The Experts below are selected from a list of 3216 Experts worldwide ranked by ideXlab platform
Marcel Delaforge - One of the best experts on this subject based on the ideXlab platform.
-
Metabolic detoxification pathways for 5-methoxy-Sterigmatocystin in primary tracheal epithelial cells
Xenobiotica, 2014Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Stéphane BretagneAbstract: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-methoxySterigmatocystin. 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 mu M 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-methoxySterigmatocystin. Nevertheless, 5-methoxy-Sterigmatocystin increases the CYP1A1 mRNA levels. The long-term consequences remain unknown.
-
metabolic detoxification pathways for 5 methoxy Sterigmatocystin in primary tracheal epithelial cells
Xenobiotica, 2014Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Stéphane BretagneAbstract:Abstract1. 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....
-
Contribution of uniformly 13C-enriched Sterigmatocystin to the study of its pulmonary metabolism.
Rapid communications in mass spectrometry : RCM, 2011Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Stéphane Bretagne, Michel Péan, Marcel DelaforgeAbstract: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% 13C 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. Copyright © 2011 John Wiley & Sons, Ltd.
-
Contribution of uniformly 13C‐enriched Sterigmatocystin to thestudy of its pulmonary metabolism
Rapid Communications in Mass Spectrometry, 2011Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Stéphane Bretagne, Michel Péan, Marcel DelaforgeAbstract:Mycotoxins are secondary metabolites of filamentous fungi which can cause a wide range of systemic effects. Humanhealth effects of inhaled mycotoxins remain poorly documented, despite the large amounts present, associated with airborneparticles.Among thesemycotoxins, Sterigmatocystin is one of themost prevalent. Because its chemical structure isclose to that of the aflatoxins, we studied its metabolism and its cellular consequences when in contact with the airwayepithelium, using the mass spectral signature from the 10% 13C uniformly enriched Sterigmatocystin. The metabolismwas studied in vitro, using recombinant cytochrome P450s enzymes, and in porcine tracheal epithelial cell (PTEC)primary cultures at an air‐liquid interface. Themetabolites were analyzed by high‐performance liquid chromatographycoupled with tandem mass spectrometry detection. Expressed enzymes and PTECs were exposed to uniformly 13CenrichedSterigmatocystin to confirm the relationship between Sterigmatocystin and its metabolites because this isotopiccluster shape is conserved for all metabolites and their product ions. Incubation of Sterigmatocystin with recombinantcytochrome 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. Inthe PTEC cultures, Sterigmatocystin metabolism resulted in a glucuro‐conjugate. Two other products were detected, asulfo‐conjugate and a glucuro‐conjugate of hydroxySterigmatocystin upon cytochrome P450 1A1 induction. This is thefirst 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 reactivemetabolites in respiratory cells, at least in pigs.
-
Metabolic Detoxication Pathways for Sterigmatocystin in Primary Tracheal Epithelial Cells
Chemical research in toxicology, 2010Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Michel Péan, Khaled Khoufache, Jean-marc Costa, Stéphane BretagneAbstract:Human health effects of inhaled mycotoxins remain poorly documented, despite the large amounts present in bioaerosols. Among these mycotoxins, Sterigmatocystin is one of the most prevalent. Our aim was to study the metabolism and cellular consequences of Sterigmatocystin once it is in contact with the airway epithelium. Metabolites were analyzed first in vitro, using recombinant P450 1A1, 1A2, 2A6, 2A13, and 3A4 enzymes, and subsequently in porcine tracheal epithelial cell (PTEC) primary cultures at an air—liquid interface. Expressed enzymes and PTECs were exposed to Sterigmatocystin, uniformly enriched with 13 C to confirm the relationship between Sterigmatocystin and metabolites. Induction of the expression of xenobiotic-metabolizing enzymes upon Sterigmatocystin exposure was examined by real-time quantitative real-time polymerase chain reaction. Incubation of 50 μM Sterigmatocystin with recombinant P450 1A1 led to the formation of three metabolites: monohydroxy-Sterigmatocystin (M1), dihydroxy-Sterigmatocystin (M2), and one glutathione adduct (M3), the latter after the formation of a transient epoxide. Recombinant P450 1A2 also led to M1 and M3. P450 3A4 led to only M3. In PTEC, 1 μM Sterigmatocystin metabolism resulted in a glucuro conjugate (M4) mainly excreted at the basal side of cells. If PTEC were treated with β-naphthoflavone prior to Sterigmatocystin incubation, two other products were detected, i.e., a sulfo conjugate (M5) and a glucoro conjugate (M6) of hydroxy-Sterigmatocystin. Exposure of PTEC for 24 h to 1 μM Sterigmatocystin induced an 18-fold increase in the mRNA levels of P450 1A1, without significantly induced 7-ethoxyresorufin O-deethylation activity. These data suggest that Sterigmatocystin is mainly detoxified and is unable to produce significant amounts of reactive epoxide metabolites in respiratory cells. However, Sterigmatocystin increases the P450 1A1 mRNA levels with unknown long-term consequences. These in vitro results obtained in the porcine pulmonary tract need to be confirmed in human epithelial cells.
