Upper Levels of Niacin Intake

Nicotinic acid (but not nicotinamide) causes a marked vasodilatation, with flushing, burning, and itching of the skin. Very large single doses of nicotinic acid may cause sufficient vasodilatation to lead to hypotension; after the administration of 1 to 3 g of nicotinic acid daily for several days, the effect wears off to a considerable extent. A number of nicotinoyl esters have been developed to permit sensitive patients to benefit from the hypolipidemic effect of nicotinic acid without the vasodilatation. The tolerable upper limit is 35 mg per day for adults (Institute of Medicine, 1998).

At intake in excess of 1 g of niacin per day, there is evidence of toxicity, with changes in liver function tests, carbohydrate tolerance, and uric acid metabolism that are reversible on withdrawal of niacin (Parsons, 1961a, 1961b). Baggenstoss and coworkers (1967) reported changes in liver ultrastructure in patients receiving high doses of niacin, including dilatation of the endoplasmic reticulum with formation of vesicles and sacs, and a diminution in the parallel arrays of rough endoplasmic reticulum, with fewer ribosomes on the outer surface. There was also elongation of the mitochondria, withbud-like projections and crystalloid inclusions. The mechanism of niacin hepatotox-icity is not known. Sustained release preparations are associated with more severe liver damage than crystalline preparations, presumably because they permit more prolonged maintenance of high concentrations of the vitamin, whereas after an acute high dose there is normally considerable excretion of unchanged nicotinic acid and nicotinamide, as the renal threshold is exceeded.

The European Health Food Manufacturers' Federation restricts over-the-counter supplements to 500 mg per day (Shrimpton, 1997). Where niacin is being used to treat clinically significant hyperlipidemia, and in trials for the prevention of type I diabetes mellitus, a tentative upper limit has been set at 3 g per day (Knip et al., 2000).

8.8 PHARMACOLOGICAL USES OF NIACIN

Nicotinic acid is used clinically in large doses (of the order of 1 to 3 g per day) as a hypolipidemic agent. It reduces both triglycerides and total cholesterol by about 20%, acting as an inhibitor of cholesterol synthesis. It has a more marked effect on cholesterol in low-density and very low-density lipoproteins, and increases high-density lipoprotein cholesterol; nicotinamide is ineffective (Brown, 1995; Capuzzi et al., 2000). It also inhibits the release of nonesterified fatty acids from adipose tissue by inhibiting the adenylate cyclase that is activated in response to hormonal stimulation, thus decreasing synthesis of very low-density lipoprotein in the liver, and stimulates the 5-lipoxygenase pathway, leading to increased formation of prostaglandin E2, thromboxane B2, and leukotriene E4 from arachidonic acid (Saareks et al., 1999). There is, however, some evidence that doses of about 1 g of nicotinic acid per day may lead to elevation of plasma homocysteine (Section 10.3.4.2), which would reduce the benefits to be expected from its hypolipidemic action (Garg et al., 1999).

In experimental animals, nicotinamide protects against the destruction of pancreatic f-islet cells caused by diabetogenic agents, such as alloxan and streptozotocin. Type I diabetes mellitus is caused by autoimmune destruction of p -cells, and autoantibodies against ft -cell proteins can be detected in the circulation several years before the clinical onset of diabetes. It has been suggested that nicotinamide may delay the development of diabetes in susceptible subjects (Gale, 1996a, 1996b). Nicotinamide may act by either inhibiting ADP-ribosyltransferase (Section8.4.2) andpoly(ADP-ribose) polymerase (Section 8.4.3) or by inhibiting the induction of cell surface antigens by interferon and tumor necrosis factor (Kolb and Burkart, 1999; Kim et al., 2002). Although nicotinamide has no effect once diabetes has developed (Vidal et al., 2000), preliminary studies in people at risk of developing type I diabetes are promising. A prospective study involving first-degree relatives of patients with type I diabetes, who are being screened for autoantibodies and randomized to receive either nicotinamide or placebo, the European Nicotinamide Diabetes Intervention Trial (ENDIT) is expected to report in 2004 (Schatz and Bingley, 2001).

Gram doses of nicotinamide have been used in so-called orthomolecular psychiatry as a treatment for schizophrenia, originally because of the similarities between schizophrenia and the depressive psychosis of pellagra. The underlying rationale for this use is that such high doses of niacin may deplete methyl donors, and at least one of the theories of the biochemical basis of schizophrenia was that the condition is caused by inappropriate methylation of neurotransmitter metabolites to yield psychotogenic compounds (Hoffer et al., 1957). There is no independent confirmation of the efficacy of nicotinamide in the treatment of schizophrenia.

FURTHER READING

Bender DA (1983) Biochemistry of tryptophan in health and disease. Molecular Aspects of Medicine 6,101-97. Bender DA (1996) Tryptophan and niacin nutrition - is there a problem? Advances in

Experimental Medicine and Biology 398, 565-9. Bender DA and Bender AE (1986) Niacin and tryptophan metabolism: the biochemical basis of niacin requirements and recommendations. Nutrition Abstracts and Reviews (Series A) 56, 695-719.

D'Amours D, Desnoyers S, D'Silva I, and Poirier GG (1999) Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochemical Journal 342, 249-68. Lee HC (1999) A unified mechanism of enzymatic synthesis of two calcium messengers:

cyclic ADP-ribose and NAADP Biological Chemistry 380, 785-93. LeeHC (2001) Physiological functions of cyclic ADP-ribose and NAADP as calcium messengers. Annual Reviews of Pharmacology and Toxicology 41, 317-45.

Magni G, Amici A, Emanuelli M, Raffaelli N, and Ruggieri S (1999) Enzymology of NAD+ synthesis. Advances in Enzymology and Related Areas of Molecular Biology 73, 135-82, xi.

Roe DA (1973) A Plague of Corn: The Social History of Pellagra. Ithaca, NY: Cornell University Press.

Shall S (1995) ADP-ribosylation reactions. Biochimie77,313-18.

Ueda K and Hayaishi O (1985) ADP-ribosylation. Annual Reviews of Biochemistry 54, 73-100.

Ziegler M (2000) New functions of a long-known molecule. Emerging roles of NAD in cellular signaling. European Journal of Biochemistry 267, 1550-64.

References cited in the text are listed in the Bibliography.

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