BIOTRANSFORMATION OF THE ANTHRAQUINONES EMODIN AND CHRYSOPHANOL BY CYTOCHROME-P450 ENZYMES - BIOACTIVATION TO GENOTOXIC METABOLITES

The studies presented here were designed to elucidate the enzymes invo lved in the biotransformation of naturally occurring 1,8-dihydroxyanth raquinones and to investigate whether biotransformation of 1,8-dihydro xyanthraquinones may represent a bioactivation pathway. We first studi ed the metabolism of emodin (1,3,8-trihydroxy-6-methylanthraquinone), a compound present in pharmaceutical preparations. With rat liver micr osomes, the formation of two emodin metabolites, omega-hydroxyemodin a nd 2-hydroxyemodin, was observed. The rates of formation of omega-hydr oxyemodin were not different with microsomes from rats that had been p retreated with inducers for different cytochrome P450 enzymes. Thus, t he formation of omega-hydroxyemodin seems to be catalyzed by several c ytochrome P450 enzymes at low rates. The formation of 2-hydroxyemodin was increased in liver microsomes from 3-methylcholanthrene-pretreated rats and was inhibited by lu-naphthoflavone, by an anti-rat cytochrom e P450 1A1/2 antibody, and, to a lesser degree, by an anti-rat cytochr ome P450 1A1 antibody. These data suggest the involvement of cytochrom e P450 1A2 in the formation of this metabolite. However, other cytochr ome P450 enzymes also seem to catalyze this reaction. The anthraquinon e chrysophanol (1,8-dihydroxy-3-methylanthraquinone) is transformed, i n a cytochrome P450-dependent oxidation, to aloe-emodin (1,8-dihydroxy -3-hydroxymethylanthraquinone) as the major product formed. The mutage nicity of the parent dihydroxyanthraquinones and their metabolites was compared in the in vitro micronucleus test in mouse lymphoma L5178Y c ells. 2-Hydroxyemodin induced much higher micronucleus frequencies, co mpared with emodin. omega-Hydroxyemodin induced lower micronucleus fre quencies, compared with emodin. Aloe-emodin induced significantly high er micronucleus frequencies than did chrysophanol, These data indicate that the cytochrome P450-dependent biotransformation of emodin and ch rysophanol may represent bioactivation pathways for these compounds.