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-amin olevulinic acid (ALA), is neurotoxic in animal models and may be respo nsible for some of the adverse neurologic outcomes in lend poisoning a nd porphyria in adult humans. ALA is a substrate for the enzyme aminol evulinic 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 plas ma ALA (ALAP) and urinary ALA (ALAU) in 65 Korean lead workers, of who m 44 were homozygous for ALAD1 (ALAD1-1 genotype) and 21 were heterozy gous for ALAD (ALAD1-2 genotype). ALAP in subjects with the ALAD1-1 ge notype was significantly higher than in those with the ALAD1-2 genotyp e (Wilcoxon rank sum test, P = 0.01). No difference between ALAD genot ypes was found for age, zinc protoporphyrin (ZPP), blood lend levels ( PbB), ALAU, ol ALAU adjusted for creatinine. ALAP was significantly co rrelated 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 s ubjects 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 neur otoxic effects of lead. (C) 1997 Wiley-Liss, Inc.