Low density lipoprotein is protected from oxidation and the progression of atherosclerosis is slowed in cholesterol-fed rabbits by the antioxidant N,N'-diphenyl-phenylenediamine.
The oxidative modification of low density lipoprotein (LDL) may play an important role in atherosclerosis. We found that the antioxidant N,N'-diphenyl-1,4-phenylenediamine (DPPD) inhibits in vitro LDL oxidation at concentrations much lower than other reported antioxidants. To test whether DPPD could prevent atherosclerosis, New Zealand White rabbits were fed either a diet containing 0.5% cholesterol and 10% corn oil (control group) or the same diet also containing 1% DPPD (DPPD-fed group) for 10 wk. Plasma total cholesterol levels were not different between the two groups, but DPPD feeding increased the levels of triglyceride (73%, P = 0.007) and HDL cholesterol (26%, P = 0.045). Lipoproteins from DPPD-fed rabbits contained DPPD and were much more resistant to oxidation than control lipoproteins. After 10 wk, the DPPD-fed animals had less severe atherosclerosis than did the control animals: thoracic aorta lesion area was decreased by 71% (P = 0.0007), and aortic cholesterol content was decreased by 51% (P = 0.007). Although DPPD cannot be given to humans because it is a mutagen, our results indicate that orally active antioxidants can have antiatherosclerotic activity. This strongly supports the theory that oxidized LDL plays an important role in the pathogenesis of atherosclerosis.
Sparrow
C P
CP
Department of Atherosclerosis Research, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
Doebber
T W
TW
Olszewski
J
J
Wu
M S
MS
Ventre
J
J
Stevens
K A
KA
Chao
Y S
YS
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000378:metabolism / Q000517:prevention & control*; D002784:Cholesterol / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D010655:Phenylenediamines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
D000975:Antioxidants; D008077:Lipoproteins, LDL; D010655:Phenylenediamines; D002784:Cholesterol; C004845:N,N'-diphenyl-4-phenylenediamine