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. 1997 Apr;54(4):241–246. doi: 10.1136/oem.54.4.241

delta-Aminolevulinic acid dehydratase genotype modifies four hour urinary lead excretion after oral administration of dimercaptosuccinic acid.

B S Schwartz 1, B K Lee 1, W Stewart 1, P Sithisarankul 1, P T Strickland 1, K D Ahn 1, K Kelsey 1
PMCID: PMC1128697  PMID: 9166129

Abstract

OBJECTIVES: Previous research suggests that binding of lead by delta-aminolevulinic acid dehydratase (ALAD) may vary by ALAD genotype. This hypothesis was tested by examining whether ALAD genotype modifies urinary lead excretion (DMSA chelatable lead) after oral administration of dimercaptosuccinic acid (DMSA). METHODS: 57 South Korean lead battery manufacturing workers were given 5 mg/kg oral DMSA and urine was collected for four hours. Male workers were randomly selected from two ALAD genotype strata (ALAD1-1, ALAD1-2) from among all current workers in the two plants (n = 290). Subjects with ALAD1-1 (n = 38) were frequency matched with subjects with ALAD1-2 (n = 19) on duration of employment in the lead industry. Blood lead, zinc protoporphyrin, and plasma aminolevulinic acid concentrations, as well as ALAD genotype, duration of exposure, current tobacco use, and weight were examined as predictors or effect modifiers of levels of DMSA chelatable lead. RESULTS: Blood lead concentrations ranged from 11 to 53 micrograms/dl, with a mean (SD) of 25.4 (10.2) micrograms/dl. After 5 mg/kg DMSA orally, the workers excreted a mean (SD) 85.4 (45.0) micrograms lead during a four hour urine collection (range 16.5-184.1 micrograms). After controlling for blood lead concentrations, duration of exposure, current tobacco use, and body weight, subjects with ALAD1-2 excreted, on average, 24 micrograms less lead during the four hour urine collection than did subjects with ALAD1-1 (P = 0.05). ALAD genotype seemed to modify the relation between plasma delta-aminolevulinic acid (ALA) and DMSA chelatable lead. Workers with ALAD1-2 excreted more lead, after being given DMSA, with increasing plasma ALA than did workers with ALAD1-1 (P value for interaction = 0.01). CONCLUSIONS: DMSA chelatable lead may partly reflect the stores of bioavailable lead, and the current data indicate that subjects with ALAD1-2 have lower stores than those with ALAD1-1. These data provide further evidence that the ALAD genotype modifies the toxicokinetics of lead-for example, by differential binding of current lead stores or by differences in long-term retention and deposition of lead.

