CLIN. CHEM.

36/11, 1870 (1990)

Lead Poisoning Mechanisms

The precise mechanisms of action of lead on cellular iron status in marrow (3).
metabolism remain largely unknown, despite the known Lead induces an iron-deficiency-like response in develop-
effects of lead on porphyrin and heme biosynthesis that ing erythroeytes, as evidenced by the same accumulation of
have been studied for decades. In fact, lead-induced alter- zinc protoporphyrin (3); lead also induces a microcytic,
ations in porphyrin metabolism have long formed the bases hypochromic anemia. Because iron must be in the reduced
of tests for the laboratory diagnosis of chronic lead poison- (ferrous) state before it can serve as substrate for ferroche-
ing. The two particular metabolic derangements that have latase, inhibition of iron reduction by lead could explain
become common clinical laboratory tests are increased the utilization of zinc as the alternative substrate. Rossi
urinary coproporphyrin excretion and accumulation of zinc and colleagues addressed the issue of iron availability by
protoporphyrin in erythrocytes. The biochemistry underly- assaying NADH-ferricyanide reductase, an iron-reduction
ing these lead-induced changes has attracted much interest enzyme that can be inhibited by lead. Although their
but few clear conclusions. results are inconclusive, they recognize certain technical
Coproporphyrin is a byproduct of nonenzymic oxidation limitations with the study of lymphocytes and provide a
of coproporphyrinogen, the porphyrinogen being the inter- rational basis for further research relating to the formation
mediate in heme biosynthesis. Zinc protoporphyrin accu- of zinc protoporphyrin.
mulates as a result of inadequate supplies of iron substrate It is worth noting that acute lead toxicity may differ from
for chelation by protoporphyrin to form heme. Following chronic lead exposure by acting through multiple mecha-
the discoveries that two enzymes, copropoi-phyrinogen ox- nisms. Schwartz et al. (4) demonstrated that in acutely
idase and ferrochelatase, are inhibited by lead in vitro, lead-poisoned rabbits an initial increase in metal-free pro-
premature conclusions that these inhibitions explain the toporphyrin is followed by the decrease of this compound
action of lead have become common and are generally and a concomitant increase in zinc protoporphyrin. This
accepted without having been experimentally established sequence suggests that a bimodal response to lead exposure
as in vivo phenomena. The enzyme measurements pre- may occur in special circumstances.
sented by Rossi et al. (1) in this issue of Clinical Chemistry The mechanism of coproporphyrinuria resulting from
help to dispel the belief that lead directly inhibits copro- lead poisoning is less clear. Increased coproporphyrin ex-
porphyrinogen oxidase and ferrochelatase. These research- cretion is a very late response to lead exposure, which could
ers found no differences between lymphocytic enzyme ac- argue against inhibition of coproporphyrinogen oxidase
tivities from workers with various degrees of lead poison- and suggest a more complex series of events. Moderate
ing and those from control subjects. coproporphyrinuria as seen in lead poisoning has many
The possibility of in vivo inhibition of ferrochelatase by etiologies, including a variety of toxic agents. Thus, copro-
lead must be generally dismissed. For this to be a viable porphyrinua may be the result of more general cellular or
mechanism resulting in an accumulation of zinc protopor- tissue damage rather than inhibition of any specific en-
phyrin, the assumed nonenzymic chelation of zinc by pro- zyme. For these reasons, measurement of coproporphyrin
toporphyrin must occur. Protoporphyria, an inherited dis- excretion is no longer a test of choice for lead poisoning.
order characterized by low ferrochelatase activity, is an Although the biochemical effects of lead remain to be
ideal model to be considered in this light. Protoporphyric fully described, the current report (1) points the way to new
patients manifest a massive accumulation of metal-free experimental approaches as well as a better understanding
protoporphyrin, but no more than normal concentrations of of important diagnostic tests.
zinc protoporphyrin, in their erythrocytes. Clearly, if lead References
were decreasing the ferrochelatase activity in vivo, it 1. Rossi E, Costin KA, Garcia-Webb P. Effect of occupational lead
should induce a similar accumulation of metal-free proto- exposure on lymphocyte enzymes involved in heme biosynthesis.
porphyrin rather than zinc protoporphyrin. Clin Chem 1990;36: 1980-3.
Several investigators have demonstrated that zinc as 2. Labb#{233} RF, Rettmer RL, Shah AG, Turnlund JR. Zinc protopor-
well as iron can serve as a metal substrate for ferroche- phyrin: past, present and future. Ann NY Aced Sci 1987;514:7-14.
3. Labbe RF, Rettmer RL. Zinc protoporphyrin: a product of iron
latase. Coincidentally, erythrocytes contain relatively high
deficient erythropoiesis [Review]. Semin Hematol 1989;26:40-6.
concentrations of zinc. Virtually all of the protoporphyrin 4. Schwartz S, Stephenson B, Sarkar D, Freyholtz H, Ruth G.
(a second ferrochelatase substrate) that forms in the devel- Quantitative assay of erythrocyte “free” and zinc-protoporphyrin:
oping erythrocyte chelates either iron or zinc in an inte- clinical and genetic studies. Int J Biochem 1980;12:1053-7.
grated process. Thus, the cellular environment allows for
iron and zinc to compete as substrates for ferrochelatase in Robert F. Labb#{233}
two parallel reactions (2). In fact, this iron-zinc interaction Dept. of Laboratory Medicine
or competition forms the basis for measurement of the zinc University of Washington
protoporphyrinlheme ratio, a test highly indicative of the Seattle, WA 98195

1870 CLINICAL CHEMISTRY, Vol.36, No. 11, 1990