The effects of the partial pressure of oxygen (pO2) on antioxidant efficiency of β-carotene in inhibiting radical-initiated lipid peroxidation were studied in murine normal and tumor thymocytes. At 150 mm Hg pO2 (the pressure of oxygen in normal air), β-carotene acted as an antioxidant, inhibiting radical-induced lipid peroxidation in both normal and tumor thymocytes. At 760 mm Hg pO2, β-carotene lost its antioxidant activity in normal thymocytes and exhibited a dose-dependent prooxidant effect in tumor thymocytes. In these cells, the prooxidant effect of β-carotene was also accompanied by an increase of endogenous α-tocopherol loss. β-Carotene radical-trapping and autooxidation reactions were faster at 760 mm Hg pO2 than at 150 mm Hg pO2 in both normal and tumor thymocytes and the carotenoid was more rapidly consumed in tumor cells. These data point out a key role of the oxygen tension on the antioxidant effectiveness of β-carotene. They also show a selective prooxidant effect of β-carotene under 100% oxygen in tumor cells. Copyright © 1997 Elsevier Science Inc.

The antitumor effect of canthaxanthin in BALB/c mice bearing a transplantable thymoma was investigated. Male or female mice received two different doses of canthaxanthin (7 or 14 micrograms/g body wt/day) starting 15 days before tumor inoculation (7 x 10(7) cells i.p.). Canthaxanthin treatment delayed the appearance of macroscopic ascites and prolonged animal survival. This effect was dose dependent and more evident in females than in males. It appeared only when the carotenoid was administered before tumor transplantation. The antitumor efficacy of the carotenoid was related to its tissue incorporation. Canthaxanthin was incorporated in a dose-dependent manner in liver and thymoma cells and to a larger extent in females than in males. Our study shows the antitumor efficacy of canthaxanthin in vivo against a transplantable murine thymoma and points out the importance of dose, administration timing, and sex in the antitumor efficacy of this compound.

It has been reported that the anticarcinogenic effect of carotenoids could be related to an antioxidant mechanism. The antioxidant efficiency of beta-carotene and canthaxanthin was evaluated in murine normal and tumor thymocytes. Normal and tumor cells were exposed under air to tert-butyl hydroperoxide (t-BOOH) and lipid peroxidation was measured in the absence or in the presence of the two carotenoids. Our results show that: (a) Both carotenoids, added at effective and comparable concentrations (from 1 to 50 microM), were able to inhibit t-BOOH-induced malondialdehyde formation in a dose-dependent manner. (b) Canthaxanthin was a more potent antioxidant that beta-carotene. (c) The inhibition of lipid peroxidation was greater in tumor thymocytes. (d) Carotenoids were consumed differentially during the incubation with the prooxidant. beta-Carotene was consumed faster than canthaxanthin and in a larger amount in tumor than in normal thymocytes. The addition of the iron chelator deferoxamine or the SH group reducing agent dithiothreitol reduced t-BOOH-induced beta-carotene consumption in tumor cells but not in normal ones. (e) The loss of endogeneous alpha-tocopherol induced by t-BOOH was enhanced by the addition of beta-carotene, suggesting the possibility of oxidative interactions between the two antioxidants. These results confirmed the antioxidant effectiveness of carotenoids in normal and tumor cells, although differences depending on the kind of cells and carotenoids used were found.

The present work was performed to study an optimal dose and duration of dietary n-3 polyunsaturated fatty acid (PUFA) supplementation that would not result in harmful modifications of oxidative cell metabolism. Forty healthy subjects were divided into four groups that received 2.5 g/d eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), 5.1 g EPA + DHA/d, 7.7 g EPA + DHA/d, or placebo. Fatty acid composition, tocopherol status, and susceptibility to lipid peroxidation induced in vitro by 2,2'-azobis-(2-amidinopropane) (AAPH) were evaluated in human red blood cell (RBC) membranes on days 30 and 180. n-3 PUFA treatment increased EPA and DHA concentrations in RBC membranes in a time-dependent manner in all of the n-3 PUFA groups. These modifications occurred with concomitant dose- and time-dependent increases in the membrane unsaturation index. After 30 d of treatment with n-3 PUFAs, alpha-to-copherol significantly increased in RBC membranes of the intermediate- and high-dose groups. Because of the higher concentration of this antioxidant in these groups, the susceptibility of RBC membranes to peroxidation was decreased. However, after 180 d of treatment, alpha-tocopherol decreased to baseline values and AAPH-induced lipid peroxidation increased in a dose-dependent manner. These results show that high doses of dietary n-3 PUFAs, as well as long-time treatments, affect human RBC susceptibility to lipid peroxidation by changes in fatty acid composition and tocopherol content.

The effect of fatty acid unsaturation on the antioxidant ability of beta-carotene and alpha-tocopherol to inhibit azobis-isobutyronitrile (AIBN)-induced malondialdehyde (MDA) formation is investigated in a hexane solution. A positive correlation is shown between the fatty acid unsaturation and MDA production in homogeneous solutions. Both beta-carotene and alpha-tocopherol act as chain-breaking antioxidants in our model, effectively suppressing AIBN-induced MDA formation. When alpha-tocopherol is added to fatty acid solutions, a lag phase of about 30 min is observed and a propagation phase is produced at a rate dependent on the degree of unsaturation and similar to that observed in the absence of the antioxidant. A specific inhibition of initiation phase by alpha-tocopherol is confirmed by its total consumption after 30 min of incubation with AIBN. On the other hand, when beta-carotene is added, a lag period is not observed and the inhibition of propagation phase progressively increases in relation to the degree of fatty acid unsaturation. These data present different antioxidant roles for beta-carotene and alpha-tocopherol in AIBN-induced lipid peroxidation and suggest that beta-carotene can be a very effective antioxidant in highly unsaturated membranes, such as those enriched with n-3 polyunsaturated fatty acids (PUFA).

The effects of long-term treatment with a high dose (7.7 g/day) of n-3 polyunsaturated fatty acids (PUFA) were studied for human red blood cells (RBCs). RBCs isolated from healthy subjects treated for 30 and 180 days with n-3 PUFA showed the following modifications: (1) a time dependent modification of membrane fatty acid composition with a concomitant increase in membrane lipid unsaturation; (2) an increase in lipid peroxidation, expressed as malondialdehyde release, induced in vitro by t-butyl hydroperoxide (t-BOOH); (3) a time-dependent decrease in susceptibility to hemolysis, expressed as K+ leakage, induced in vitro by t-BOOH; (4) a time -dependent decrease in total and ouabain-insensitive Mg, NaK-ATPase activity. These results suggest that long term dietary supplementation with high doses of n−3 PUFA significantly modifies RBC structure and function that might lead to harmful side effects.

Subjects at high risk for colon cancer received different doses of fish oil on a 30-day randomized double-blind trial to evaluate the chemopreventive effect of n-3 fatty acids against colorectal cancer. Using rectal mucosal proliferation, assessed with 3H-thymidine autoradiography, fish oil induced in the treated groups but not in the placebo group a change in the proliferative pattern, which resulted similar to that observed in low risk population; in the same groups rectal mucosal n-3 fatty acid content increased, where arachidonic acid level decreased. Moreover, n-3 PUFA treatment induced modifications of Vitamin E status. The results suggest that n-3 PUFA could protect high-risk subjects from colon cancer by a mechanism involving a modulation of Vitamin E.