© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 13, 1004-1007,
July 2, 2003
© 2003 Oxford University Press
BRIEF COMMUNICATION |
Zinc Supplement Use and Risk of Prostate Cancer
Affiliations of authors: M. F. Leitzmann, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; M. J. Stampfer, W. C. Willett, E. L. Giovannucci, Departments of Epidemiology and Nutrition, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA; K. Wu, Department of Nutrition, Harvard School of Public Health; G. A. Colditz, Department of Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital.
Corresponding author: Michael F. Leitzmann, M.D., Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Blvd., EPS-MSC 7232, Bethesda, MD 20892 (e-mail: leitzmann{at}mail.nih.gov).
ABSTRACT
The high concentration of zinc in the prostate suggests that zinc may play a role in prostate health. We examined the association between supplemental zinc intake and prostate cancer risk among 46 974 U.S. men participating in the Health Professionals Follow-Up Study. During 14 years of follow-up from 1986 through 2000, 2901 new cases of prostate cancer were ascertained, of which 434 cases were diagnosed as advanced cancer. Supplemental zinc intake at doses of up to 100 mg/day was not associated with prostate cancer risk. However, compared with nonusers, men who consumed more than 100 mg/day of supplemental zinc had a relative risk of advanced prostate cancer of 2.29 (95% confidence interval = 1.06 to 4.95; Ptrend = .003), and men who took supplemental zinc for 10 or more years had a relative risk of 2.37 (95% confidence interval = 1.42 to 3.95; Ptrend<.001). Although we cannot rule out residual confounding by supplemental calcium intake or some unmeasured correlate of zinc supplement use, our findings, that chronic zinc oversupply may play a role in prostate carcinogenesis, warrant further investigation.
Approximately 15% of the U.S. population uses dietary supplements that contain zinc (1). Ten percent of men who take zinc supplements have an average daily zinc intake that is 2–3 times the recommended dietary allowance of 11 mg/day for men (2). The reasons why individuals take supplemental zinc are not well documented.
The concentration of zinc in the prostate is higher than that in any other soft tissue in the body (3). Zinc levels in prostate adenocarcinoma are markedly lower than those in the surrounding normal prostate tissues (3). Several findings that link zinc with the suppression of prostate cancer cell growth (4–6) and inhibition of prostate tumor cell invasion (7,8) suggest that high intraprostatic zinc levels may protect against prostate carcinogenesis. However, results of other studies suggest that high intraprostatic zinc concentrations may adversely affect prostate cancer risk. For example, zinc enhances the activity of telomerase (9), an enzyme thought to be responsible for unlimited proliferation of tumor cells and whose activity is increased in prostate cancer (10). Zinc has also been found to antagonize the potential inhibitory effect of bisphosphonates on prostate tumor cell invasion (11).
Whether dietary zinc intake affects intraprostatic zinc levels is unknown. However, ingestion of 150 mg/day or more of zinc has undesirable metabolic effects, such as immune dysfunction (12) and impaired antioxidant defense (13), that are potentially related to prostate cancer. In animal studies, subtoxic zinc levels at doses of 200 parts per million of zinc in supply water may interfere with a cancer-protecting activity associated with selenium intake (14). In humans, zinc intake is positively correlated with circulating levels of insulin-like growth factor-I (15) and testosterone (16), growth factors that are directly related to prostate carcinogenesis. Thus, results of studies that have addressed the systemic effects of dietary zinc suggest that high zinc intakes may be positively associated with prostate cancer risk (12–16). To address this issue, we examined the relationship between supplemental zinc intake and prostate cancer risk among participants in the Health Professionals Follow-Up Study. The Health Professionals Follow-Up Study was initiated in 1986, when 51 529 U.S. male health professionals aged 40 to 75 years responded to a mailed questionnaire concerning their medical history and disease risk factors. Since then, follow-up questionnaires have been mailed biennially to cohort members to update information on newly diagnosed illnesses. The Health Professionals Follow-Up Study was approved by the institutional review board on the use of human subjects in research of the Harvard School of Public Health.
Dietary intake was assessed in 1986 with the use of a 131-item semiquantitative food-frequency questionnaire that requested detailed information on the amount and duration of supplement use, including questions on the brand of multivitamin used and the use of vitamins A, C, and E, zinc, iron, and calcium. The Pearson correlation coefficient between zinc intake reported in this questionnaire and in two 1-week dietary records was 0.71 (17), indicating reasonable validity of our questionnaire-based assessment of zinc intake. On each follow-up questionnaire, participants were asked to report whether they had been diagnosed with prostate cancer during the previous 2 years. We requested permission from men who reported a prostate cancer diagnosis (or from the next of kin for decedents) to obtain medical records and pathology reports, which were used to confirm the diagnosis and to determine the stage of the cases of prostate cancer. Multivariable relative risks (RRs) were computed using the Cox proportional hazards model (18). The proportional hazards assumption was satisfied. All statistical tests were two-sided.
