All of this Weston Price stuff has started to influence my thinking about what constitutes a healthy source of Vitamin A, and I find myself viewing beta-carotene with some newfound suspicion. The carotenoids have different properties: a few can be converted into retinol (most can't), and they are either protective or damaging to lipids depending on their structure.
Am J Cardiol. 2008 May 22;101(10A):20D-29D.
Biologic activity of carotenoids related to distinct membrane physicochemical interactions.
McNulty H, Jacob RF, Mason RP.
Elucida Research, Beverly, MA 01915, USA.
Carotenoids are naturally occurring organic pigments that are believed to have therapeutic benefit in treating cardiovascular disease (CVD) because of their antioxidant properties. However, prospective randomized trials have failed to demonstrate a consistent benefit for the carotenoid beta-carotene in patients at risk for CVD. The basis for this apparent paradox is not well understood but may be attributed to the distinct antioxidant properties of various carotenoids resulting from their structure-dependent physicochemical interactions with biologic membranes. To test this hypothesis, we measured the effects of astaxanthin, zeaxanthin, lutein, beta-carotene, and lycopene on lipid peroxidation using model membranes enriched with polyunsaturated fatty acids. The correlative effects of these compounds on membrane structure were determined using small-angle x-ray diffraction approaches. The nonpolar carotenoids, lycopene and beta-carotene, disordered the membrane bilayer and stimulated membrane lipid peroxidation (>85% increase in lipid hydroperoxide levels), whereas astaxanthin (a polar carotenoid) preserved membrane structure and exhibited significant antioxidant activity (>40% decrease in lipid hydroperoxide levels). These results suggest that the antioxidant potential of carotenoids is dependent on their distinct membrane lipid interactions. This relation of structure and function may explain the differences in biologic activity reported for various carotenoids, with important therapeutic implications.
PMID: 18474269
So I interpret this to mean, in the context of lipid peroxidation, nonpolar carotenoids (lycopene, beta-carotene) = bad, polar carotenoids (astaxanthin, lutein) = good.
Am J Clin Nutr. 2000 Apr;71(4):878-84.
The vitamin A spectrum: from deficiency to toxicity.
Russell RM.
US Department of Agriculture, Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA. russell@hnrc.tufts.edu
PMID: 10731492
...........excerpt:
b-CAROTENE TOXICITY
About the same time that these studies were published, b-carotene toxicity was described by Leo et al (30) in the livers of alcohol-fed animals, which showed swollen mitochondria after b-carotene feeding. Of interest is the possibility that retinoid metabolites of b-carotene could also have biological and possibly toxic potential. Wang et al (31) showed that b-carotene molecules in an in vitro system, in addition to splitting into retinal, could also be split at several double bonds, yielding apo carotenals and
apo carotenoic acids. They showed that at low doses, these carotenoic acids could be converted directly to retinoic acid (32–34). That is, for retinoic acid to be formed, b-carotene need not be converted to retinal first because in the presence of citral, which blocks the oxidation of retinal to retinoic acid, retinoic acid was still detected (35). Yeum et al (36) showed that this eccentric cleavage of b-carotene could occur by a cooxidation mechanism in the cytosol. These investigations showed that when lipoxyge-
nase was incubated with b-carotene alone, very small amounts of eccentric cleavage products of b-carotene appeared; however, when the substrate linoleic acid was added to the system, the cleavage metabolites of b-carotene increased dramatically. Thus, it appears that eccentric cleavage can be initiated in tissues by a cooxidation mechanism and then possibly completed by either conversion to retinaldehyde to form retinoic acid or by a mitochondrial mechanism, as Wang et al (37) described, to form retinoic acid. However, the question arises as to what happens when these eccentric cleavage products accumulate in large amounts? Do they have biological activity of their own? Could these metabolites interfere with the action of retinoic acid? This may, in fact, partially explain the results from 2 carotene intervention trials in which the effects of high doses of b-carotene supplements were studied in smokers and in asbestos-exposed workers (38, 39). These studies showed a higher incidence of lung cancer in smokers who consumed high doses of b-carotene than in smokers who did not take b-carotene supplements.
