COMBINED NONENZYMATIC AND ENZYMATIC REDUCTION FAVORS BIOACTIVATION OFRACEMIC LIPOIC ACID - AN ADVANTAGE OF A RACEMIC DRUG

For the antioxidant effect of lipoic acid, reduction to dihydrolipoic acid is considered to be important. Dihydrolipoamide dehydrogenase (Li pHD) preferentially reduces R-lipoic acid and in a subsequent: reactio n, the R-dihydrolipoic acid formed may non-enzymatically reduce S-lipo ic acid. Using circular dichroism (CD) spectroscopy, the second order rate constant of the latter reaction was determined (k(2) = 15 M-1 sec (-1)),In vitro, it was found that S-lipoic acid is reduced by LipDH us ing R-lipoic acid as a catalyst. The non-enzymatic dithiol-disulfide r eaction leads to synergistic reduction of the enantiomers which can ex plain the higher antioxidant activity of racemic lipoic acid found in vivo (Maitra et al. Biochem, Biophys. Res. Commun. 221:422-429, 1996) in comparison to the enantiomers. Lipoic acid is therapeutically activ e in several diseases via antioxidant activity. These findings suggest that racemic lipoic acid can be therapeutically more active than the separate enantiomers. (C) 1997 Wiley-Liss, Inc.