Odile Cabaret - One of the best experts on this subject based on the ideXlab platform.
-
Metabolic detoxification pathways for 5-methoxy-Sterigmatocystin in primary tracheal epithelial cells
Xenobiotica, 2014Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Stéphane BretagneAbstract: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-methoxySterigmatocystin. 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 mu M 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-methoxySterigmatocystin. Nevertheless, 5-methoxy-Sterigmatocystin increases the CYP1A1 mRNA levels. The long-term consequences remain unknown.
-
metabolic detoxification pathways for 5 methoxy Sterigmatocystin in primary tracheal epithelial cells
Xenobiotica, 2014Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Stéphane BretagneAbstract:Abstract1. 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....
-
Contribution of uniformly 13C-enriched Sterigmatocystin to the study of its pulmonary metabolism.
Rapid communications in mass spectrometry : RCM, 2011Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Stéphane Bretagne, Michel Péan, Marcel DelaforgeAbstract: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% 13C 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. Copyright © 2011 John Wiley & Sons, Ltd.
-
Contribution of uniformly 13C‐enriched Sterigmatocystin to thestudy of its pulmonary metabolism
Rapid Communications in Mass Spectrometry, 2011Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Stéphane Bretagne, Michel Péan, Marcel DelaforgeAbstract:Mycotoxins are secondary metabolites of filamentous fungi which can cause a wide range of systemic effects. Humanhealth effects of inhaled mycotoxins remain poorly documented, despite the large amounts present, associated with airborneparticles.Among thesemycotoxins, Sterigmatocystin is one of themost prevalent. Because its chemical structure isclose to that of the aflatoxins, we studied its metabolism and its cellular consequences when in contact with the airwayepithelium, using the mass spectral signature from the 10% 13C uniformly enriched Sterigmatocystin. The metabolismwas studied in vitro, using recombinant cytochrome P450s enzymes, and in porcine tracheal epithelial cell (PTEC)primary cultures at an air‐liquid interface. Themetabolites were analyzed by high‐performance liquid chromatographycoupled with tandem mass spectrometry detection. Expressed enzymes and PTECs were exposed to uniformly 13CenrichedSterigmatocystin to confirm the relationship between Sterigmatocystin and its metabolites because this isotopiccluster shape is conserved for all metabolites and their product ions. Incubation of Sterigmatocystin with recombinantcytochrome 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. Inthe PTEC cultures, Sterigmatocystin metabolism resulted in a glucuro‐conjugate. Two other products were detected, asulfo‐conjugate and a glucuro‐conjugate of hydroxySterigmatocystin upon cytochrome P450 1A1 induction. This is thefirst 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 reactivemetabolites in respiratory cells, at least in pigs.
