1. Highly selective bioactivation of 1- and 2-hydroxy-3-methylcholanthrene to mutagens by individual human and other mammalian sulphotransferases expressed in Salmonella typhimurium
- Author
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Walter Meinl, Zachary E. Tibbs, Carrie Tsoi, Hansruedi Glatt, Stellan Swedmark, and Charles N. Falany
- Subjects
Salmonella typhimurium ,Health, Toxicology and Mutagenesis ,Mutagen ,Toxicology ,medicine.disease_cause ,Mice ,chemistry.chemical_compound ,Dogs ,Sulfation ,Isomerism ,Species Specificity ,Genetics ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,IC50 ,Genetics (clinical) ,Carcinogen ,Acetaminophen ,chemistry.chemical_classification ,biology ,Mutagenicity Tests ,Active site ,Arylsulfotransferase ,Molecular biology ,Recombinant Proteins ,In vitro ,Rats ,Molecular Docking Simulation ,Enzyme ,chemistry ,Methylcholanthrene ,biology.protein ,Sulfotransferases ,Mutagens - Abstract
The benzylic alcohols 1- and 2-hydroxy-3-methylcholanthrene (OH-MC) are major primary metabolites of the carcinogen 3-methylcholanthrene (MC). We investigated them for mutagenicity in TA1538-derived Salmonella typhimurium strains expressing mammalian sulphotransferases (SULTs). 1-OH-MC was efficiently activated by human (h) SULT1B1 (2400 revertants/nmol), weakly activated by hSULT1C3 and hSULT2A1 (2-9 revertants/nmol), but not activated by the other hSULTs studied (1A2, 1A3, 1C2 and 1E1). Mouse, rat and dog SULT1B1 activated 1-OH-MC (8-100 revertants/nmol) with much lower efficiency than their human orthologue. The other isomer, 2-OH-MC, was activated to a potent mutagen by hSULT1A1 (4000-5400 revertants/nmol), weakly activated by hSULT1A2 or hSULT2A1 (1-12 revertants/nmol), but not activated by the other hSULTs. In contrast to their human orthologue, mouse, rat and dog SULT1A1 did not appreciably activate 2-OH-MC (
- Published
- 2013