Metabolism of Carcinogenic Azo Dye Sudan I by Rat, Rabbit, Minipig and Human Hepatic Microsomes

We investigated the ability of hepatic microsomal samples from different species including human to metabolize rodent carcinogen Sudan I (C.I. Solvent Yellow 14, 1-(phenylazo)-2-naphthol). A comparison between experimental animals and the human microsomal enzymatic system is essential for the extrapolation of animal carcinogenicity data to assess human health risk. Major metabolites produced from Sudan I by microsomes of all species were C-hydroxylated derivatives identified as 1-[(4-hydroxyphenyl)azo]-2-naphthol and 1-(phenylazo)naphthalene-2,6-diol. Additional minor C-hydroxylated products of Sudan I oxidation were 1-[(4-hydroxyphenyl)azo]naphthalene-2,6-diol and 1-[(3,4-dihydroxyphenyl)- azo]-2-naphthol. Human microsomes generated the pattern of Sudan I metabolites reproducing that formed by hepatic microsomes of rats. While microsomes of rabbit and minipig favored the production of the metabolite hydroxylated in position 6 of the naphthol ring of the Sudan I molecule, those of human and rat predominantly produced 1-[(4-hydroxyphenyl)azo]-2-naphthol. Therefore, rat microsomes are a suitable in vitro system mimicking the metabolism of Sudan I in humans. To define the role of specific cytochromes P450 in the Sudan I metabolism by rat microsomes, we investigated the modulation of Sudan I oxidation by specific inducers and selective inhibitors of these enzymes. The results suggest that cytochromes P450 1A1 and 3A are responsible for Sudan I metabolism by rat microsomes. Using purified enzymes, their ability to oxidize Sudan I was confirmed. The data clearly demonstrate the predominant role of cytochrome P450 1A1 in the Sudan I metabolism and suggest a carcinogenic potency of this rodent carcinogen for humans.