doi:10.1016/j.bbamem.2006.09.010
Copyright © 2006 Elsevier B.V. All rights reserved.
Differential effects of carotenoids on lipid peroxidation due to membrane interactions: X-ray diffraction analysis
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Hyesun P. McNultya, 
, 
, Jungsoo Byuna, Samuel F. Lockwoodb, Robert F. Jacoba and R. Preston Masona, c
aElucida Research, 100 Cummings Center, Suite 135L, P.O. Box 7100, Beverly, MA 01915-0091, USA
bCardax Pharmaceuticals Inc., 99-193 Aiea Heights Drive, Suite 400, Aiea, HI 96701, USA
cCardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
Received 18 July 2006;
revised 13 September 2006;
accepted 15 September 2006.
Available online 22 September 2006.
Abstract
The biological benefits of certain carotenoids may be due to their potent antioxidant properties attributed to specific physico-chemical interactions with membranes. To test this hypothesis, we measured the effects of various carotenoids on rates of lipid peroxidation and correlated these findings with their membrane interactions, as determined by small angle X-ray diffraction approaches. The effects of the homochiral carotenoids (astaxanthin, zeaxanthin, lutein, β-carotene, lycopene) on lipid hydroperoxide (LOOH) generation were evaluated in membranes enriched with polyunsaturated fatty acids. Apolar carotenoids, such as lycopene and β-carotene, disordered the membrane bilayer and showed a potent pro-oxidant effect (> 85% increase in LOOH levels) while astaxanthin preserved membrane structure and exhibited significant antioxidant activity (40% decrease in LOOH levels). These findings indicate distinct effects of carotenoids on lipid peroxidation due to membrane structure changes. These contrasting effects of carotenoids on lipid peroxidation may explain differences in their biological activity.
Keywords: Astaxanthin; β-carotene; Antioxidant; Lipid peroxidation; Liposome; X-ray diffraction
Abbreviations: ABIN, 2,2′-azobis-isobutyronitrile; AMVN, 2,2′-azobis(2,4′-dimethylvaleronitrile); C/P, cholesterol to phospholipid mole ratio; DLPC, 1,2-dilinoleoyl-3-sn-glycero phosphatidylcholine; DMPC, 1,2-dimyristoyl-3-sn-glycero phosphatidylcholine; DOPC, 1,2-dioleoyl-3-sn-glycero phosphatidylcholine; DPPC, 1,2-dipalmitoy-3-sn-glycero phosphatidylcholine; EPR, electron paramagnetic resonance; EYPC, egg-yolk phosphatidylcholine; LOOH, lipid peroxide; POPC, 1-palmitoyl 2-oleoyl-3-sn-glycero phosphatidylcholine
Fig. 1. Molecular structures of the carotenoids investigated in this study.
Fig. 2. Representative X-ray diffraction pattern of POPC membrane samples containing cholesterol at a C/P mole ratio of 0.2. Data were collected on a position-sensitive electronic detector at 20 °C and 87% relative humidity. Four diffraction orders were obtained from these membranes, as indicated by the numbers above each peak.
Fig. 3. Effects of polar versus apolar carotenoids on membrane structure. Superimposed one-dimensional electron density profiles (electrons/Å3 vs. Å) of POPC membrane bilayers at a C/P mole ratio of 0.2. The data were collected at 87% relative humidity and 20 °C. Lycopene and astaxanthin were incorporated into membranes at a carotenoid/phospholipid mole ratio of 0.07. The two peaks of electron density on either side of the centrosymmetric profile correspond to phospholipid headgroups, while the minimum of electron density at the center of the membrane is associated with terminal methyl segments of the phospholipid acyl chains. Addition of astaxanthin did not appreciably affect membrane structure, whereas the other carotenoids altered the lipid packing characteristics in the hydrophobic region. The disordering effect on the membrane was especially evident for lycopene, as shown in this figure.
Fig. 4. Effect of hydrostatic pressure on membrane structure changes with lycopene. Superimposed one-dimensional electron density profiles (electrons/Å3 vs. Å) of POPC membrane bilayers at 20 °C. The relative humidity was systematically decreased from 87% to 74% in hermetically-sealed sample chambers. Lycopene was incorporated into the membrane at a carotenoid/phospholipid mole ratio of 0.07. The two peaks of electron density on either side of the centrosymmetric profile correspond to phospholipid headgroups, while the minimum of electron density at the center of the membrane is associated with terminal methyl segments of the phospholipid acyl chains. The disordering effect of lycopene was greatly reduced compared to that of 87% relative humidity (Fig. 3).
Fig. 5. Correlation between membrane structure changes and LOOH formation. Differences in relative electron density as a function of treatment with various carotenoids in POPC membranes containing a C/P mole ratio of 0.2. For the peroxidation study, various carotenoids (10 μM) were incorporated into DLPC membranes and underwent lipid peroxidation at 37 °C for 48 h. 
P < 0.001 vs. control; ‡P < 0.01 vs. control; †P < 0.05 vs. control; n = 5
6.
Table 1.
Effect of carotenoids on structure of POPC model membranes as a function of hydration
Carotenoids were incorporated at a carotenoid/phospholipid mole ratio of 0.07 (or 6.25 mol%) into POPC membranes containing cholesterol at a C/P mole ratio of 0.2. Small angle X-ray analysis was conducted sequentially at two different relative humidities of 87% and 74% at 20 °C. Decreasing the relative humidity from 87% to 74% attenuated the effects of the carotenoids, including changes in lipid membrane width.
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