title: Activities of human recombinant cytochrome P450 isoforms and human hepatic microsomes for the hydroxylation ofAlternaria toxins.
abstract: TheAlternaria toxins alternariol (AOH), alternariol-9-methyl ether (AME), altenuene (ALT) and isoaltenuene (iALT) undergo extensive oxidative metabolism, but the cytochrome P450 (CYP) isoforms responsible for the reported hydroxylation reactions are yet unknown. In the present study, the activities of twelve human CYP isoforms for the hydroxylation of AOH, AME, ALT and iALT at different positions have been determined. The most active monooxygenase for AOH and AME was CYP1A1, and lower activities were observed for CYP1A2, 2C19 and 3A4. Hydroxylation at C-2 of AOH and AME was the preferred reaction of most isoforms. For ALT and iALT, CYP2C19 had the highest activity, followed by 2C9 and 2D6. The dominating metabolite of all active isoforms was the 8-hydroxylated ALT and iALT. The activities of the CYP isoforms are consistent with the pattern of metabolites of theAlternaria toxins obtained with pooled human hepatic microsomes. Based on the activities of the CYP isoforms, a significant extrahepatic hydroxylation must be expectede.g. in the lung and esophagus for AOH and AME, and in the intestine and ovaries for ALT and iALT. As all major hydroxylation products are catechols, the extrahepatic metabolism ofAlternaria toxins may be of toxicological relevance.
authors.affiliation: Institute of Applied Biosciences, Chair of Food Chemistry, Karisruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Pfeiffer
authors.forename: B
authors.initials: B
authors.lastname: Burkhardt
authors.forename: M
authors.initials: M
authors.lastname: Altemöller
authors.forename: J
authors.initials: J
authors.lastname: Podlech
authors.forename: M
authors.initials: M
authors.lastname: Metzler