During 587 444 person-years of follow-up, we documented 2901 new cases of prostate cancer. Among the men in our study population, supplemental zinc provided 32% of total zinc intake and thus represented by far the major source of zinc. Other sources of zinc included beef and breakfast cereals, which provided 11% and 5%, respectively, of zinc intake. The median value of the highest category of supplemental zinc intake (reported by approximately 1% of the study population) was 143 mg/day, a dose that exceeds the current recommended dietary allowance by 13-fold. We examined supplemental zinc use in relation to various risk factors for prostate cancer (Table 1
). Compared with nonusers, men who consumed supplemental zinc also consumed more multivitamins, supplemental calcium, supplemental vitamin E, lycopene, copper, iron, folate, and fish, but had lower intakes of red meat, and were slightly less likely to have had a history of prostate-specific antigen screening.
|
We next examined the association between supplemental zinc use and prostate cancer risk (Table 2
). In age-adjusted and multivariable models, we observed no statistically significant associations between supplemental zinc intakes at doses less than or equal to 100 mg/day and the risk of prostate cancer. However, compared with nonusers of zinc supplements, men who consumed more than 100 mg/day of supplemental zinc had a multivariable RR of advanced prostate cancer of 2.29 (95% confidence interval [CI] = 1.06 to 4.95; Ptrend = .003). By contrast, zinc obtained from food sources was not associated with prostate cancer risk (data not shown). We also examined the association between duration of supplemental zinc and the risk of prostate cancer (Table 2). Increasing duration of supplemental zinc use was unrelated to the risk of total or organ-confined prostate cancer. However, the multivariable RR of advanced prostate cancer for men who used supplemental zinc for 10 years or longer compared with nonusers was 2.37 (95% CI = 1.42 to 3.95; Ptrend<.001).
|
Apart from chance, possible explanations for these findings are residual confounding by supplemental calcium intake or by some unmeasured correlate of zinc supplement use. We examined these possibilities in various subanalyses by restricting our study population to men who reported supplemental calcium intakes of less than 900 mg/day, by adjusting for intakes of copper, iron, and folate; by controlling for benign prostatic hyperplasia; and by excluding nonusers of zinc supplements. The results were essentially unchanged. Because zinc has long been associated with prostate health, the observed associations may also reflect the effects of self-medication of longstanding prostate symptoms with surplus amounts of supplemental zinc. In addition, increased zinc supplement use may have coincided with decreased medical surveillance, which could ultimately have resulted in late detection of prostate cancer and, thus, a greater probability of advanced prostate cancer in these men. However, accounting for history of prostate-specific antigen screening and excluding the early years of follow-up did not materially alter the results. In summary, we found that excessively high supplemental zinc intake was associated with an increased risk of advanced prostate cancer. Strong evidence to support a specific mechanism for this association is lacking at present. Nevertheless, our findings suggest that the role of chronic oversupply of zinc in prostate carcinogenesis requires further investigation.
NOTES
Supported by Public Health Service research grants CA55075 from the National Cancer Institute (to W. C. Willett) and HL35464 from the National Heart, Lung, and Blood Institute (to W. C. Willett), National Institutes of Health (NIH), Department of Human Services (DHHS), and by Cancer Epidemiology Training Grant 5T32 CA09001-26 (to M. F. Leitzmann) from the National Cancer Institute, NIH, DHHS.
REFERENCES
1 Briefel RR, Bialostosky K, Kennedy-Stephenson J, McDowell MA, Ervin RB, Wright JD. Zinc intake of the U.S. population: findings from the third National Health and Nutrition Examination Survey, 1988– 1994. J Nutr 2000;130(5S Suppl):1367S– 73S.
2 Moss AJ, Levy AS, Kim I, Park YK. Use of vitamin and mineral supplements in the United States: current users, types of products, and nutrients. Advance data from vital and health statistics; No. 174. Hyattsville (MD): National Center for Health Statistics; 1989. p. 1–20.
