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The Effect of Zinc Supplementation in Humans on Plasma Lipids, Antioxidant Status and Thrombogenesis

Human Nutrition Unit, School of Molecular and Microbial Biosciences, University of Sydney, New South Wales, AUSTRALIA

Address correspondence to: Samir Samman, PhD, Human Nutrition Unit, School of Molecular and Microbial Biosciences, University of Sydney, NSW 2006, AUSTRALIA. E-mail: s.samman{at}mmb.usyd.edu.au

ABSTRACT

The potential exists for zinc to influence numerous metabolic functions and to impact a range of diseases. In the present review we examine the reported relationships between zinc and plasma lipids, haemostasis and other factors postulated to play a role in atherogenesis. Ecological studies that investigated zinc intake or status, and incidence of coronary heart disease (CHD) reveal no consistent pattern. The conflicting observations may be explained by differences in the extent of CHD, site of atherosclerosis, or confounding factors. In most studies the diurnal variation in serum zinc concentrations, and the lifestyle factors that affect cholesterol metabolism were not explicitly considered. Results of randomised controlled trials show that low-density lipoprotein (LDL) oxidation and the concentrations of LDL-cholesterol (c), total cholesterol and triglycerides in plasma are unaffected by supplementation with up to 150 mg Zn/d. In contrast, plasma high-density lipoprotein (HDL)-c concentrations decline when zinc supplements provide a dose >50 mg/d. Limited data suggest that sustained hyperzincaemia predisposes individuals to thrombogenesis, whereas acute zinc depletion impairs platelet aggregation and prolongs bleeding time. In addition, Zinc supplements have been shown in some studies to decrease Cu/Zn-superoxide dismutase activity, primarily due to the antagonistic relationship between high zinc intakes and copper absorption. Besides the demonstrated adverse effect of zinc supplementation on plasma HDL-c concentrations in apparently healthy men, there is insufficient evidence to determine the role of zinc supplementation in influencing other risk factors for CHD such as antioxidant status and thrombogenesis.

Key words: zinc, cholesterol, lipids, antioxidants, haemostasis, heart disease, humans

Key teaching points:

• In epidemiological studies there is no clear effect of zinc on heart disease risk.

• In randomised controlled trials, zinc supplements result in a decrease in HDL-cholesterol.

• The effect of zinc supplements on antioxidant status as indicated by superoxide dismutase activity, and thrombogenesis is unclear.

• Further research is required in order to elucidate the role of zinc in heart disease.

INTRODUCTION

Zinc is involved in a myriad of biological processes that include catalysis, stabilisation of cell membranes and regulation of gene expression [1]. The physiological significance of zinc is reflected in the diverse range of symptoms which is observed in zinc deficiency [2]. Thus the potential exists for zinc to influence many metabolic functions and to impact a range of diseases. Coronary heart disease (CHD) remains the leading cause of death in western countries. The established and proposed risk factors for CHD include age, gender, family history of CHD, dyslipidemia, hypertension, diabetes mellitus, obesity, cigarette smoking and increased thrombogenicity [3]. Environmental factors play an important role in the development of CHD and although the effects of macronutrients, mainly dietary fats, have been investigated extensively, the potential effects of most of the inorganic nutrients especially zinc, have received limited attention [4]. In the present review we examine the reported relationships between zinc and clinical endpoints of CHD, plasma lipids and haemostasis and other factors postulated to play a role in atherogenesis.

Observational Studies of Zinc, Plasma Lipids and Incidence of CHD
Reports of the relationship between zinc status and CHD incidence, are conflicting. Five cross-sectional studies reported that patients with various forms of CHD had lower zinc concentrations in hair [5], serum [6,7] or plasma [8,9]; six studies, including a case-control study, reported that the zinc concentrations in toenails [10], serum [6,11,12] or plasma [13,14] of patients with a history of CHD or lower limb atherosclerosis were no different from controls; and three studies found that zinc concentrations in the serum [15,16] or hair [17] of patients with lower limb atherosclerosis or CHD were higher than those of the control group. One observational study examined the association between the intake of zinc and CHD [18]. The prevalence of CHD was associated with lower zinc intakes however, no adjustment was reported for dietary factors known to affect CHD risk factors which also appeared to be associated with zinc intake.

