Drug Toxicity Studies

Drug-induced toxicity is almost invariably associated with oxidative stress in the target organ or tissue. This stems from a variety of sources, including increased generation of reactive oxygen species as an inevitable consequence of certain enzyme activities, the conversion of the drug itself into a radical or a compound able to generate radicals, and drug-induced inhibition of antioxidant enzyme activities. Spirulina contains a variety of antioxidants, including ascorbic acid (vitamin C), «-tocopherol (vitamin E), j-carotenes, and phenolic compounds.7 Various aqueous or alcoholic extracts of this alga can scavenge a variety of radicals in vitro and exhibit antioxidant activity in vivo.7-10 Another constituent of Spirulina, phycocyanin, has been demonstrated to scavenge peroxyl,11 hydroxyl,12,13 alkoxyl,12 and superoxide radicals10 as well as peroxynitrite.14 There are also results suggesting that phycocyanin is capable of chelating iron,11 which can be a powerful pro-oxidant. It has been proposed that much of the radical scavenging and antioxidant activity of Spirulina is attributable to phycocyanin, particularly its chromophore, phycocyanobilin.15 Note, however, that phycocyanin was more effective than phycocyanobilin in scavenging peroxynitrite.14

In addition to antioxidant molecules, a variety of antioxidant enzymes protect humans and animals from oxidative stress. These include superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase. There have been several investigations of the effects of Spirulina on the activity of these enzymes, but the results have been somewhat controversial. In mice treated with 250 or 500 mg/kg of S. platensis orally for 15 days, the activities of hepatic SOD, GPx, and catalase along with reduced glutathione levels were significantly increased compared to saline-treated controls.3 In contrast, another group of researchers did not observe a significant effect of orally administered S. fusiformis at doses of 250 and 500 mg/kg per day for 5 days on the activities of these antioxidant enzymes in mouse liver.4 At the highest dose (1000 mg/kg), however, Spirulina significantly induced SOD, but not GPx and catalase, activity. There are also several studies that examined the effect of Spirulina treatment on antioxidant enzymes in the kidneys, since the major focus was the prevention of drug-induced nephrotoxicity. Neither S. platensis nor S. fusiformis alone markedly altered the activities of any of these enzymes in kidney tissue of rats treated for between 5 and 17 days, even though treatment with these algae reversed the inhibition of SOD, GPx, and catalase activities induced by cisplatin or cyclosporine.16-18 The ability of Spirulina to act as an antioxidant and, possibly, induce endogenous antioxidant enzymes prompted several groups of researchers to investigate the effectiveness of this alga in ameliorating drug-induced toxicities. The results of these studies are summarized below. The study design and the effects of Spirulina on antioxidant enzyme activity in the various studies are summarized in Table 14.1.

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