3 Zaichick V, Sviridova TV, Zaichick SV. Zinc in the human prostate gland: normal, hyperplastic and cancerous. Int Urol Nephrol 1997;29:565–74.[Medline]
4 Liang JY, Liu YY, Zou J, Franklin RB, Costello LC, Feng P. Inhibitory effect of zinc on human prostatic carcinoma cell growth. Prostate 1999;40:200–7.[CrossRef][Web of Science][Medline]
5 Feng P, Liang JY, Li TL, Guan ZX, Zou J, Franklin R, et al. Zinc induces mitochondria apoptogenesis in prostate cells. Mol Urol 2000;4:31–6.[Web of Science][Medline]
6 Iguchi K, Hamatake M, Ishida R, Usami Y, Adachi T, Yamamoto H, et al. Induction of necrosis by zinc in prostate carcinoma cells and identification of proteins increased in association with this induction. Eur J Biochem 1998;253:766–70.[Web of Science][Medline]
7 Ishii K, Usui S, Sugimura Y, Yoshida S, Hioki T, Tatematsu M, et al. Aminopeptidase N regulated by zinc in human prostate participates in tumor cell invasion. Int J Cancer 2001;92:49–54.[CrossRef][Web of Science][Medline]
8 Ishii K, Usui S, Sugimura Y, Yamamoto H, Yoshikawa K, Hirano K. Inhibition of aminopeptidase N (AP-N) and urokinase-type plasminogen activator (uPA) by zinc suppresses the invasion activity in human urological cancer cells. Biol Pharm Bull 2001;24:226–30.[CrossRef][Web of Science][Medline]
9 Nemoto K, Kondo Y, Himeno S, Suzuki Y, Hara S, Akimoto M, et al. Modulation of telomerase activity by zinc in human prostatic and renal cancer cells. Biochem Pharmacol 2000;59:401–5.[CrossRef][Web of Science][Medline]
10 Sommerfeld HJ, Meeker AK, Piatyszek MA, Bova GS, Shay JW, Coffey DS. Telomerase activity: a prevalent marker of malignant human prostate tissue. Cancer Res 1996;56:218–22.
11 Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M, et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 2000;60:2949–54.
12 Chandra RK. Excessive intake of zinc impairs immune responses. JAMA 1984;252:1443–6.
13 Samman S, Roberts DC. The effect of zinc supplements on lipoproteins and copper status. Atherosclerosis 1988;70:247–52.[CrossRef][Web of Science][Medline]
14 Schrauzer GN, White DA, Schneider CJ. Inhibition of the genesis of spontaneous mammary tumors in C3H mice: effects of selenium and of selenium-antagonistic elements and their possible role in human breast cancer. Bioinorg Chem 1976;6:265–70.[CrossRef][Web of Science][Medline]
15 Holmes MD, Pollak MN, Willett WC, Hankinson SE. Dietary correlates of plasma insulin-like growth factor-1 and insulin-like growth factor binding protein 3 concentrations. Cancer Epidemiol Biomarkers Prev 2002;11:852–61.
16 Prasad AS, Mantzoros CS, Beck FW, Hess JW, Brewer GJ. Zinc status and serum testosterone levels of healthy adults. Nutrition 1996;12:344–8.[CrossRef][Web of Science][Medline]
17 Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB, Willett WC. Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am J Epidemiol 1992;135:1114–26.
18 Cox DR. Regression models and lifetables (with discussions). J R Stat Soc [Ser B] 1972;34:187–220.
Manuscript received October 21, 2002; revised April 9, 2003; accepted April 16, 2003.
Correspondence about this Article
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2003 95: 1556.
J Natl Cancer Inst 2003 95: 1556-1557.
J Natl Cancer Inst 2004 96: 239-240.
J Natl Cancer Inst 2004 96: 240-241.
J Natl Cancer Inst 2004 96: 1108.
J Natl Cancer Inst 2004 96: 1108-1109.
