Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Abstract

&Aminolevulinate dehydratase (ALAD) is the second enzyme in the heme biosynthesis pathway. ALAD is a zinc metalloenzyme, and its inhibition by lead substitution for zinc is one of the most sensitive indicators of blood-lead accumulation, a measure of recent lead exposure. Stoichiometry calculations indicate that a significant portion of blood lead is stored in ALAD. Human ALAD exhibits a charge polymorphism, with about 20% of Caucasians expressing the rarer ALAD2 allele. Human ALAD1 and ALAD2 cDNAs and the 16-kb ALAD gene have been cloned and sequenced. A simple polymerase chain reaction test has been established and validated for determining ALAD genotypes. Two population studies have indicated that lead-exposed individuals with the ALAD allele have blood-lead levels about 10 pg/dl greater than similarly exposed individuals carrying only the ALAD1 allele. Ongoing work is directed toward determining the biochemistry underlying the allele-specific accumulation of blood lead, and toward determining the contribution of human ALAD genotype to lead accumulation in other tissues in transgenic mouse models and to final lead deposition in bone in both mouse and man. -Environ Health Perspect 102(Suppl 3): 215-219 (1994)

Genetic Susceptibility to Lead Poisoning

“…However, it must be noted that the genetic difference in these mice is due to a duplication of the to which the metal can bind. This is consistent with the estimations of high proportions of lead in blood bound to ALAD (27,58 Figure 4. The vitamin D hormone circulating in the blood can then bind to VDRs in the nucleus of intestinal cells as well as in kidney and bone (26).…”

Lead effects on protamine-DNA binding

“…by a competition between lead and zinc or by a displacement of lead by zinc [Batra et al, 1998]. It is known that several cysteine-zinc-containing proteins have shown af®-nity for Pb 2 [Waalkes et al, 1984;Wetmur, 1994], but lead also has high af®nity for carboxyl-rich proteins [Habermann et al, 1983;Quintanilla-Vega et al, 1995;Smith et al, 1998]. HP2 binding to other metals has been reported for Cd 2 [Gatewood et al, 1990], and for Ni 2 and Cu 2 which are able to bind to the N-terminal motif of HP2 [Bal et al, 1997].…”

Association Between δ-Aminolevulinic Acid Dehydratase (ALAD) Polymorphism and Blood Lead Levels: A Meta-regression Analysis

“…ALAD 1/2 and 2/2 encode enzymes that are more electronegative than that of ALAD 1/1. Thus ALAD 2 protein may bind lead (Pb) more tightly such that Pb may more easily accumulate in humans (Wetmur, 1994).…”