Sudan I is a potential carcinogen for humans: Evidence for its metabolic activation and detoxication by human recombinant cytochrome P450 1A1 and liver microsomes

1-Phenylazo-2-hydroxynaphthol (Sudan I, C.I. Solvent Yellow 14) is a liver and urinary bladder carcinogen in mammals. We compared the ability of hepatic microsomal samples from different species including human to metabolize Sudan I. Comparison between experimental animals and human cytochromes P450...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2002-10, Vol.62 (20), p.5678-5684
Main Authors: STIBOROVA, Marie, MARTINEK, Vaclav, RYDLOVA, Helena, HODEK, Petr, FREI, Eva
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Biotransformation
Carcinogenesis, carcinogens and anticarcinogens
Carcinogens - pharmacokinetics
Carcinogens - toxicity
Chemical agents
Cytochrome P-450 CYP1A1 - metabolism
Humans
Inactivation, Metabolic
Medical sciences
Microsomes, Liver - enzymology
Microsomes, Liver - metabolism
Naphthols - pharmacokinetics
Naphthols - toxicity
Oxidation-Reduction
Rabbits
Rats
Recombinant Proteins - metabolism
Swine
Swine, Miniature
Tumors
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Summary:1-Phenylazo-2-hydroxynaphthol (Sudan I, C.I. Solvent Yellow 14) is a liver and urinary bladder carcinogen in mammals. We compared the ability of hepatic microsomal samples from different species including human to metabolize Sudan I. Comparison between experimental animals and human cytochromes P450 (CYP) is essential for the extrapolation of animal carcinogenicity data to assess human health risk. Human microsomes generated the pattern of Sudan I metabolites reproducing that formed by hepatic microsomes of rats. Using hepatic microsomes of rats pretreated with specific CYP inducers, microsomes from Baculovirus-transfected insect cells expressing recombinant human CYP enzymes, purified CYP enzymes, and selective CYP inhibitors, we found that rat CYP1A1 and recombinant human CYP1A1 are the most efficient enzymes metabolizing Sudan I. Microsomes from livers (the target of Sudan I carcinogenicity) of different human donors were used to estimate whether authentic human CYPs oxidize Sudan I. Using Western blot analysis and NH(2)-terminal sequencing, we were able to detect and quantify CYP1A1 in human hepatic microsomes. The sequence of nine amino acids of the protein band cross-reacting with antirat CYP1A1 in human microsomes, LFPISMSAT, matched the sequence of human CYP1A1 perfectly (residues 2-10). CYP1A1 expression levels varied significantly among the different human microsomes (0.04-2.4 pmol/mg protein), and constituted
ISSN:0008-5472
1538-7445