title: Biotransformation of the anthraquinones emodin and chrysophanol by cytochrome P450 enzymes. 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, omega-hydroxyemodin and 2-hydroxyemodin, was observed. The rates of formation of omega-hydroxyemodin were not different with microsomes from rats that had been pretreated with inducers for different cytochrome P450 enzymes. Thus, the formation of omega-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 alpha-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. omega-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.
authors.affiliation: Department of Toxicology, University of Würzburg, Versbacherstr. 9, 97078 Würzburg, Germany.
authors.forename: S O
authors.initials: SO
authors.lastname: Mueller
authors.forename: H
authors.initials: H
authors.lastname: Stopper
authors.forename: W
authors.initials: W
authors.lastname: Dekant
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004642:Emodin / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D006900:Hydroxylation; D007700:Kinetics; D008223:Lymphoma / Q000235:genetics; D008297:Male; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000880:Anthraquinones; D009153:Mutagens; D003577:Cytochrome P-450 Enzyme System; C518327:aloe emodin; D004642:Emodin; C027113:chrysophanic acid