Does delta-aminolaevulinic acid induce genotoxic effects?
5-Aminolaevulinic acid (ALA) is a precursor of protoporphyrin IX (PpIX) in the biosynthetic pathway of haem. The presence of exogenous ALA bypasses the feedback control and may induce the accumulation of PpIX. Since haem-containing enzymes are essential for energy metabolism, every nucleated cell in the body must have at least a minimal capacity to synthesize PpIX. Photodynamic therapy (PDT), which is the treatment of malignant lesions with light following the administration of a tumour-localizing photosensitizer, leads to oxidative damage, including the formation of genotoxic membrane degradation products via lipid peroxidation. In addition, it has been demonstrated that ALA itself can form the reactive oxygen species Ox.-, H2O2 and OH. by auto-oxidation, suggesting that it could potentially induce DNA damage. Therefore cultures of rat hepatocytes, which have been demonstrated to be very sensitive indicators for genotoxic effects induced by the lipid peroxidation product 4-hydroxynonenal and analogous aldehydes, were examined for possible mutagenic effects after treatment with ALA in the absence of light. The cytogenetic endpoints determined were chromosomal aberrations and the induction of micronuclei. Compared with the controls, significantly elevated levels of chromosomal aberrations and micronuclei were observed at concentrations of 1 microgram ml-1 or greater. Chromosomal aberrations and micronuclei were found to increase up to a concentration of 100 micrograms ml-1 ALA. While micronuclei decrease at higher concentrations, chromosomal aberrations remain at the same level. The kinetics of PpIX formation after induction with 100 and 1000 micrograms ml-1 ALA appear to be the same for both concentrations, suggesting that the induction of chromosomal aberrations may be due to PpIX.
Fiedler
D M
DM
University of Salzburg, Institute of Physics and Biophysics, Austria.
Eckl
P M
PM
Krammer
B
B
D000622:Aminolevulinic Acid / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D005260:Female; D008099:Liver / Q000166:cytology / Q000378:metabolism; D015162:Micronucleus Tests; D008940:Mitotic Index; D009153:Mutagens / Q000633:toxicity*; D011524:Protoporphyrins / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344
D009153:Mutagens; D011524:Protoporphyrins; D000622:Aminolevulinic Acid