Roles of cyclooxygenase and lipoxygenases in ochratoxin A genotoxicity in human epithelial lung cells.

The roles of constitutive prostaglandin-H-synthetase (PGHS) and lipoxygenases in ochratoxin A (OTA) genotoxicity, as reflected by DNA adduct formation, have been investigated in vitro: (1) in culture of human epithelial cells and (2) by incubation in presence of pig seminal vesicle microsomes. Indomethacin (0.1 μM), which inhibits PGHS and significantly increases leukotriene C(4) production by enhancement of lipoxygenases, enhanced formation of OTA-DNA adducts tenfold. At highest dose of 10 μM, indomethacin inhibited all pathways (PGHS and lipoxygenases) and thus prevented OTA-DNA adduct formation. Nordihydroguaiaretic acid, which inhibits lipoxygenases, suppressed OTA-DNA adduct formation. The OTA metabolites formed were analysed by HPLC. OTα, 4[R]- and 4[S]-hydroxy-OTA and a unidentified derivative were formed in control cells. After pre-incubation with indomethacin (0.1 μM), further unidentified metabolites were obtained. They were similar to those obtained in presence of pig seminal vesicle microsomes. These data demonstrate that OTA is biotransformed into genotoxic metabolites via a lipoxygenase, whereas PGHS decreases OTA genotoxicity.