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Selected References

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  1. Alessio L., Castoldi M. R., Monelli O., Toffoletto F., Zocchetti C. Indicators of internal dose in current and past exposure to lead. Int Arch Occup Environ Health. 1979 Sep;44(2):127–132. doi: 10.1007/BF00386746. [DOI] [PubMed] [Google Scholar]
  2. Aposhian H. V., Aposhian M. M. meso-2,3-Dimercaptosuccinic acid: chemical, pharmacological and toxicological properties of an orally effective metal chelating agent. Annu Rev Pharmacol Toxicol. 1990;30:279–306. doi: 10.1146/annurev.pa.30.040190.001431. [DOI] [PubMed] [Google Scholar]
  3. Aposhian H. V., Maiorino R. M., Dart R. C., Perry D. F. Urinary excretion of meso-2,3-dimercaptosuccinic acid in human subjects. Clin Pharmacol Ther. 1989 May;45(5):520–526. doi: 10.1038/clpt.1989.67. [DOI] [PubMed] [Google Scholar]
  4. Araki S., Aono H., Murata K. Mobilisation of heavy metals into the urine by CaEDTA: relation to erythrocyte and plasma concentrations and exposure indicators. Br J Ind Med. 1986 Sep;43(9):636–641. doi: 10.1136/oem.43.9.636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Battistuzzi G., Petrucci R., Silvagni L., Urbani F. R., Caiola S. delta-Aminolevulinate dehydrase: a new genetic polymorphism in man. Ann Hum Genet. 1981 Jul;45(Pt 3):223–229. doi: 10.1111/j.1469-1809.1981.tb00333.x. [DOI] [PubMed] [Google Scholar]
  6. Bellinger D., Hu H., Titlebaum L., Needleman H. L. Attentional correlates of dentin and bone lead levels in adolescents. Arch Environ Health. 1994 Mar-Apr;49(2):98–105. doi: 10.1080/00039896.1994.9937461. [DOI] [PubMed] [Google Scholar]
  7. Bruenger F. W., Stevens W., Stover B. J. The association of 210Pb with constituents of erythrocytes. Health Phys. 1973 Jul;25(1):37–42. doi: 10.1097/00004032-197307000-00004. [DOI] [PubMed] [Google Scholar]
  8. Cory-Slechta D. A. Mobilization of lead over the course of DMSA chelation therapy and long-term efficacy. J Pharmacol Exp Ther. 1988 Jul;246(1):84–91. [PubMed] [Google Scholar]
  9. Cory-Slechta D. A., Weiss B., Cox C. Mobilization and redistribution of lead over the course of calcium disodium ethylenediamine tetraacetate chelation therapy. J Pharmacol Exp Ther. 1987 Dec;243(3):804–813. [PubMed] [Google Scholar]
  10. GIBSON K. D., NEUBERGER A., SCOTT J. J. The purification and properties of delta-aminolaevulic acid dehydrase. Biochem J. 1955 Dec;61(4):618–629. doi: 10.1042/bj0610618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Graziano J. H., Siris E. S., LoIacono N., Silverberg S. J., Turgeon L. 2,3-Dimercaptosuccinic acid as an antidote for lead intoxication. Clin Pharmacol Ther. 1985 Apr;37(4):431–438. doi: 10.1038/clpt.1985.67. [DOI] [PubMed] [Google Scholar]
  12. Hansen J. P., Døssing M., Paulev P. E. Chelatable lead body burden (by calcium-disodium EDTA) and blood lead concentration in man. J Occup Med. 1981 Jan;23(1):39–43. doi: 10.1097/00043764-198101000-00017. [DOI] [PubMed] [Google Scholar]
  13. Lee B. K., Schwartz B. S., Stewart W., Ahn K. D. Provocative chelation with DMSA and EDTA: evidence for differential access to lead storage sites. Occup Environ Med. 1995 Jan;52(1):13–19. doi: 10.1136/oem.52.1.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lolin Y., O'Gorman P. An intra-erythrocytic low molecular weight lead-binding protein in acute and chronic lead exposure and its possible protective role in lead toxicity. Ann Clin Biochem. 1988 Nov;25(Pt 6):688–697. doi: 10.1177/000456328802500616. [DOI] [PubMed] [Google Scholar]
  15. Maiorino R. M., Akins J. M., Blaha K., Carter D. E., Aposhian H. V. Determination and metabolism of dithiol chelating agents: X. In humans, meso-2,3-dimercaptosuccinic acid is bound to plasma proteins via mixed disulfide formation. J Pharmacol Exp Ther. 1990 Aug;254(2):570–577. [PubMed] [Google Scholar]
