater than 0.28 to 0.37 µmol/L (15 to 20 µg/dL) are associated with reduced risk of many cancers. This approximate threshold for cancer risk reduction is concordant with that for the prevention of all-cause mortality, given above. Furthermore, these studies show that increased consumption of foods containing these carotenoids, including carotenoids lacking vitamin A activity, is associated with risk reduction. However, in three large randomized clinical trials using high-dose β-carotene supplements (20 or 30 mg/day or 50 mg given every other day) for 4 to 12 years, no protection was reported with respect to lung cancer, or any other cancer.

Cardiovascular Disease

Epidemiological studies, including descriptive, cohort, and case-control studies, suggest that carotenoid- and β-carotene-rich diets are associated with a reduced risk of cardiovascular disease (Gaziano and Hennekens, 1993; Kohlmeier and Hastings, 1995; Manson et al., 1993). Beginning with biochemical epidemiological studies of plasma carotenoids, Gey et al. (1993a) reported data from the Vitamin Substudy of the World Health Organization's Monitoring Cardiovascular (WHO/MONICA) Project, in which plasma was obtained from approximately 100 apparently healthy men from each of 16 study sites within Europe. A comparison between median plasma β-carotene concentrations and ischemic heart disease mortality revealed no association when all 16 study sites were considered (r 2 = 0.04). However, a reasonably strong inverse association was evident (r 2 = 0.50) when three study sites, all apparent outliers (and all Finnish sites), were excluded from the analysis.

Men in the Basel Prospective Study, who had low blood concentrations of β-carotene and vitamin C initially and who were followed for 12 years, had a significantly higher risk of subsequent ischemic heart disease (RR = 1.96; p = 0.022) and stroke (RR = 4.17; p = 0.002) (Eichholzer et al., 1992; Gey et al., 1993b). Based upon these and other data, Gey et al. (1993a) proposed that more than 0.4 to 0.5 µmol/L (21 to 27 µg/dL) α-plus β-carotene or 0.3 to 0.4 µmol/L (16 to 21 µg/dL) β-carotene is needed to reduce the risk of ischemic heart disease.

Total serum carotenoids, measured at baseline in the placebo group of the Lipid Research Clinics Coronary Primary Prevention Trial, were inversely related to subsequent coronary heart disease events (Morris et al., 1994). Men in the highest quartile of total serum carotenoids (more than 3.16 µmol/L [172 µg/dL]) had an adjusted relative risk of 0.64 (95 percent CI = 0.44−0.92); among those who never smoked, the relative risk was 0.28 (95 percent CI = 0.11−0.73). Riemersma e t al. (1991) reported that persons with plasma carotene concentrations in the lowest quintile (less than 0.26 µmol/L [14 µg/dL]) had 2.64 times the risk of angina pectoris. Adjustment for smoking reduced the magnitude of risk. However, because smoking may be part of the causal path, adjustment may not be appropriate.

The U.S. Health Professionals Follow-up Study of over 39,000 men reported a relative risk for coronary heart disease of 0.71 (95 percent CI = 0.55−0.92) for those at the top quintile of total carotene intake relative to the lowest quintile of intake (Rimm et al., 1993). The effect of β-carotene varied by smoking status: among current smokers, the relative risk was 0.30 (95 percent CI = 0.11−0.82); among former smokers, the risk was 0.60 (95 percent CI = 0.38−0.94), and among nonsmokers, the risk was 1.09 (95 percent CI = 0.66−1.79). A prospective cohort study of postmenopausal women found that the lowest risk of coronary heart disease was found for dietary carotenoid intakes greater than 8,857 IU/day (RR = 0.77; p = NS) (Kushi et al., 1996). A case-control study in 10 European countries found that lycopene concentrations, but not other carotenoid concentrations, in adipose tissue were inversely associated with the risk of myocardial infarction (Kohlmeier et al., 1997).