An animal model was used to try to mimic the results of these studies in humans (40). Ferrets were divided into 2 groups: b-carotene supplemented and non-b-carotene supplemented (control group). The dose of b-carotene used was equivalent to 30 mg/d in the human intervention trials. The b-carotene–supplemented and non-b-carotene–supplemented groups were further divided into smoke-exposed and non-smoke-exposed groups. The smoke-exposed group was exposed to cigarette smoke within a chamber twice in the morning and twice in the afternoon for 30 min each time, providing an exposure equivalent to that from 1.5 packs of cigarettes/d in humans. The animals tolerated this exposure well; they experienced no decrease in appetite or weight and behaved no differently from non-smoke-exposed animals. Animals were treated for 6 mo and then killed. b-Carotene concentrations in the plasma and lungs were greater in the b-carotene–supplemented ferrets than in the non-supplemented ferrets; however, b-carotene concentrations in the lungs were significantly lower in the smoke-exposed ferrets than in the non-smoke-exposed ferrets in both the b-carotene–supplemented and nonsupplemented control animals. Retinoic acid concentrations in the lung tissue were also significantly lower in all 3 treatment groups than in the control group (Table 3). The dramatic decreases in lung and blood b-carotene concentrations as a result of smoke exposure correlated with the enhanced breakdown of b-carotene into eccentric cleavage oxidation products.
When the lung sections of the 4 groups of ferrets were examined, it was found that smoke exposure alone caused mild aggregation and proliferation of macrophages. However, localized proliferation of alveolar cells and alveolar macrophages and keratinized squamous epithelial cells were observed in the ferrets in the 2 b-carotene–sup-
plemented groups. The most severe proliferation of alveolar cells and squamous metaplasia was observed in the b-carotene–supplemented, smoke-exposed ferrets. Keratinized squamous metaplasia was confirmed by immunohistochemical staining with anti-keratin antibody in the lung sections of all ferrets in the b-carotene–supplemented, smoke-exposed and non-smoke-exposed groups. Retinoic acid concentrations were lower in the smoke-exposed ferrets than in the non-smoke-exposed ferrets, presumably because of increased oxidative breakdown. In turn, the expression of RAR b (a subtype of RAR) activity was down-regulated in the lungs of the 3 treatment groups compared with that in the control group. RAR b is known to play an important role in normal lung development, and primary lung tumors and lung cancer cell lines lack RAR b expression (41–46). Thus, a role for RAR b as a tumor suppressor gene in the lung has been proposed (47). Because lung carcinogenesis is also associated with an alteration in retinoid signaling involving the AP-1 complex, AP-1 transcriptional activity was studied in these ferrets (48). c-Fos and c-Jun expression were up-regulated in the b-carotene–supplemented, smoke-exposed group. Additionally, AP-1 expression in this study was positively correlated with squamous metaplasia and inversely with RAR b expression in these animals.
Thus, it appears that high doses of b-carotene under highly oxidative conditions result in many eccentric cleavage oxidative breakdown products, which could have biological activity of their own. One possibility is that these products interfere with retinoic acid binding to retinoid receptors, but another likely possibility is
that these metabolites induce local enzymes in the lung, such as P450 enzymes, which increase the catabolism of retinoic acid and thus diminish retinoic acid signaling. A local deficiency of retinoic acid can then result in squamous metaplasia. Salgo et al (49) reported that b-carotene oxidation products promote the binding of benzo[a]pyrene (a smoke-borne carcinogen) to calf thymus DNA. Incubation of DNA with intact b-carotene decreased such binding, whereas incubation with b-carotene oxidation products (eg, 5,6-epioxide) for 1, 2, 3, and 4 h significantly increased the binding. These are all possible explanations for why toxicity occurs after high doses of b-carotene and may explain the increased incidence of lung cancers observed in the 2 large intervention trials mentioned previously (38, 39).
Here we have beta-carotene inducing proliferation of alveolar cells and keratinized squamous metaplasia in ferrets without smoke exposure at human equivalent doses.