The relationship between zinc and plasma lipids is inconclusive. A positive association between serum zinc and cholesterol concentrations was found in 7 of 16 cross-sectional studies [19–25] and no association was found in the other 9 studies [10–13,26–30].

The conflicting nature of these observations may be explained by differences in the extent of CHD, site of atherosclerosis, or confounding factors. It is noteworthy that in most studies the diurnal variation in plasma or serum zinc concentrations [1], and the lifestyle factors that are known to affect plasma lipids [3] were not explicitly considered.

Zinc Supplementation and Plasma Lipids
The effect of zinc supplementation on plasma lipids is summarised in Tables 1 and 2. The majority of controlled trials have shown that plasma cholesterol concentrations are unaffected by supplementation with 15–150 mg Zn/d whether consumed as zinc alone or in combination with copper or vitamins [25,31–39,42,44]. In an elderly population, where zinc intakes or serum zinc concentrations at baseline were below the recommended range, supplementation with 20 or 53 mg Zn/d decreased plasma cholesterol concentrations [40,41]. This outcome may indicate repletion of zinc status and raises the possibility that inadequate zinc intake has a deleterious effect on cholesterol metabolism in elderly subjects. Plasma triglycerides are unaffected by zinc supplementation [25,32,33,35–39].

A limited number of studies in women has reported that LDL-c concentrations fall with zinc supplementation administered during a metabolic ward study [40] and a randomised controlled trial [33]. A large proportion of participants in the latter study reported gastro-intestinal side effects [43] that may have altered their dietary intake.

The effect of supplemental zinc on plasma high-density lipoprotein (HDL)-c in males appears to be dependent on the dose of zinc and the duration of the supplementation period. The majority of studies report that doses 75 mg Zn/d decrease HDL-c concentrations within 5–6 w [35,36,38]. Smaller doses (50 mg Zn/d) decreased HDLC concentrations at 12 w [38] but not at 4–6 w [32,38,44]. Doses of 30 mg Zn/d for up to 14 w had no significant effect on HDL-c concentrations [37,39]. Plasma HDL-c concentrations in women are unaffected by zinc supplementation [33,45].

A case series study reported that plasma HDL-c concentrations in elderly subjects rose when zinc supplementation ceased [42]. In contrast, a randomised controlled trial showed that in older as in younger populations, zinc supplements alone [41] or combined with copper [25,31] produced no change in plasma HDL-c concentrations at least in the short-term despite a rise in serum zinc concentrations.

Thus on the basis of randomised controlled trials, the concentrations of LDL-c, total cholesterol and triglycerides in plasma are unaffected by up to 150 mg Zn/d, however, plasma HDL-c concentrations decline when supplementation is >50 mg Zn/d. The decline in plasma HDL-c concentrations in apparently healthy young males suggests that zinc supplements induce an atherogenic lipoprotein profile. In addition, it was noted as part of safety monitoring in the elderly that the number of circulatory adverse effects rose with doses of 80 mg Zn/d however the nature of these events was not detailed [46].

Thrombogenesis
Zinc is purported to influence haemostasis by impacting on platelet aggregation and coagulation. Results of in vitro studies have demonstrated that zinc enhances thrombin activity of the common coagulation pathway [47], the acceleration of fibrin polymerisation [47], platelet activation [48,49] and the initiation of the intrinsic pathway [50,51]. In many of these experiments, the in vitro concentration of unbound (free) zinc (10 µM) is greater than that found in the circulation (0.15–0.5 µM). However, the intra-platelet concentration of zinc is 30–60 times greater than that of plasma [52] and responds to changes in extracellular zinc [53]. Thus, although the concentration of zinc in vitro appears high, it is hypothesised that such concentrations are achieved in vivo by the localised release of unbound zinc from activated platelets [50,54].

