ABSTRACT
A metabolic event that occurs with lipoate in humans as well as most organisms is that uptake at cellular level results in much being reduced to the dihydro form. The reduction of free lipoate (and lipoamide) at rather high levels has been attributed mainly to NADPH-dependent thioredoxin reductase.[4] The subsequent fate of both lipoate and dihydrolipoate is summarized in Fig. 2. Some essential lipoate is routed through lipoyl-AMP to form lipoylated holoproteins wherein the attachment is at the e-amino function of lysyl residues. The two reactions involved are catalyzed in mammals by separate mitochondrial enzymes. The gene for the second enzyme, lipoyl transferase, has been shown to be located on chromosome 2q11.2 in the human.[5] It has been reported that the lethal syndrome of metabolic acidosis found in an infant reflected suppression of the mitochondrial dehydrogenases for pyruvate, a-ketoglutarate, and branchedchain keto acids.[6] The decreased activities were
attributable to inability to normally utilize lipoate as cofactor, since addition of lipoate to a medium containing the patient’s fibroblasts markedly improved conversions of leucine and valine. A severe acidosis found in an 8-mo-old boy was attributed to a deficiency of lipoamide (lipoyl) dehydrogenase, which was improved by oral administration of 25-50mg=kg of lipoate.[7] Less clear is the case of primary biliary cirrhosis in which antimitochondrial antibodies are reported to be present against the transacetylase of the pyruvate dehydrogenase complex.[8]
Catabolic events with a-lipoate, elucidated in microbes and mammals,[9] are noted in Fig. 3, as are the more recently discovered catabolites of dihydrolipoate, which are the methylated and sulfoxidized compounds found in plasma and urine after high oral intakes of lipoate.[10,11]
SUPPLEMENT USES AND CLAIMS
Investigations and reviews of the noncofactor nature of a-lipoate have burgeoned in the past dozen years. The focus has been on the antioxidant, generally thiol, nature of the lipoate-dihydrolipoate interconversion in cells. In most cases, a therapeutic effect, real or potential, is stated. For example, a review, ‘‘The pharmacology of the antioxidant lipoic acid,’’[12] lists four antioxidant properties of lipoate including its metal chelating capacity, its ability to scavenge reactive oxygen species (ROS), regenerate endogenous antioxidants, and repair oxidative damage. Dihydrolipoate, formed by the reduction of lipoate, has the capacity to regenerate the antioxidants vitamins C and E as well as glutathione. It can also provide peptide methionine sulfoxide reductase with reducing equivalents. Other reviews on thiol-based antioxidants suggest therapeutic potential for N-acetyl-L-cysteine and lipoate but point out that an advantage of the latter is that it is readily recycled in the cell.[13,14] Interestingly, some proponents of the use of lipoate as an antioxidant also recognize the pro-oxidant activities of lipoate and dihydrolipoate.[15]
Among effects reported for lipoate is that it inhibits the in vitro glycation of albumin by glucose.[16] The decrease in advanced glycation end-products (AGEs) has been extended by studies of lipoate with endothelial cells[17,18] and erythrocytes.[19] Incubation of lipoate with Jurkat T (human leukemic T-lymphocyte) cells was reported to inhibit nuclear factor kappaB (NF-kB) activation.[20] Lipoate treatment of these cells also potentiates caspase 3 activation, which leads to Fas-mediated apoptosis.[21] The myeloperoxidasedependent activation of caspase and apoptosis in human HL-60 leukemic cells is protected against by
incubation with lipoate as well as dehydroascorbic acid, both of which act via their reduced forms, viz. dihydrolipoate and ascorbate, respectively.[22] Reduction of NF-kB activity, which regulates production of many inflammatory cytokines and adhesion factors, occurred when lipoate was incubated with Mono Mac6 (a human monocyte) cells.[23] Such inhibition of NF-kB was also reported for lipoate with human aortic endothelial cells.[24] Given the presumption of the investigators in these studies of NF-kB that it is the activation by ROS that is sequestered by lipoate, it is of interest that recent analyses have questioned the role of oxidative stress in activation of NF-kB.[25]
Further along lines of the antioxidant potential of lipoate with cells, there have been reports of it leading to an increase in glutathione biosynthesis by improving cystine utilization in several cell types.[26] Nitric oxide synthesis in human aortic endothelial cells is stimulated by lipoate as well as vitamin C independent of glutathione status.[27] In a comparison of the effects of a-lipoate and a-tocopherol given in high oral doses (600mg=day lipoate; 400 IU=day a-tocopherol) to healthy adults for 2mo separately and then 2mo in combination, it was determined that lipoate functions as an antioxidant, because it decreases plasma-and LDL-oxidation and urinary isoprostanes. However, no additional benefit was seen with the combination of lipoate plus vitamin E.[28]
In connecting lipoate (and other antioxidants) with the ability to decrease such reactive oxygen intermediates as are thought to cause ‘‘oxidative stress,’’ including that in aging, some reviewers have suggested lipoate to be ‘‘a highly promising thiol antioxidant supplement’’.[29] Generally, the amounts currently available in over-the-counter or over-thenet sales are in the 30-200mg range.