-
Metabolic Detoxication Pathways for Sterigmatocystin in Primary Tracheal Epithelial Cells
Chemical research in toxicology, 2010Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Michel Péan, Khaled Khoufache, Jean-marc Costa, Stéphane BretagneAbstract:Human health effects of inhaled mycotoxins remain poorly documented, despite the large amounts present in bioaerosols. Among these mycotoxins, Sterigmatocystin is one of the most prevalent. Our aim was to study the metabolism and cellular consequences of Sterigmatocystin once it is in contact with the airway epithelium. Metabolites were analyzed first in vitro, using recombinant P450 1A1, 1A2, 2A6, 2A13, and 3A4 enzymes, and subsequently in porcine tracheal epithelial cell (PTEC) primary cultures at an air—liquid interface. Expressed enzymes and PTECs were exposed to Sterigmatocystin, uniformly enriched with 13 C to confirm the relationship between Sterigmatocystin and metabolites. Induction of the expression of xenobiotic-metabolizing enzymes upon Sterigmatocystin exposure was examined by real-time quantitative real-time polymerase chain reaction. Incubation of 50 μM Sterigmatocystin with recombinant P450 1A1 led to the formation of three metabolites: monohydroxy-Sterigmatocystin (M1), dihydroxy-Sterigmatocystin (M2), and one glutathione adduct (M3), the latter after the formation of a transient epoxide. Recombinant P450 1A2 also led to M1 and M3. P450 3A4 led to only M3. In PTEC, 1 μM Sterigmatocystin metabolism resulted in a glucuro conjugate (M4) mainly excreted at the basal side of cells. If PTEC were treated with β-naphthoflavone prior to Sterigmatocystin incubation, two other products were detected, i.e., a sulfo conjugate (M5) and a glucoro conjugate (M6) of hydroxy-Sterigmatocystin. Exposure of PTEC for 24 h to 1 μM Sterigmatocystin induced an 18-fold increase in the mRNA levels of P450 1A1, without significantly induced 7-ethoxyresorufin O-deethylation activity. These data suggest that Sterigmatocystin is mainly detoxified and is unable to produce significant amounts of reactive epoxide metabolites in respiratory cells. However, Sterigmatocystin increases the P450 1A1 mRNA levels with unknown long-term consequences. These in vitro results obtained in the porcine pulmonary tract need to be confirmed in human epithelial cells.
Stéphane Bretagne - One of the best experts on this subject based on the ideXlab platform.
-
Metabolic detoxification pathways for 5-methoxy-Sterigmatocystin in primary tracheal epithelial cells
Xenobiotica, 2014Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Stéphane BretagneAbstract: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-methoxySterigmatocystin. 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 mu M 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-methoxySterigmatocystin. Nevertheless, 5-methoxy-Sterigmatocystin increases the CYP1A1 mRNA levels. The long-term consequences remain unknown.
-
metabolic detoxification pathways for 5 methoxy Sterigmatocystin in primary tracheal epithelial cells
Xenobiotica, 2014Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Stéphane BretagneAbstract:Abstract1. 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....
-
Contribution of uniformly 13C-enriched Sterigmatocystin to the study of its pulmonary metabolism.
Rapid communications in mass spectrometry : RCM, 2011Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Stéphane Bretagne, Michel Péan, Marcel DelaforgeAbstract: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% 13C 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. Copyright © 2011 John Wiley & Sons, Ltd.
-
Contribution of uniformly 13C‐enriched Sterigmatocystin to thestudy of its pulmonary metabolism
Rapid Communications in Mass Spectrometry, 2011Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Stéphane Bretagne, Michel Péan, Marcel DelaforgeAbstract:Mycotoxins are secondary metabolites of filamentous fungi which can cause a wide range of systemic effects. Humanhealth effects of inhaled mycotoxins remain poorly documented, despite the large amounts present, associated with airborneparticles.Among thesemycotoxins, Sterigmatocystin is one of themost prevalent. Because its chemical structure isclose to that of the aflatoxins, we studied its metabolism and its cellular consequences when in contact with the airwayepithelium, using the mass spectral signature from the 10% 13C uniformly enriched Sterigmatocystin. The metabolismwas studied in vitro, using recombinant cytochrome P450s enzymes, and in porcine tracheal epithelial cell (PTEC)primary cultures at an air‐liquid interface. Themetabolites were analyzed by high‐performance liquid chromatographycoupled with tandem mass spectrometry detection. Expressed enzymes and PTECs were exposed to uniformly 13CenrichedSterigmatocystin to confirm the relationship between Sterigmatocystin and its metabolites because this isotopiccluster shape is conserved for all metabolites and their product ions. Incubation of Sterigmatocystin with recombinantcytochrome 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. Inthe PTEC cultures, Sterigmatocystin metabolism resulted in a glucuro‐conjugate. Two other products were detected, asulfo‐conjugate and a glucuro‐conjugate of hydroxySterigmatocystin upon cytochrome P450 1A1 induction. This is thefirst 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 reactivemetabolites in respiratory cells, at least in pigs.
