Role of cytochrome P-450 isoenzymes in the bioactivation of hydroxy anthraquinones.

The reductive and the P-450-dependent oxidative bioactivation of various anthraquinones (AQs), 1-hydroxy AQ, 1,2-dihydroxy AQ, 1,4-dihydroxy AQ, 1,8-dihydroxy AQ, 1,2,4-trihydroxy AQ, 1,4-dihydroxy 6-carboxy AQ and 1,8-dihydroxy 3-carboxy AQ, were investigated using purified enzymes, subcellular fractions and four Chinese hamster V79 cell lines lacking and expressing cytochrome P-450 oxidative enzymes. The reduction of AQs performed by NADH-dehydrogenase, NADPH-cytochrome P-450 reductase, homogenates and microsomes of V79 cells, indicated that only the carboxy-containing drugs were fairly good superoxide anion stimulators. The P-450 dependent oxidation of AQs, assayed as NADPH consumption with microsomes and reconstituted enzymic systems, demonstrated that the P-450 1A1 and 1A2 were, as expected, the most active catalysts. However, they appeared to catalyze the formation of polyphenols rather than arene oxides or phenoxy radicals. Further support to the lack of generation of reactive intermediates during the oxidative metabolism of AQs came from the genotoxicity studies. In the three V79 cell lines expressing rat cytochrome P-450 1A1, 1A2 and 2B1, AQs did not significantly enhance the sister chromatid exchange induction above that elicited in the parental V79 line. Thus the present results, collectively taken, suggest that the P-450-mediated oxidation pathway plays a minor role in the bioactivation of AQs.