Carcinogenesis Advance Access originally published online on December 19, 2003
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Carcinogenesis, Vol. 25, No. 5, 827-831,
May 2004
Carcinogenesis vol.25 no.5 © Oxford University Press 2004; all rights reserved.
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Cytotoxic and genotoxic effects of ß-carotene breakdown products on primary rat hepatocytes
Institute of Genetics and General Biology, University of Salzburg, Hellbrunnerstrasse 34, A-5020 Salzburg, Austria, 1 Children's Hospital, University of Ulm, Ulm, Germany and 2 Herzog-Julius Hospital for Rheumatology and Orthopedics, Kurhausstrasse 13–17, D-38667 Bad Harzburg, Germany
3 To whom correspondence should be addressed. Tel: +43 662 8044 5782; Fax: +43 662 8044 144; Email: peter.eckl{at}sbg.ac.at
According to Siems and colleagues, free radical attack on ß-carotene results in the formation of high amounts of cleavage products with prooxidant activities towards subcellular organelles such as mitochondria. This finding may be an explanation for the contradictory results obtained with ß-carotene in clinical efficacy and cancer prevention trials. Since primary hepatocytes proved to be very sensitive indicators of the genotoxic action of suspect mutagens/carcinogens we therefore investigated a ß-carotene cleavage products mixture (CP), apo8'- carotenal (apo8') and ß-carotene utilizing primary cultures of rat hepatocytes. The end-points tested were: the mitotic index, the percentage of necrotic and apoptotic cells, micronucleated cells, chromosomal aberrations and sister chromatid exchanges (SCE). Our results indicate a genotoxic potential of both CP and apo8' already at the concentrations 100 nM and 1 µM, i.e. at pathophysiologically relevant levels of ß-carotene and ß-carotene breakdown products. A 3 h treatment with CP induced statistically significant levels of micronuclei at concentrations of 0.1, 1 and 10 µM and chromosomal aberrations at concentrations of 1, 5 and 10 µM. Apo8' induced statistically significant levels of micronuclei at concentrations of 0.1, 1 and 5 µM and chromosomal aberrations at concentrations of 0.1, 1 and 10 µM. Statistically significant increases in SCE induction were only observed at a concentration of 10 µM CP and apo8'. In contrast, no significant cytotoxic effects of these substances were observed. Since ß-carotene induced neither significant cytotoxic nor genotoxic effects at concentrations ranging from 0.01 up to 10 µM, these observations indicate that most likely ß-carotene breakdown products are responsible for the occurrence of carcinogenic effects found in the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study and the Beta-CArotene and RETinol Efficacy Trial (CARET).
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