Catechol formation: a novel pathway in the metabolism of sterigmatocystin and 11-methoxysterigmatocystin.
The mycotoxin sterigmatocystin (STC) has an aflatoxin-like structure including a furofuran ring system. Like aflatoxin B1, STC is a liver carcinogen and forms DNA adducts after metabolic activation to an epoxide at the furofuran ring. In incubations of STC with human P450 isoforms, one monooxygenated and one dioxygenated STC metabolite were recently reported, and a GSH adduct was formed when GSH was added to the incubations. However, the chemical structures of these metabolites were not unambiguously elucidated. We now report that hepatic microsomes from humans and rats predominantly form the catechol 9-hydroxy-STC via hydroxylation of the aromatic ring. No STC-1,2-oxide and only small amounts of STC-1,2-dihydrodiol were detected in microsomal incubations, suggesting that epoxidation is a minor pathway compared to catechol formation. Catechol formation was also much more pronounced than furofuran epoxidation in the microsomal metabolism of 11-methoxysterigmatocystin (MSTC). In support of the preference of catechol formation, only trace amounts of the thiol adduct of the 1,2-oxides but large amounts of the thiol adducts of the 9-hydroxy-8,9-quinones were obtained when N-acetyl-l-cysteine was added to the microsomal incubations of STC and MSTC. In addition to hydroxylation at C-9, smaller amounts of 12c-hydroxylated, 9,12c-dihydroxylated, and 9,11-dihydroxylated metabolites were formed. Our study suggests that hydroxylation of the aromatic ring, yielding a catechol, represents a major and novel pathway in the oxidative metabolism of STC and MSTC, which may contribute to the toxic and genotoxic effects of these mycotoxins.
Institute of Applied Biosciences, Unit of Food Chemistry and Toxicology, Karlsruhe Institute of Technology (KIT) , Karlsruhe D-76131, Germany.
Erika
E
Pfeiffer
Stefanie C
SC
Fleck
Manfred
M
Metzler
D000818:Animals; D002396:Catechols / Q000378:metabolism*; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D013241:Sterigmatocystin / Q000031:analogs & derivatives / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
C000600387:13-methoxysterigmatocystin; D002396:Catechols; D013241:Sterigmatocystin; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; C034221:catechol