Cellular Mechanisms of Toxicity
The toxic mechanism of lead is caused by its ability to substitute for other polyvalent cations (particularly divalent cations, such as calcium [Ca2+] and zinc [Zn2+]) in the molecular machinery of living organisms{{440 Godwin,H.A. 2001; }}. In most instances, the characteristics of lead allow it to bind with greater affinity than calcium and zinc ions to protein binding-sites. These interactions allow lead to affect different biologically significant processes, including metal transport, energy metabolism, apoptosis, ionic conduction, cell adhesion, inter- and intracellular signaling, diverse enzymatic processes, protein maturation, and genetic regulation. Membrane ionic channels and signaling molecules seem to be one of the most relevant molecular targets contributing to lead’s neurotoxicity; the developing central nervous system is particularly susceptible. At critical times in development, lead may have a disorganizing influence with long-lasting effects that may continue into teenage years and beyond{{439 Garza,A. 2006; }}.
Fundamentally, lead in the aqueous solution of cells is in an ionic form that interacts with other elements. It is particularly attracted to sulfhydryls, amides, and oxides, molecules that are components of proteins. For example, when calcium and lead are added in equimolar concentrations to solutions containing calcium-binding proteins such as troponin, the lead will bind preferentially over the calcium. The protein-lead combination may not function normally, disrupting both intra- and intercellular communication, the latter because neurotransmitter release is, in part, calcium-mediated{{424 Markowitz,M. 2000; }}.
Enzyme function may decrease as a consequence of lead binding. For example, in the multistep process of producing heme, a pathway found in all cells, at least three of the enzymes are sensitive to lead. A cascade in lead toxicities may ensue because the decrease in enzyme activity results not only in less product (eg, heme), but also in the accumulation of precursors (eg, aminolevulinic acid, protoporphyrin). In excess, these biochemicals also may be toxic, as in the porphyria syndromes. One of the puzzles in the field of lead poisoning is the apparent variability in sensitivity among individuals. Part of the answer may lie in genetic variants of proteins that bind lead. Recent work has examined the interaction between the two primary alleles that code for delta aminolevulinic acid dehydratase, a heme pathway enzyme. People who have the type II allele appear less sensitive to lead than those who have the more common type I allele. This area deserves more research. Other biochemical abnormalities have been associated with lead. Anemia could be due to impaired heme synthesis. However, in a leadpoisoned child, it is more likely due to concomitant iron deficiency or a hemoglobinopathy. At very high levels (4.83 mcmol/L [100 mcg/dL]), lead can cause a Fanconi syndrome with tubular dysfunction manifested by glycosuria, proteinuria, and phosphaturia. {{424 Markowitz,M. 2000; }}.
