title: Metabolic detoxification pathways for 5-methoxy-sterigmatocystin in primary tracheal epithelial cells.
abstract: 1.  The health effects of inhaled mycotoxins remain poorly documented despite their presence in bioaerosols. 5-methoxy-sterigmatocystin is produced in association with sterigmatocystin by some Aspergillus spp., sometimes in larger amounts than sterigmatocystin. Whereas sterigmatocystin can be metabolized through cytochromes P450 (CYP), UDP-glucuronosyltransferases and sulfotransferases in airway epithelial cells, little is known about 5-methoxy-sterigmatocystin. 2.  The 5-methoxy-sterigmatocystin metabolites were analyzed using human recombinant CYP and porcine tracheal epithelial cell (PTEC) primary cultures at an air-liquid interface. The induction of xenobiotic-metabolizing enzymes was examined by real-time quantitative PCR for mRNA expression and 7-ethoxyresorufin O-deethylation activity. 3.  CYP1A1 metabolized 5-methoxy-sterigmatocystin into hydroxy-nor-methoxy-sterigmatocystin, nor-methoxy-sterigmatocystin and dihydroxy-methoxy-sterigmatocystin. CYP1A2 led to monohydroxy-methoxy-sterigmatocystin. In PTEC, 5-methoxy-sterigmatocystin metabolism resulted into a glucuroconjugate of 5-methoxy-sterigmatocystin, a sulfoconjugate and a glucuroconjugate of monohydroxy-methoxy-sterigmatocystin. The exposure of PTEC for 24 h to 1 µM 5-methoxy-sterigmatocystin induced a significant increase in the mRNA levels of CYP1A1, without significant induction of the 7-ethoxyresorufin O-deethylation activity. 4.  These data suggest that 5-methoxy-sterigmatocystin is mainly detoxified in airway cells through conjugation, as sterigmatocystin. However, while CYP produced a reactive metabolite of sterigmatocystin, no such metabolite was detected with 5-methoxy-sterigmatocystin. Nevertheless, 5-methoxy-sterigmatocystin increases the CYP1A1 mRNA levels. The long-term consequences remain unknown.
authors.affiliation: UMR BIPAR, U-PEC, AFSSA, ENVA , Créteil Cedex , France .
authors.forename: Odile
authors.initials: O
authors.lastname: Cabaret
authors.forename: Olivier
authors.initials: O
authors.lastname: Puel
authors.forename: Françoise
authors.initials: F
authors.lastname: Botterel
authors.forename: Marcel
authors.initials: M
authors.lastname: Delaforge
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bretagne
mesh_terms: D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D015394:Molecular Structure; D060888:Real-Time Polymerase Chain Reaction; D013241:Sterigmatocystin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D013552:Swine; D053719:Tandem Mass Spectrometry; D014132:Trachea / Q000166:cytology*
chemical_list: C578082:5-methoxysterigmatocystin; D013241:Sterigmatocystin; D019363:Cytochrome P-450 CYP1A1