Bioactivation to Genotoxic Metabolites
Abstract
The studies presented here were designed to elucidate the enzymes involved in the biotransformation of naturally occurring 1,8-dihydroxyanthraquinones and to investigate whether biotransformation of 1,8-dihydroxyanthraquinones may represent a bioactivation pathway. We first studied the metabolism of emodin (1,3,8-trihydroxy-6-methylanthraquinone), a compound present in pharmaceutical preparations. With rat liver microsomes, the formation of two emodin metabolites, ω-hydroxyemodin and 2-hydroxyemodin, was observed. The rates of formation of ω-hydroxyemodin were not different with microsomes from rats that had been pretreated with inducers for different cytochrome P450 enzymes. Thus, the formation of ω-hydroxyemodin seems to be catalyzed by several cytochrome P450 enzymes at low rates. The formation of 2-hydroxyemodin was increased in liver microsomes from 3-methylcholanthrene-pretreated rats and was inhibited by α-naphthoflavone, by an anti-rat cytochrome P450 1A1/2 antibody, and, to a lesser degree, by an anti-rat cytochrome P450 1A1 antibody. These data suggest the involvement of cytochrome P450 1A2 in the formation of this metabolite. However, other cytochrome P450 enzymes also seem to catalyze this reaction. The anthraquinone chrysophanol (1,8-dihydroxy-3-methylanthraquinone) is transformed, in a cytochrome P450-dependent oxidation, to aloe-emodin (1,8-dihydroxy-3-hydroxymethylanthraquinone) as the major product formed. The mutagenicity of the parent dihydroxyanthraquinones and their metabolites was compared in the in vitro micronucleus test in mouse lymphoma L5178Y cells. 2-Hydroxyemodin induced much higher micronucleus frequencies, compared with emodin. ω-Hydroxyemodin induced lower micronucleus frequencies, compared with emodin. Aloe-emodin induced significantly higher micronucleus frequencies than did chrysophanol. These data indicate that the cytochrome P450-dependent biotransformation of emodin and chrysophanol may represent bioactivation pathways for these compounds.
Footnotes
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Send reprint requests to: Dr. W. Dekant, Department of Toxicology, University of Würzburg, Versbacherstr. 9, 97078 Würzburg, Germany.
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This study was supported by the Swiss Federal Office of Public Health (Bundesamt für Gesundheit Grant FE 316.95.0500) and by the Biomed Program of the European Union (Contract BMH4-CT96–0184).
- Received August 13, 1997.
- Accepted January 24, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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