Aminolevulinic acid dehydratase genotype mediates plasma levels of the neurotoxin, 5-aminolevulinic acid, in lead-exposed workers.
The first intermediate substrate in the heme synthetic pathway, 5-aminolevulinic acid (ALA), is neurotoxic in animal models and may be responsible for some of the adverse neurologic outcomes in lead poisoning and porphyria in adult humans. ALA is a substrate for the enzyme aminolevulinic acid dehydratase (ALAD; EC 4.2.1.24), which is encoded by the ALAD gene containing 2 co-dominant alleles, 1 and 2. We measured plasma ALA (ALAP) and urinary ALA (ALAU) in 65 Korean lead workers, of whom 44 were homozygous for ALADI (ALAD1-1 genotype) and 21 were heterozygous for ALAD (ALAD1-2 genotype). ALAP in subjects with the ALAD1-1 genotype was significantly higher than in those with the ALAD1-2 genotype (Wilcoxon rank sum test, P = 0.01). No difference between ALAD genotypes was found for age, zinc protoporphyrin (ZPP), blood lead levels (PbB), ALAU, or ALAU adjusted for creatinine. ALAP was significantly correlated with ZPP (Spearman's r = 0.38, P = 0.002) and with PbB (r = 0.34, P = 0.006), and marginally with employment duration (r = 0.22, P = 0.08). ALAP remained significantly elevated (P = 0.032) in ALAD1-1 subjects after adjustment for PbB and age by multiple linear regression. These results suggest that ALAD1-1 subjects respond differently and may be more susceptible than ALAD1-2 subjects to the ALA-mediated neurotoxic effects of lead.
Sithisarankul
P
P
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA.
Schwartz
B S
BS
Lee
B K
BK
Kelsey
K T
KT
Strickland
P T
PT
D000328:Adult; D000622:Aminolevulinic Acid / Q000097:blood*; D005838:Genotype; D006801:Humans; D007723:Korea; D007854:Lead; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D000623:Porphobilinogen Synthase / Q000235:genetics*
D007854:Lead; D000622:Aminolevulinic Acid; D000623:Porphobilinogen Synthase