Cardiovascular epidemiology studies are now pursuing the use of intermediate endpoints, such as intima-media thickness, which can be estimated via ultrasonography as a measure of atherosclerosis. Bonithon-Kopp et al. (1997) reported a decrease in the intima-media thickness of the common carotid arteries with increasing concentrations of total plasma carotenoids in both men and women. Plasma carotenoid concentrations in excess of 2.07 µmol/L (111 µg/dL) were optimal for men; concentrations in excess of 3.73 µmol/L (200 µg/dL) were optimal for women. Salonen et al. (1993) evaluated the change in the intima-media thickness as a measure of atherosclerotic progression and reported that progression was 92 percent greater in the lowest (less than or equal to 0.27 µmol/L [14 µg/dL]) versus the highest (more than or equal to 0.64 µmol/L [34 µg/dL]) quartile of plasma β-carotene.

Age-Related Macular Degeneration

Dietary carotenoids have been suggested to decrease the risk of age-related macular degeneration (AMD), the most common cause of irreversible blindness in people over age 65 in the United States, Canada, and Europe (Seddon et al., 1994; Snodderly, 1995). The macula lutea (macula) is a bright yellow spot in the center of the retina and is specialized and functions to maintain acute central vision. Of all the carotenoids circulating in the body, only two polar species, lutein and zeaxanthin, are contained in the macula (Bone et al., 1985; Handelman et al., 1988). Two groups of investigators have suggested pathways by which these two carotenoids are biochemically interchanged in the macula (Bone et al., 1993; Khachik et al., 1997a).

The potential role of carotenoids in the prevention of AMD has been comprehensively reviewed (Snodderly, 1995). Seddon et al. (1994) analyzed the association between carotenoid intake and advanced AMD in a large, multicenter, case-control study involving 356 cases and 520 control subjects with other ocular conditions. Those in the highest quintile of dietary carotenoid intake had a 43 percent lower risk for macular degeneration compared with those in the lowest (OR = 0.57; 95 percent CI = 0.35−0.92). Among the specific carotenoids, intake of lutein and zeaxanthin (grouped in the carotenoid food composition database) was most strongly associated with decreased risk. Those in the highest quintile of intake had a 60 percent lower risk compared to the lowest quintile of intake.

Some, but not all, studies using blood carotenoid concentrations also suggest protective effects against risk of AMD. The Eye Disease Case-Control Study (EDCCSG, 1993) measured serum carotenoids in 391 cases with neovascular AMD and 577 control subjects. The study reported protective effects of total carotenoids, α-carotene, β-carotene, β-cryptoxanthin, and lutein and zeaxanthin, with odds ratios ranging from 0.3 to 0.5 for the high group (more than the eightieth percentile) versus the low group (less than the twentieth percentile). Carotenoid concentrations associated with the lowest risk are shown in .

TABLE 8-4

Example of Plasma Carotenoid Concentrations Associated with Lowest Risk of Age-Related Macular Degeneration.

Mares-Perlman et al. (1994) examined the association between serum carotenoid concentrations and age-related maculopathy in 167 case-control pairs and reported no association for any of the carotenoids, except lycopene, with persons in the lowest quintile of lycopene having a doubling in risk of maculopathy (cutpoint not stated). West et al. (1994) examined the relationship between plasma β-carotene concentration and AMD in 226 subjects and found the risk was lowest for the highest quartile of plasma β-carotene (more than 0.88 µmol/L [47 µg/dL] ) (OR high quartile versus low = 0.62). Plasma lutein and zeaxanthin were not measured in this study.

Hammond and Fuld (1992) developed an optical system that, in situ, measures the intensity of the unique yellow color of the macula and presumably estimates the levels of lutein and zeaxanthin. This measure is known as Macular Pigment Optical Density (MPOD). Dietary intake of carotenoids, fat, and iron, as well as plasma concentrations of lutein and zeaxanthin, were positively related with MPOD in men, but only plasma concentrations of lutein and zeaxanthin were associated with MPOD values for women (Hammond et al., 1996). In the same studies, men had significantly higher MPOD readings than women despite similar plasma carotenoid concentrations and similar dietary intake, except for fat. These investigators also demonstrated that the MPOD of most subjects could be substantially increased by the addition of relatively small amounts of foods to the diet that are high in lutein (1/2 cup spinach per day) or lutein and zeaxanthin (1 cup of corn per day) (Hammond et al., 1997). Interestingly, when MPOD was enhanced following dietary modification, it was maintained at that level for several months despite resumption of an unmodified diet.