This article has been cited by other articles:
|
|
 |
|
  C.-T. Han, N. W. Schoene, and K. Y. Lei Influence of zinc deficiency on Akt-Mdm2-p53 and Akt-p21 signaling axes in normal and malignant human prostate cells Am J Physiol Cell Physiol, November 1, 2009; 297(5): C1188 - C1199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bilger, R. Sullivan, A. J. Prunuske, L. Clipson, N. R. Drinkwater, and W. F. Dove Widespread hyperplasia induced by transgenic TGF{alpha} in ApcMin mice is associated with only regional effects on tumorigenesis Carcinogenesis, September 1, 2008; 29(9): 1825 - 1830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yan, Y. Song, C. P. Wong, K. Hardin, and E. Ho Zinc Deficiency Alters DNA Damage Response Genes in Normal Human Prostate Epithelial Cells J. Nutr., April 1, 2008; 138(4): 667 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. M. Shih, S. H. K. Wong, N. W. Schoene, and K. Y. Lei Suppression of Gadd45 Alleviates the G2/M Blockage and the Enhanced Phosphorylation of p53 and p38 in Zinc Supplemented Normal Human Bronchial Epithelial Cells Experimental Biology and Medicine, March 1, 2008; 233(3): 317 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Lawson, M. E. Wright, A. Subar, T. Mouw, A. Hollenbeck, A. Schatzkin, and M. F. Leitzmann Multivitamin Use and Risk of Prostate Cancer in the National Institutes of Health-AARP Diet and Health Study J Natl Cancer Inst, May 16, 2007; 99(10): 754 - 764. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Giovannucci, Y. Liu, M. J. Stampfer, and W. C. Willett A prospective study of calcium intake and incident and fatal prostate cancer. Cancer Epidemiol. Biomarkers Prev., February 1, 2006; 15(2): 203 - 210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Chan, P. H. Gann, and E. L. Giovannucci Role of Diet in Prostate Cancer Development and Progression J. Clin. Oncol., November 10, 2005; 23(32): 8152 - 8160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Waters, S. Shen, L. T. Glickman, D. M. Cooley, D. G. Bostwick, J. Qian, G. F. Combs Jr, and J. S. Morris Prostate cancer risk and DNA damage: translational significance of selenium supplementation in a canine model Carcinogenesis, July 1, 2005; 26(7): 1256 - 1262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Giovannucci, Y. Liu, M. F. Leitzmann, M. J. Stampfer, and W. C. Willett A Prospective Study of Physical Activity and Incident and Fatal Prostate Cancer Arch Intern Med, May 9, 2005; 165(9): 1005 - 1010. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Henrique, C. Jeronimo, M. O. Hoque, S. Nomoto, A. L. Carvalho, V. L. Costa, J. Oliveira, M. R. Teixeira, C. Lopes, and D. Sidransky MT1G Hypermethylation Is Associated with Higher Tumor Stage in Prostate Cancer Cancer Epidemiol. Biomarkers Prev., May 1, 2005; 14(5): 1274 - 1278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Magda, P. Lecane, R. A. Miller, C. Lepp, D. Miles, M. Mesfin, J. E. Biaglow, V. V. Ho, D. Chawannakul, S. Nagpal, et al. Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines Cancer Res., May 1, 2005; 65(9): 3837 - 3845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. S. Rogers, D. Gunnell, P. M. Emmett, L. R. Glynn, D. B. Dunger, J. M. Holly, and and ALSPAC Study Team Cross-Sectional Associations of Diet and Insulin-Like Growth Factor Levels in 7- to 8-Year-Old Children Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 204 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. F. Jarrard Does Zinc Supplementation Increase the Risk of Prostate Cancer? Arch Ophthalmol, January 1, 2005; 123(1): 102 - 103. [Full Text] [PDF]
|
|
|
|
|
|
E. T. Chang, M. Hedelin, H.-O. Adami, H. Gronberg, and K. A. Balter Re: Zinc Supplement Use and Risk of Prostate Cancer J Natl Cancer Inst, July 21, 2004; 96(14): 1108 - 1108. [Full Text] [PDF]
|
|
|
|
|
|
M. F. Leitzmann and E. Giovannucci RESPONSE: Re: Zinc Supplement Use and Risk of Prostate Cancer J Natl Cancer Inst, July 21, 2004; 96(14): 1108 - 1109. [Full Text] [PDF]
|
|
|
|
|
|
J. A. Mares, T. L. La Rowe, and B. A. Blodi Doctor, What Vitamins Should I Take for My Eyes? Arch Ophthalmol, April 1, 2004; 122(4): 628 - 635. [Full Text] [PDF]
|
|
|
|
|
|
L. C. Costello, R. B. Franklin, P. Feng, and M. Tan Re: Zinc Supplement Use and Risk of Prostate Cancer J Natl Cancer Inst, February 4, 2004; 96(3): 239 - 240. [Full Text] [PDF]
|
|
|
|
|
|
M. F. Leitzmann and E. Giovannucci RESPONSE: Re: Zinc Supplement Use and Risk of Prostate Cancer J Natl Cancer Inst, February 4, 2004; 96(3): 240 - 241. [Full Text] [PDF]
|
|
|
|
|
|
C. A. Krone and L. C. Harms Re: Zinc Supplement Use and Risk of Prostate Cancer J Natl Cancer Inst, October 15, 2003; 95(20): 1556 - 1556. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||