  16. Maiorino R. M., Aposhian M. M., Xu Z. F., Li Y., Polt R. L., Aposhian H. V. Determination and metabolism of dithiol chelating agents. XV. The meso-2,3-dimercaptosuccinic acid-cysteine (1:2) mixed disulfide, a major urinary metabolite of DMSA in the human, increases the urinary excretion of lead in the rat. J Pharmacol Exp Ther. 1993 Dec;267(3):1221–1226. [PubMed] [Google Scholar]
  17. Marcus A. H. The body burden of lead: comparison of mathematical models for accumulation. Environ Res. 1979 Jun;19(1):79–90. doi: 10.1016/0013-9351(79)90036-7. [DOI] [PubMed] [Google Scholar]
  18. O'Flaherty E. J. Physiologically based models for bone-seeking elements. IV. Kinetics of lead disposition in humans. Toxicol Appl Pharmacol. 1993 Jan;118(1):16–29. doi: 10.1006/taap.1993.1004. [DOI] [PubMed] [Google Scholar]
  19. Ong C. N., Lee W. R. High affinity of lead for fetal haemoglobin. Br J Ind Med. 1980 Aug;37(3):292–298. doi: 10.1136/oem.37.3.292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Potluri V. R., Astrin K. H., Wetmur J. G., Bishop D. F., Desnick R. J. Human delta-aminolevulinate dehydratase: chromosomal localization to 9q34 by in situ hybridization. Hum Genet. 1987 Jul;76(3):236–239. doi: 10.1007/BF00283614. [DOI] [PubMed] [Google Scholar]
  21. Raghavan S. R., Culver B. D., Gonick H. C. Erythrocyte lead-binding protein after occupational exposure. I. Relationship to lead toxicity. Environ Res. 1980 Jun;22(1):264–270. doi: 10.1016/0013-9351(80)90138-3. [DOI] [PubMed] [Google Scholar]
  22. Schwartz B. S., Lee B. K., Stewart W., Ahn K. D., Springer K., Kelsey K. Associations of delta-aminolevulinic acid dehydratase genotype with plant, exposure duration, and blood lead and zinc protoporphyrin levels in Korean lead workers. Am J Epidemiol. 1995 Oct 1;142(7):738–745. doi: 10.1093/oxfordjournals.aje.a117705. [DOI] [PubMed] [Google Scholar]
  23. Tell I., Somervaille L. J., Nilsson U., Bensryd I., Schütz A., Chettle D. R., Scott M. C., Skerfving S. Chelated lead and bone lead. Scand J Work Environ Health. 1992 Apr;18(2):113–119. doi: 10.5271/sjweh.1603. [DOI] [PubMed] [Google Scholar]
  24. Tomokuni K., Ichiba M., Fujishiro K. Interrelation between urinary delta-aminolevulinic acid (ALA), serum ALA, and blood lead in workers exposed to lead. Ind Health. 1993;31(2):51–57. doi: 10.2486/indhealth.31.51. [DOI] [PubMed] [Google Scholar]
  25. Tomokuni K., Ichiba M., Hirai Y. HPLC micro-method for determining delta-aminolevulinic acid in plasma. Clin Chem. 1993 Jan;39(1):169–170. [PubMed] [Google Scholar]
  26. Tomokuni K., Ichiba M., Hirai Y. Measurement of urinary delta-aminolevulinic acid (ALA) by fluorometric HPLC and colorimetric methods. Ind Health. 1992;30(3-4):119–128. doi: 10.2486/indhealth.30.119. [DOI] [PubMed] [Google Scholar]
  27. Wetmur J. G., Bishop D. F., Cantelmo C., Desnick R. J. Human delta-aminolevulinate dehydratase: nucleotide sequence of a full-length cDNA clone. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7703–7707. doi: 10.1073/pnas.83.20.7703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wetmur J. G., Kaya A. H., Plewinska M., Desnick R. J. Molecular characterization of the human delta-aminolevulinate dehydratase 2 (ALAD2) allele: implications for molecular screening of individuals for genetic susceptibility to lead poisoning. Am J Hum Genet. 1991 Oct;49(4):757–763. [PMC free article] [PubMed] [Google Scholar]
  29. Wetmur J. G., Lehnert G., Desnick R. J. The delta-aminolevulinate dehydratase polymorphism: higher blood lead levels in lead workers and environmentally exposed children with the 1-2 and 2-2 isozymes. Environ Res. 1991 Dec;56(2):109–119. doi: 10.1016/s0013-9351(05)80001-5. [DOI] [PubMed] [Google Scholar]
  30. Ziemsen B., Angerer J., Lehnert G., Benkmann H. G., Goedde H. W. Polymorphism of delta-aminolevulinic acid dehydratase in lead-exposed workers. Int Arch Occup Environ Health. 1986;58(3):245–247. doi: 10.1007/BF00432107. [DOI] [PubMed] [Google Scholar]

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