Mycotoxins are secondary metabolites of filamentous fungi which can cause a wide range
of systemic effects. Human health effects of inhaled mycotoxins remain poorly documented,
despite the large amounts present, associated with air-borne particles. Among these
mycotoxins, sterigmatocystin is one of the most prevalent. Because its chemical structure
is close to that of the aflatoxins, we studied its metabolism and its cellular consequences
when in contact with the airway epithelium, using the mass spectral signature from
the 10% (13)C uniformly enriched sterigmatocystin. The metabolism was studied in vitro,
using recombinant cytochrome P450s enzymes, and in porcine tracheal epithelial cell
(PTEC) primary cultures at an air-liquid interface. The metabolites were analyzed
by high-performance liquid chromatography coupled with tandem mass spectrometry detection.
Expressed enzymes and PTECs were exposed to uniformly (13)C-enriched sterigmatocystin
to confirm the relationship between sterigmatocystin and its metabolites because this
isotopic cluster shape is conserved for all metabolites and their product ions. Incubation
of sterigmatocystin with recombinant cytochrome P450 1A1 led to the formation of three
metabolites identified as monohydroxysterigmatocystin, dihydroxysterigmatocystin and
one glutathione adduct, the latter after the formation of a transient intermediate.
In the PTEC cultures, sterigmatocystin metabolism resulted in a glucuro-conjugate.
Two other products were detected, a sulfo-conjugate and a glucuro-conjugate of hydroxysterigmatocystin
upon cytochrome P450 1A1 induction. This is the first study to report sterigmatocystin
metabolism in airway epithelium, and it suggests that, contrary to the aflatoxins,
sterigmatocystin is mainly detoxified into its conjugates and is unable to produce
significant amounts of reactive metabolites in respiratory cells, at least in pigs.