-
Metabolic Detoxication Pathways for Sterigmatocystin in Primary Tracheal Epithelial Cells
Chemical research in toxicology, 2010Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Michel Péan, Khaled Khoufache, Jean-marc Costa, Stéphane BretagneAbstract:Human health effects of inhaled mycotoxins remain poorly documented, despite the large amounts present in bioaerosols. Among these mycotoxins, Sterigmatocystin is one of the most prevalent. Our aim was to study the metabolism and cellular consequences of Sterigmatocystin once it is in contact with the airway epithelium. Metabolites were analyzed first in vitro, using recombinant P450 1A1, 1A2, 2A6, 2A13, and 3A4 enzymes, and subsequently in porcine tracheal epithelial cell (PTEC) primary cultures at an air—liquid interface. Expressed enzymes and PTECs were exposed to Sterigmatocystin, uniformly enriched with 13 C to confirm the relationship between Sterigmatocystin and metabolites. Induction of the expression of xenobiotic-metabolizing enzymes upon Sterigmatocystin exposure was examined by real-time quantitative real-time polymerase chain reaction. Incubation of 50 μM Sterigmatocystin with recombinant P450 1A1 led to the formation of three metabolites: monohydroxy-Sterigmatocystin (M1), dihydroxy-Sterigmatocystin (M2), and one glutathione adduct (M3), the latter after the formation of a transient epoxide. Recombinant P450 1A2 also led to M1 and M3. P450 3A4 led to only M3. In PTEC, 1 μM Sterigmatocystin metabolism resulted in a glucuro conjugate (M4) mainly excreted at the basal side of cells. If PTEC were treated with β-naphthoflavone prior to Sterigmatocystin incubation, two other products were detected, i.e., a sulfo conjugate (M5) and a glucoro conjugate (M6) of hydroxy-Sterigmatocystin. Exposure of PTEC for 24 h to 1 μM Sterigmatocystin induced an 18-fold increase in the mRNA levels of P450 1A1, without significantly induced 7-ethoxyresorufin O-deethylation activity. These data suggest that Sterigmatocystin is mainly detoxified and is unable to produce significant amounts of reactive epoxide metabolites in respiratory cells. However, Sterigmatocystin increases the P450 1A1 mRNA levels with unknown long-term consequences. These in vitro results obtained in the porcine pulmonary tract need to be confirmed in human epithelial cells.
Françoise Botterel - One of the best experts on this subject based on the ideXlab platform.
-
Metabolic detoxification pathways for 5-methoxy-Sterigmatocystin in primary tracheal epithelial cells
Xenobiotica, 2014Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Stéphane BretagneAbstract: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-methoxySterigmatocystin. 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 mu M 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-methoxySterigmatocystin. Nevertheless, 5-methoxy-Sterigmatocystin increases the CYP1A1 mRNA levels. The long-term consequences remain unknown.
-
metabolic detoxification pathways for 5 methoxy Sterigmatocystin in primary tracheal epithelial cells
Xenobiotica, 2014Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Stéphane BretagneAbstract:Abstract1. 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....
-
Contribution of uniformly 13C-enriched Sterigmatocystin to the study of its pulmonary metabolism.
Rapid communications in mass spectrometry : RCM, 2011Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Stéphane Bretagne, Michel Péan, Marcel DelaforgeAbstract: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% 13C 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. Copyright © 2011 John Wiley & Sons, Ltd.
