Handbook of Vitamin C Research

132Chin-San LiuOthersGastrointestinal distress seems to be the most common adverse effect of high vitamin Cintake [57]. When these symptoms occur, the vitamin C dosage is usually >2 g/day. Singleoral doses of 5–10 g produce transient intestinal discomfort caused by osmotic diarrhea [78].The symptoms generally disappear within a week or two with no further consequences, andcan occasionally be attributed to other components such as sorbitol [81]. Harmful effectsincluding hypoglycemia, rebound scurvy, infertility, mutagenesis, and destruction of vitaminB12 have been mistakenly attributed to large doses of vitamin C [2]. Health professionalsshould recognize that vitamin C does not produce these effects [82]. Other studies havedemonstrated that large doses of vitamin C are safe [35, 83-85]. A recent reviewdemonstrated that vitamin C supplements of 2000 mg/day are safe for most adults and thatintakes of up to 4000 mg/day are well tolerated in the general population [78]. No consistentor compelling data demonstrating serious adverse effects of vitamin C in humans have beenestablished, although the tolerable upper limit intake has been estimated at 2000 mg/day [86].Ischemic Heart DiseaseVitamin C in Health and DiseaseIt has been shown that oxidation of low-density lipoprotein (LDL) and lipid membranesplays an important role in atherosclerosis [87]. Although the mechanism is still unclear, it hasbeen suggested vitamin C protects circulating and membrane lipids from free radicals.Vitamin C is believed to protect lipids indirectly by reconstituting the active forms of vitaminE [88]. Atherosclerotic plaques impair endothelium-dependent vasodilation in humancoronary and peripheral blood vessels [87, 89-91], and it has been suggested that short-termadministration of ascorbic acid may reverse this endothelial dysfunction [92, 93]. Indeed,there is emerging evidence linking high intake of vitamin C with reduced mortality fromheart disease [94]. A cross-sectional survey of population groups throughout Europe noted aninverse relationship between plasma levels of vitamin C and ischemic heart disease [95].HypertensionNitric oxide (NO), a labile endothelial relaxing factor, is derived from L-arginine by theenzyme NO synthase [96]. Essential hypertension is characterized by impaired endotheliumdependentvasodilation to specific agonists caused by an alteration in the L-arginine-NOpathway [97-101]. This appears to be associated with the production of superoxide anions,which impair the ability of the endothelium to induce NO-mediated relaxations of vascularsmooth muscles [102-104]. In patients with essential hypertension, this impaired endothelialvasodilation can be improved by the administration of vitamin C, an effect that can bereversed by a NO synthase inhibitor [105]. A cross-sectional study showed an association