DNA damage by 3,6-dihydropyrazine-2,5-dipropanoic acid, the cyclic dimerization product of 5-aminolevulinic acid

Biol Chem. 2001 Jun;382(6):913-8. doi: 10.1515/BC.2001.113.


5-Aminolevulinic acid (ALA) is a heme precursor that accumulates in lead poisoning and inborn porphyrias. It has been shown to produce reactive oxygen species upon metal-catalyzed aerobic oxidation and to cause oxidative damage to proteins, liposomes, DNA, and subcellular structures. Studies have also shown that ALA may condense to yield the cyclic product 3,6-dihydropyrazine-2,5-dipropanoic acid (DHPY). Here we propose that DHPY could be involved in DNA damage in the presence of high concentrations of ALA. Exposure of plasmid pUC19 DNA to low concentrations of DHPY (2-10 microM) in the presence of 0.1 mM Cu2+ ions causes DNA strand breaks, as demonstrated by agarose gel electrophoresis. It was also shown that in the presence of Cu2+ ions DHPY is able to increase the oxidation of monomeric 2'-deoxyguanosine to form 8-oxo-7,8-dihydro-2'-deoxyguanosine as inferred from high performance liquid chromatography measurements using electrochemical detection. Addition of a metal chelator (bathocuproine, 0.5 mM), the DNA compacting polyamines spermidine (1 mM) and spermine (1 mM) or antioxidant enzymes such as superoxide dismutase (10 microg/ml) and catalase (20 pg/ml) protect the DNA against these damages. The data presented here are discussed with respect to the increased frequency of liver cancer in patients with acute intermittent porphyria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminolevulinic Acid / metabolism*
  • Aminolevulinic Acid / pharmacology
  • Copper / pharmacology
  • Cyclization
  • DNA Damage / drug effects*
  • Deoxyguanosine / metabolism
  • Dimerization
  • Oxidation-Reduction
  • Oxidoreductases / pharmacology
  • Plasmids / metabolism
  • Plasmids / pharmacology
  • Porphyrias / metabolism
  • Propionates / chemical synthesis
  • Propionates / pharmacology*
  • Pyrazines / chemical synthesis
  • Pyrazines / pharmacology*


  • 3,6-dihydropyrazine-2,5-dipropanoic acid
  • Propionates
  • Pyrazines
  • Copper
  • Aminolevulinic Acid
  • Oxidoreductases
  • Deoxyguanosine