-
Contribution of uniformly 13C‐enriched Sterigmatocystin to thestudy of its pulmonary metabolism
Rapid Communications in Mass Spectrometry, 2011Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Stéphane Bretagne, Michel Péan, Marcel DelaforgeAbstract:Mycotoxins are secondary metabolites of filamentous fungi which can cause a wide range of systemic effects. Humanhealth effects of inhaled mycotoxins remain poorly documented, despite the large amounts present, associated with airborneparticles.Among thesemycotoxins, Sterigmatocystin is one of themost prevalent. Because its chemical structure isclose to that of the aflatoxins, we studied its metabolism and its cellular consequences when in contact with the airwayepithelium, using the mass spectral signature from the 10% 13C uniformly enriched Sterigmatocystin. The metabolismwas studied in vitro, using recombinant cytochrome P450s enzymes, and in porcine tracheal epithelial cell (PTEC)primary cultures at an air‐liquid interface. Themetabolites were analyzed by high‐performance liquid chromatographycoupled with tandem mass spectrometry detection. Expressed enzymes and PTECs were exposed to uniformly 13CenrichedSterigmatocystin to confirm the relationship between Sterigmatocystin and its metabolites because this isotopiccluster shape is conserved for all metabolites and their product ions. Incubation of Sterigmatocystin with recombinantcytochrome 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. Inthe PTEC cultures, Sterigmatocystin metabolism resulted in a glucuro‐conjugate. Two other products were detected, asulfo‐conjugate and a glucuro‐conjugate of hydroxySterigmatocystin upon cytochrome P450 1A1 induction. This is thefirst 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 reactivemetabolites in respiratory cells, at least in pigs.
-
Metabolic Detoxication Pathways for Sterigmatocystin in Primary Tracheal Epithelial Cells
Chemical research in toxicology, 2010Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Michel Péan, Khaled Khoufache, Jean-marc Costa, Stéphane BretagneAbstract:Human health effects of inhaled mycotoxins remain poorly documented, despite the large amounts present in bioaerosols. Among these mycotoxins, Sterigmatocystin is one of the most prevalent. Our aim was to study the metabolism and cellular consequences of Sterigmatocystin once it is in contact with the airway epithelium. Metabolites were analyzed first in vitro, using recombinant P450 1A1, 1A2, 2A6, 2A13, and 3A4 enzymes, and subsequently in porcine tracheal epithelial cell (PTEC) primary cultures at an air—liquid interface. Expressed enzymes and PTECs were exposed to Sterigmatocystin, uniformly enriched with 13 C to confirm the relationship between Sterigmatocystin and metabolites. Induction of the expression of xenobiotic-metabolizing enzymes upon Sterigmatocystin exposure was examined by real-time quantitative real-time polymerase chain reaction. Incubation of 50 μM Sterigmatocystin with recombinant P450 1A1 led to the formation of three metabolites: monohydroxy-Sterigmatocystin (M1), dihydroxy-Sterigmatocystin (M2), and one glutathione adduct (M3), the latter after the formation of a transient epoxide. Recombinant P450 1A2 also led to M1 and M3. P450 3A4 led to only M3. In PTEC, 1 μM Sterigmatocystin metabolism resulted in a glucuro conjugate (M4) mainly excreted at the basal side of cells. If PTEC were treated with β-naphthoflavone prior to Sterigmatocystin incubation, two other products were detected, i.e., a sulfo conjugate (M5) and a glucoro conjugate (M6) of hydroxy-Sterigmatocystin. Exposure of PTEC for 24 h to 1 μM Sterigmatocystin induced an 18-fold increase in the mRNA levels of P450 1A1, without significantly induced 7-ethoxyresorufin O-deethylation activity. These data suggest that Sterigmatocystin is mainly detoxified and is unable to produce significant amounts of reactive epoxide metabolites in respiratory cells. However, Sterigmatocystin increases the P450 1A1 mRNA levels with unknown long-term consequences. These in vitro results obtained in the porcine pulmonary tract need to be confirmed in human epithelial cells.
Olivier Puel - One of the best experts on this subject based on the ideXlab platform.
-
Metabolic detoxification pathways for 5-methoxy-Sterigmatocystin in primary tracheal epithelial cells
Xenobiotica, 2014Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Stéphane BretagneAbstract: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-methoxySterigmatocystin. 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 mu M 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-methoxySterigmatocystin. Nevertheless, 5-methoxy-Sterigmatocystin increases the CYP1A1 mRNA levels. The long-term consequences remain unknown.
-
metabolic detoxification pathways for 5 methoxy Sterigmatocystin in primary tracheal epithelial cells
Xenobiotica, 2014Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Stéphane BretagneAbstract:Abstract1. 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....
-
Contribution of uniformly 13C-enriched Sterigmatocystin to the study of its pulmonary metabolism.
Rapid communications in mass spectrometry : RCM, 2011Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Stéphane Bretagne, Michel Péan, Marcel DelaforgeAbstract: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% 13C 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. Copyright © 2011 John Wiley & Sons, Ltd.
