A substance need not excel in meeting all these
criteria to be considered a good antioxidant. For example,
vitamin E acts only in the membrane or lipid domains,
its dominant action is to quench lipid peroxyl
radicals, and it has little or no activity against radicals
in the aqueous phase, yet it is considered one of the
central antioxidants of the body. Epidemiological studies
are confirming its role in the prevention of numerous
oxidant-related diseases, such as heart disease. 7"s
An "ideal" antioxidant would fulfill all of the
above criteria. The c~-lipoic acid/dihydrolipoic acid redox
couple approaches the ideal; it has been called
"a universal antioxidant. ''9 a-Lipoic acid is readily
absorbed from the diet. It is probably rapidly converted
to DHLA in many tissues, as recent advances in assay
technique have made evident) °'H One or both of the
components of the redox couple effectively quench a
number of free radicals in both lipid and aqueous domains.
Both DHLA 21'32'33 and a-lipoic acid 13'19"23'24
have metal-chelating activity. DHLA acts synergistically
with other antioxidants, indicating that it is capable
of regenerating other antioxidants from their radical
or inactive forms. Finally, there is evidence that they
may have effects on regulatory proteins and on genes
involved in normal growth and metabolism.
Because of these antioxidant attributes, a number
of experimental and clinical studies have been carried
out which show a-lipoic acid to be useful or potentiaily
useful as a therapeutic agent in such conditions as
diabetes, ischemia-reperfusion injury, heavy-metal
poisoning, radiation damage, neurodegeneration, and
HIV infection.
An antioxidant function for tz-lipoic acid was suggested
as early as 1959 by Rosenberg and Culik, 4 who
observed that administration of ot-lipoic acid prevented
scurvy symptoms in vitamin C-deficient guinea pigs
as well as preventing symptoms of vitamin E deficiency
in rats fed a diet lacking ot-tocopherol. It has
only been recently, however, that the specific effects
of ol-lipoic acid and DHLA in free radical quenching,
metal chelation, antioxidant recycling, and gene expression
have been investigated.
Lipoic acid. There is general agreement about the antioxidant
properties of a-lipoic acid. It scavenges hydroxyl
radicals, hypochlorous acid, and singlet oxygen.
It does not appear to scavenge hydrogen peroxide or
superoxide radical and probably does not scavenge peroxyl
radicals (Table 1). It may chelate transition
metals.
Two studies indicate that tr-lipoic acid is a potent
hydroxyl radical scavenger. In one, 12 hydroxyl radical
was generated by 2 mM HzO2 + 0.2 mM FeSO4. The
radical was detected by electron spin resonance (ESR)
using the spin-trapping agent 5,5-Dimethylpyrroline-
N-oxide (DMPO). 1 mM ot-lipoic acid completely
eliminated the DMPO-OH adduct signal. Another
study, 13 using a similar hydroxyl radical-generating
system (2.8 mM HzO2, 0.05 mM FeC13, 0.1 mM EDTA,
and 0.1 mM ascorbate) but a different assay for the
radical (deoxyribose degradation) also found ct-lipoic
acid to be a hydroxyl radical scavenger. In this study,
a rate constant of 4.7 × 101° M-is -~ was calculated;
this is an essentially diffusion-limited reaction rate.
Hence, ot-lipoic acid appears to be a highly effective
scavenger of hydroxyl radical.
There is similar agreement about the ability of otlipoic
acid to scavenge hypochlorous acid. Haenen and
Bast 14 and Scott et al.13 both found that 50 #M t~-lipoic
acid almost completely abolished the inactivation of
a 1-antiproteinase by 50/zM HOC1. This is in contrast
to glutathione, whose reduced form is a potent scavenger
of HOCI, comparable to ct-lipoic acid, but whose
oxidized form is almost completely ineffective. ~4 The
authors of this study speculate that the greater reactivity
of c~-lipoic acid compared to oxidized glutathione