Supplementation with 50 mg Zn/d resulting in a postprandial rise in the plasma zinc concentration, increased platelet reactivity [55]. At lower doses of zinc (30 mg) and in the presence of adequate copper [31,39,56,57], fibrinolytic factors and platelet zinc concentrations are unaffected. In support of a role for zinc in haemostasis [58], acute zinc depletion that results in hypozincaemia impairs platelet aggregation and prolongs bleeding times [59]. There is insufficient evidence to determine the role of zinc supplementation in thrombogenesis.

Zinc and Antioxidant Activity
Superoxide anions are potent oxidants that are capable of binding nitric oxide (NO) to form peroxynitrite [60], also a potent oxidant that promotes further superoxide production [61]: an oxidative spiral that is moderated by the activities of various forms of superoxide dismutase (SOD) [60]. Zinc is postulated to influence CHD via its role as a cofactor for Cu,Zn-SOD [58,62,63], a function that contributes to the cellular antioxidant capacity and ensures that sufficient NO is available to maintain normal endothelial function. Both low and high intakes of zinc impact Cu,Zn-SOD activity. Zinc deficiency is associated with lower SOD activity [64] and a greater susceptibility to oxidative damage from elevated peroxynitrite concentrations [28,63]. In contrast, increased zinc intake reduces Cu,Zn-SOD activity by limiting the bioavailability of copper [65,66].

Although some studies have investigated the role of aortic SOD activity in atherogenesis [67], the majority of investigators have focused on the relationship between zinc intake and erythrocyte (E)-SOD activity (Tables 3, 4) [68]. Zinc supplements have been shown to decrease E-SOD activity in females [33,69,70] but not in elderly subjects [71,72]. In males, the effect of zinc supplementation on E-SOD activity is equivocal [33,73]. The differences may be due to the low statistical power of the studies or confounding factors such as, copper status. There are few studies examining the effect of dietary zinc intake on extracellular (EC)-SOD activity. It has been observed that increased zinc intake raises plasma EC-SOD [74], whereas zinc deficiency decreases plasma EC-SOD activity [64]. In contrast, a cross sectional study found no correlation between plasma EC-SOD activity and dietary zinc intake [76]. The clinical relevance of these observations is unclear given that patients with atherosclerosis had elevated E-SOD activity [77] but lower Cu,Zn-SOD activity in the aorta [67].

Zinc and Gene Expression
Micro array studies have identified genes that are potential candidates for regulation by zinc and have highlighted the complexity of the effects of zinc status on gene expression: some genes are positively affected; others negatively; while some are affected only by extremes of zinc status (deficiency or excess) [78]. The genes identified include those involved in the regulation of redox state, fatty acid synthesis and degradation, signal transduction, growth factor activity, platelet activation and the regulation of homocysteine concentrations, possible factors in the pathogenesis of CHD [78–81]. The roles of zinc in signal transduction and apoptosis are currently being defined and the implications of these findings for zinc deficiency and atherogenesis have been reviewed [82]. Undoubtedly, the application of these and other molecular biological techniques will provide insights into the relationship between zinc and CHD.

Conclusions
Intervention studies have shown that zinc supplementation (50 mg Zn/d) has the potential to impact adversely on CHD primarily by decreasing plasma HDL-c concentrations in males. The propensity of LDL to oxidative modification and the concentrations of LDL-c, total cholesterol and triglycerides in plasma are unaffected by supplementation with up to 150 mg Zn/d. In contrast, ecological studies that investigated zinc intake or status, and incidence of CHD reveal no consistent pattern. Further research is required to address the conflicting nature and limitations of these observations by taking into consideration factors such as, differences that may exist in the extent of CHD, the site of atherosclerosis, the diurnal variation in plasma or serum zinc concentrations, and the diet and lifestyle factors that are known to affect plasma lipids. Further research is required also to determine the relationship between plasma zinc concentrations and haemostasis.

Besides the demonstrated adverse effect of zinc supplementation on plasma HDL-c concentrations in apparently healthy men, there is insufficient evidence to determine the role of zinc supplementation in influencing other risk factors for CHD.

Received April 11, 2005. Accepted December 21, 2005.

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