NEPHROLOGY 2005; 10, 623–625 © 2005 Asian Pacific Society of Nephrology Blackwell Science, LtdOxford, UKNEPNephrology1320-53582005 Asian Pacific Society of Nephrology10623625Letter to the Editor Letters to the EditorLetters to the Editor Letters to the Editor MEGA DOSE OF VITAMIN C AUGMENTS THE NEPHROTOXICITY OF PARACETAMOL To the Editor, Paracetamol (acetaminophen-APAP) is a widely used over-the-counter analgesic and antipyretic drug. Even though paracetamol is considered a safe drug, under over- dose situations (such as accidental or suicidal ingestion) it produces hepatic necrosis and renal failure in both humans 1,2 and experimental animals. 3 Renal tubular damage and acute renal failure can occur even in the absence of liver injury. 2 Oxidative stress is reported to play a role in the pathogenesis of paracetamol-induced renal damage as evi- denced by depletion of non-protein thiol, approximately 95% of which is reduced glutathione and increased lipid peroxidation. 4,5 Because APAP can induce life-threatening renal lesions, the search for antidotes or treatments for APAP nephrotoxicity is of clear toxicological importance. Vitamin C is known to act as antioxidant both in vitro and in vivo. Vitamin C functions as chain-breaking antiox- idant, free radical scavenger and is involved in the recycling of vitamin E and glutathione. 6,7 Besides, pretreatment with vitamin C has been shown to be protective against APAP induced hepatotoxicity in animals. 8 The present study is an attempt to find out whether pretreatment with vitamin C protects against APAP induced renal damage. To a group of adult male Wistar rats was administered i.p. injection of acetaminophen at the dose of 1 g/kg body weight. To another group of rats, vitamin C was adminis- tered orally at the dose of 1 g/kg body weight 1 h before the administration of APAP. The control rats received vitamin C or saline alone. The rats were sacrificed 24 h after the dose of APAP, after the withdrawal of blood. Plasma was sepa- rated and used for the assay of creatinine by standard method. Kidney tissue was used for the assay of non-protein thiol (reduced glutathione), protein thiol and, lipid perox- ide level by established methods. 9 The results are shown in Table 1. Vitamin C pretreated rats showed significantly higher plasma creatinine values (twofold) compared with the rats treated with APAP alone, suggesting that vitamin C potentiates the toxicity of APAP. However, vitamin C pretreatment prevented APAP- induced depletion of non-protein thiol (mainly reduced glutathione) almost completely. The ability of vitamin C to restore reduced glutathione can be explained thus: (i) vita- min C is a free radical scavenger (chain-breaking antioxi- dant) that scavenges free radicals thereby sparing reduced glutathione from being used by the free radical detoxifying reactions such as glutathione peroxidase; 10,11 and (ii) vita- min C has been recently shown to increase reduced glu- tathione level in the cells by the stimulation of glutathione reductase activity and activation of the hexose monophos- phate pathway, that generates reduced nicotinamide ade- nine dinucleotide phosphate (NADP), the cofactor required for the glutathione reductase. 12,13 Surprisingly, although vitamin C prevented the deple- tion of non-protein thiol, it did not prevent APAP-induced renal damage and enhanced lipid peroxidation; in fact, it potentiated the renal damage as evidenced by higher plasma creatinine values. This may be due to the pro-oxidant activ- ity of vitamin C when present in excess. It is known that vitamin C can switch from antioxidant- to pro-oxidant- activity depending on its concentration and the presence of free transition metals such as iron and copper. 14 Studies have shown that vitamin C increases oxidative DNA dam- age in isolated human lymphocytes, 15 and in neurones and hepatocytes it increases lipid peroxidation and cell toxic- ity. 16,17 Many studies have reported that pro-apoptotic effects of ascorbic acid might be related to hydroxylation or formation of ascorbyl radicals via the Fenton reaction with iron. 18 The reduction of transition metal ions by ascorbic acid can also have damaging effects via production of hydroxyl radicals by reaction of the reduced metal ions with hydrogen peroxide. 19 Pro-oxidant activity of ascorbic acid is unlikely to be relevant to the in vivo situation in healthy organisms, because the transition metals, such as iron, are sequestered by proteins, such as transferrin and ferritin, and therefore cannot participate in the Fenton reaction. Only under pathological conditions that cause the release of heme or metal ions from the binding proteins, such as. haemoglobin 20 or ferritin, 21 could ascorbate act as pro-oxidant. Pro-oxidant activity of vitamin C is quite likely to occur in APAP-induced renal damage because of two reasons. First, in APAP-induced organ injury, iron is reported to play an important role. Both in vitro and in vivo studies have shown that the cytotoxicity of APAP can be prevented by the administration of the iron chelator, deferrioxamine. 22,23 Second, a recent study has shown that the gene for heme oxygenase, an important enzyme that is involved in the deg- radation of heme and the release of iron, is upregulated in the livers of APAP-intoxicated rats. 24 These studies suggest the availability of free iron which is required for the pro- oxidant activity of ascorbic acid. In summary, it is suggested that oxidative stress may not be the only mechanism of APAP-induced renal damage and that vitamin C, when taken in excess, may increase the nephrotoxicity of drugs such as acetaminophen. Therefore, individuals who are on drugs that are likely to be nephro- toxic should be careful about their vitamin C intake. Premila Abraham Department of Biochemistry, Christian Medical College, Bagayam, Vellore, Tamil Nadu, India