Carcinogenesis Advance Access published online on December 19, 2003
Carcinogenesis, doi:10.1093/carcin/bgh056
© 2003 by Oxford University Press
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CARCINOGENESIS
1 Institute of Genetics and General Biology, University of Salzburg, Hellbrunnerstr.34, A-5020 Salzburg, Austria
Received 30 July 2003
; revised 1 December 2003
; accepted 8 December 2003
According to Siems and his colleagues, free radical attack on
Cytotoxic and genotoxic effects of beta carotene breakdown products on primary rat hepatocytes
2 Children's Hospital, University of Ulm, Germany
3 Herzog-Julius Hospital for Rheumatology and Orthopedics, Kurhausstrasse 13-17, D-38667 Bad Harzburg, Germany
-carotene results in the formation of high amounts of cleavage products with prooxidant activities towards subcellular organelles such as mitochondria. This finding may give an explanation for the contradictory results obtained with -carotene in clinical efficacy and cancer prevention trials. Since primary hepatocytes proved to be very sensitive indicators for the genotoxic action of suspect mutagens/carcinogens we therefore investigated a -carotene cleavage products mixture (CP), apo8'-carotenal (apo8') and -carotene utilising primary cultures of rat hepatocytes. The endpoints tested were: the mitotic index, the percentage of necrotic and apoptotic cells, micronucleated cells, chromosomal aberrations and SCE (sister chromatid exchanges). Our results indicate a genotoxic potential of both CP and apo8' already in the concentration range of 100 nM and 1 µM, i.e. at pathophysiologically relevant levels of -carotene and -carotene breakdown products. A 3h treatment with CP induced statistically significant levels of micronuclei at concentrations of 0.1, 1 and 10µM, and chromosomal aberrations at concentrations of 1, 5 and 10µM. Apo8' induced statistically significant levels of micronuclei at concentrations of 0.1, 1 and 5µM, and chromosomal aberrations at concentrations of 0.1, 1 and 10µM. Statistically significant increases of SCE induction were only observed at a concentration of 10 µM of CP and apo8'. In contrast, no significant cytotoxic effects of these substances were observed. Since -carotene induced neither significant cytotoxic nor genotoxic effects at concentrations ranging from 0.01 up to 10 µM, these observations indicate that most likely -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 (CARET) Trial.-carotene breakdown products, apo8'-carotenal, -carotene, genotoxicity, hepatocytes
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