Copper Deficiency, Lead, and Paraoxonase
Environ Health Perspect 115:2-8 (2007). doi:10.1289/ehp.10151 available via http://dx.doi.org [Online 19 June 2007]
Referencing: Lead Exposure Is Associated with Decreased Serum Paraoxonase 1 (PON1) Activity and Genotypes
Li et al. (2006) measured paraoxonase 1 (PON1) in workers and found an inverse association between lead exposure and enzyme activity. This observation compliments some epidemiology and related experiments with animals, because low paraoxonase activity is associated with diabetes mellitus, familial hypercholesterolemia, ischemic heart disease, and metabolic syndrome (Klevay 2004). Paraoxonase, although studied most extensively because of its ability to detoxify organophosphate insecticides (James 2006; van Himbergen et al. 2006), has drawn increasing attention because it hydrolyzes homocysteine thiolactone, a vascular toxin that inhibits copper enzymes (Klevay 2006).
Lead intoxication has many manifestations (Fischbein 1998), lesser-known of which is induction of copper deficiency (Klauder and Petering 1977). Rats deficient in copper have an approximately 28% decrease in paraoxonase activity (Klevay 2004). These observations are consonant with the decrease in superoxide dismutase (SOD) associated with occupational exposure to lead (Ito et al. 1985) because this enzyme also depends on adequate copper nutriture for activity (Linder and Goode 1980; Owen 1981). Thus, SOD is an index of copper nutriture in humans (Uauy et al. 1985).
Li et al. (2006) stated that "the mechanism by which heavy metals inhibit serum PON1 activity is still not clear." It seems likely that lead interferes with copper utilization in the workers, leading to low copper nutritional status (Li et al. 2006). Low copper status has been related to a large variety of adverse cardiovascular phenomena in both animals and people; in this context, the most important are hypercholesterolemia, hypertension, and impaired oxidative defense (Klevay 2000, 2002).
Are there unpublished copper data on the workers, or can they be reexamined to test this copper hypothesis? Plasma copper and ceruloplasmin are not likely to be useful because they are increased by inflammation (Pepys 1996) and may be falsely high. Extracellular SOD may be helpful because it is sensitive to low copper status (Johnson et al. 2005), and low values have been associated with atherosclerosis in humans (Landmesser et al. 2000; Wang et al. 1998).
The author declares he has no competing financial interests.
Leslie M. Klevay
University of North Dakota
School of Medicine and Health Sciences Grand Forks, North Dakota
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Li WF, Pan MH, Chung MC, Ho CK, Chuang HY. 2006. Lead exposure is associated with decreased serum paraoxonase 1 (PON1) activity and genotypes. Environ Health Perspect 114:1233–1236; doi:10.1289/ehp.9163 [Online 18 May 2006].
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Copper Deficiency, Lead, and Paraoxonase: Li et al. Respond
Environ Health Perspect 115:2-8 (2007). doi:10.1289/ehp.10151R available via http://dx.doi.org [Online 19 June 2007]
We appreciate the opportunity to discuss the issue raised by Klevay in his letter. Klevay suggested that the decrease of PON1 activity in lead workers, as we reported in our article (Li et al. 2006), might be due to copper deficiency induced by lead intoxication. Because the scope of our study did not include the interaction between lead and copper, we did not measure plasma copper level, ceruloplasmin, or superoxide dismutase (SOD) activity in our cohort. Therefore, it is not possible to test Klevay's hypothesis at this point.
Although animal studies have shown that lead ingestion caused a decrease in blood copper level in cattle (Doyle and Younger 1984) and weanling rats (Mylroie et al. 1986), the relationship between lead exposure and copper deficiency in humans is less evident. Although Ito et al. (1985) and Patil et al. (2006) showed a decrease of SOD activity in lead workers, results of other studies did not agree with such findings (el-Gazzar and Hamid 1998; Oktem et al. 2004). Whether long-term lead exposure induces copper deficiency in humans is still in question.
To our knowledge, there are very few studies dealing with the effects of copper on PON1 activity. Debord et al. (2003) showed that copper ion had weak inhibitory effects on PON1 activity in vitro, whereas Klevay (2004) claimed that a copper deficiency diet caused PON1 activity reduction in rats. With little information available, it is difficult to conclude whether copper has any effects on PON1 activity in humans.
However, because of the link between copper deficiency and cardiovascular disease, we agree with Klevay that in the future, the association between lead exposure, copper deficiency, and serum PON1 activity should be examined.
The authors declare they have no competing financial interests.
Wan-Fen Li
Division of Environmental Health and Occupational Medicine
National Health Research Institutes
Zhunan, Taiwan
Hung-Yi Chuang
Graduate Institute of Public Health
Kaohsiung Medical University
Kaohsiung, Taiwan
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Ito Y, Niiya Y, Kurita H, Shima S, Sarai S. 1985. Serum lipid peroxide level and blood superoxide dismutase activity in workers with occupational exposure to lead. Int Arch Occup Environ Health 56(2):119–127; doi: 10.1007/BF00379383.
Klevay LM. 2004. Ischemic heart disease as deficiency disease. Cell Mol Biol (Noisy-le-grand) 50: 877–884.
Li WF, Pan MH, Chung MC, Ho CK, Chuang HY. 2006. Lead exposure is associated with decreased serum paraoxonase 1 (PON1) activity and genotype. Environ Health Perspect 114:1233–1236; doi:10.1289/ehp.9163 [Online 18 May 2006].
Mylroie AA, Collins H, Umbles C, Kyle J. 1986. Erythrocyte superoxide dismutase activity and other parameters of copper status in rats ingesting lead acetate. Toxicol Appl Pharmacol 82(3):512–520; doi: 10.1016/0041-008X(86)90286-3 [Online 24 September 2004].
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Patil AJ, Bhagwat VR, Patil JA, Dongre NN, Ambekar JG, Jailkhani R, Das KK. 2006. Effect of lead (Pb) exposure on the activity of superoxide dismutase and catalase in battery manufacturing workers (BMW) of Western Maharashtra (India) with reference to heme biosynthesis. Int J Environ Res Public Health. 3(4):329–337.