In summary, results of studies that have investigated MPOD as a biological indicator of carotenoid adequacy suggest that it has substantial potential as an indicator for estimating the requirements for lutein and zeaxanthin. Because of the unique metabolism of carotenoids in the macula, this technique will be useful in associating dietary intakes of lutein and zeaxanthin with the health of the macula. However, insufficient MPOD studies have been conducted to date to make recommendations relative to the dietary intakes of lutein and zeaxanthin.

Cataracts

Cataracts are also problematic, with cataract extraction being the most frequently performed surgical procedure in the elderly (Taylor, 1993). Although the etiology of this condition is not known, oxidative processes may play a role. Cataracts are thought to result from photo-oxidation of lens proteins, resulting in protein damage, accumulation, aggregation, and precipitation in the lens (Taylor, 1993). The cornea and lens filter out ultraviolet light, but visible blue light reaches the retina and may contribute to photic damage or other oxidative insults (Seddon et al., 1994).

Higher dietary intake of carotenoids or higher blood concentrations of carotenoids have been found to be inversely associated with the risk of various forms of cataract in some, but not all, studies. Jacques and Chylack (1991) reported that subjects with low plasma carotenoid concentrations (those with concentrations less than the twentieth percentile: less than 1.7 µmol/L [90 µg/dL]) had a 5.6-fold increased risk of any senile cataract and a 7.2-fold increased risk of cortical cataract, compared with subjects with high plasma total carotenoid concentrations (greater than the eightieth percentile; more than 3.3 µmol/L [177 µg/dL]). Mares-Perlman et al. (1995) performed a cross-sectional analysis of serum α-carotene, β-carotene, β-cryptoxanthin, lutein and zeaxanthin, and lycopene versus the severity of nuclear and cortical opacities, and found that higher concentrations of individual or total carotenoids were not associated with the severity of nuclear or cortical opacities overall. However, higher serum β-carotene (highest quintile median concentration 0.32 µmol/L [17 µg/dL] ) was associated with less opacity in men, and higher concentrations of α-carotene (highest quintile median 0.14 µmol/L [7.5 µg/dL]), β-cryptoxanthin (highest quintile median 0.31 µmol/L [17 µg/dL]), and lutein (highest quintile median 0.44 µmol/L [25 µg/dL]) were associated with less nuclear sclerosis in men who smoked. In women, however, higher concentrations of some carotenoids (highest quintile median 2.19 µmol/L [118 µg/dL]) were associated with an increased severity of nuclear sclerosis.

Recently, the U.S. Health Professionals Follow-up Study reported a relative risk for cataract extraction in men of 0.81 (95 percent CI = 0.65−1.01) for those at the top quintile of lutein and zeaxanthin intake (median intake of 6.87 mg/day) relative to the lowest quintile of intake (Brown et al., 1999). Similar inverse associations for dietary lutein and zeaxanthin were seen in the Nurses' Health Study cohort, with a relative risk of 0.78 (95 percent CI = 0.63−0.95) for those at the top quintile of total lutein and zeaxanthin intake (median intake of 11.68 mg/day) relative to the lowest quintile of intake (Chasan-Taber et al., 1999). This decreased risk of cataracts (severe enough to require extraction) with higher intakes of lutein and zeaxanthin was not found with higher intakes of other carotenoids (α-carotene, β-carotene, lycopene, and β-cryptoxanthin) in either of these studies.

What are provitamins quizlet?

Which of the following is A function of carotenoids?

Which is an example of provitamin A quizlet?

Which is an example of provitamin A?