Effect of cytochrome P450 induction on the metabolism and toxicity of ochratoxin A

Abstract

Liver microsomes from rats treated with various P450 inducers were examined for their ability to metabolize the mycotoxin ochratoxin A (OTA) to 4( R)-4-hydroxyochratoxin A (4 R), the major metabolite, and 4( S)-4-hydroxyochratoxin A (4 S), the minor metabolite. Pretreatment of rats with phénobarbital (PB), dexamethasone (DXM), 3-methylcolcanthrene (3MC) and isosafrole (ISF) greatly induced 4 R formation. PB, DXM, 3MC, clofibrate (CLF) and ISF treatments also induced 4 S formation. Isoniazid (INH) pretreatment primarily induced 4 S formation. The pH optimum for 4 R formation was found to be 6.0 with 3MC microsomes, and 6.5 with PB and DXM microsomes. For 4 S formation, the pH optimum was 7.0. At the optimum pH (compared with pH 7.4), 4 R formation increased 40–50% with PB and DXM microsomes but 8.0-fold with 3MC microsomes. Studies using the inhibitors metyrapone and α-naphthoflavone as well as monoclonal antibodies against various P450s suggested that at least the P450 isoforms IA1/IA2, IIB1 and IIIA1/IIIA2 are involved in 4 R formation. Using urinary excretion of the enzymes alkaline phosphatase and γ-glutamyl transferase as an index of renal damage, we observed that pretreatment of rats with PB, which induced hepatic P450 (P450II2B1), protected against OTA nephrotoxicity, whereas cobalt-protoporphyrin IX pretreatment, which decreased P450 levels, exacerbated OTA nephrotoxicity. