Differential mutagenic, antimutagenic and cytotoxic responses induced by apomorphine and its oxidation product, 8-oxo-apomorphine-semiquinone, in bacteria and yeast.

摘要

Apomorphine (APO) is considered to be a classical mixed type dopamine D(1) and D(2) receptor agonist. It has been used in the therapy of Parkinson's disease and, more recently, for the treatment of erectile dysfunction. Like other catechols (e.g. dopamine), APO easily autoxidizes, producing quinone and semiquinone derivatives that may lead to the formation of reactive oxygen species and induce neurotoxicity. We assayed mutagenicity, antimutagenicity, and cytotoxicity of these compounds by means of the Salmonella/microsome assay, WP2 Mutoxitest and sensitivity assay in Saccharomyces cerevisiae yeast strains lacking antioxidant defenses. In the absence of S9 mix both compounds Apomorphine and its oxidation derivative, 8-oxo-apomorphine-semiquinone (8-OASQ), both at doses ranging from 20 to 80 microg per plate, induced frameshift mutations in TA98 and TA97 S. typhimurium strains, with 8-OASQ being up to two times more mutagenic. However, for strains which detect oxidative mutagens, 8-OASQ acted as a mutagen while APO was an antimutagen, inhibiting H(2)O(2) and t-BOOH-induced mutagenicity in TA102 S. typhimurium and WP2-derived E. coli strains. The S9 mix inhibited all mutagenic effects, probably either by conjugation of APO and 8-OASQ to proteins or by quenching reactive oxygen species. In sensitivity assays with S. cerevisiae, APO was only clearly cytotoxic to some strains at higher doses (200 and 400 microg/ml), whereas 8-OASQ dose-dependently sensitized all the strains, mainly the mutants lacking catalase (deltactt1), superoxide dismutase (deltasod1) and Yap1 transcription factor (deltayap1), suggesting that 8-OASQ cytotoxicity towards S. cerevisiae results from its pro-oxidant properties. APO also tended to protect S. cerevisiae strains against oxidative damage induced by high concentrations of H(2)O(2) and t-BOOH, while 8-OASQ enhanced pro-oxidant effects and induced adaptation responses to these agents. These results suggest that the 8-OASQ oxidation product of APO might induce cytotoxic and genotoxic effects.