-
Contribution of uniformly 13C‐enriched Sterigmatocystin to thestudy of its pulmonary metabolism
Rapid Communications in Mass Spectrometry, 2011Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Stéphane Bretagne, Michel Péan, Marcel DelaforgeAbstract:Mycotoxins are secondary metabolites of filamentous fungi which can cause a wide range of systemic effects. Humanhealth effects of inhaled mycotoxins remain poorly documented, despite the large amounts present, associated with airborneparticles.Among thesemycotoxins, Sterigmatocystin is one of themost prevalent. Because its chemical structure isclose to that of the aflatoxins, we studied its metabolism and its cellular consequences when in contact with the airwayepithelium, using the mass spectral signature from the 10% 13C uniformly enriched Sterigmatocystin. The metabolismwas studied in vitro, using recombinant cytochrome P450s enzymes, and in porcine tracheal epithelial cell (PTEC)primary cultures at an air‐liquid interface. Themetabolites were analyzed by high‐performance liquid chromatographycoupled with tandem mass spectrometry detection. Expressed enzymes and PTECs were exposed to uniformly 13CenrichedSterigmatocystin to confirm the relationship between Sterigmatocystin and its metabolites because this isotopiccluster shape is conserved for all metabolites and their product ions. Incubation of Sterigmatocystin with recombinantcytochrome 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. Inthe PTEC cultures, Sterigmatocystin metabolism resulted in a glucuro‐conjugate. Two other products were detected, asulfo‐conjugate and a glucuro‐conjugate of hydroxySterigmatocystin upon cytochrome P450 1A1 induction. This is thefirst 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 reactivemetabolites in respiratory cells, at least in pigs.
-
Metabolic Detoxication Pathways for Sterigmatocystin in Primary Tracheal Epithelial Cells
Chemical research in toxicology, 2010Co-Authors: Odile Cabaret, Olivier Puel, Françoise Botterel, Marcel Delaforge, Michel Péan, Khaled Khoufache, Jean-marc Costa, Stéphane BretagneAbstract:Human health effects of inhaled mycotoxins remain poorly documented, despite the large amounts present in bioaerosols. Among these mycotoxins, Sterigmatocystin is one of the most prevalent. Our aim was to study the metabolism and cellular consequences of Sterigmatocystin once it is in contact with the airway epithelium. Metabolites were analyzed first in vitro, using recombinant P450 1A1, 1A2, 2A6, 2A13, and 3A4 enzymes, and subsequently in porcine tracheal epithelial cell (PTEC) primary cultures at an air—liquid interface. Expressed enzymes and PTECs were exposed to Sterigmatocystin, uniformly enriched with 13 C to confirm the relationship between Sterigmatocystin and metabolites. Induction of the expression of xenobiotic-metabolizing enzymes upon Sterigmatocystin exposure was examined by real-time quantitative real-time polymerase chain reaction. Incubation of 50 μM Sterigmatocystin with recombinant P450 1A1 led to the formation of three metabolites: monohydroxy-Sterigmatocystin (M1), dihydroxy-Sterigmatocystin (M2), and one glutathione adduct (M3), the latter after the formation of a transient epoxide. Recombinant P450 1A2 also led to M1 and M3. P450 3A4 led to only M3. In PTEC, 1 μM Sterigmatocystin metabolism resulted in a glucuro conjugate (M4) mainly excreted at the basal side of cells. If PTEC were treated with β-naphthoflavone prior to Sterigmatocystin incubation, two other products were detected, i.e., a sulfo conjugate (M5) and a glucoro conjugate (M6) of hydroxy-Sterigmatocystin. Exposure of PTEC for 24 h to 1 μM Sterigmatocystin induced an 18-fold increase in the mRNA levels of P450 1A1, without significantly induced 7-ethoxyresorufin O-deethylation activity. These data suggest that Sterigmatocystin is mainly detoxified and is unable to produce significant amounts of reactive epoxide metabolites in respiratory cells. However, Sterigmatocystin increases the P450 1A1 mRNA levels with unknown long-term consequences. These in vitro results obtained in the porcine pulmonary tract need to be confirmed in human epithelial cells.
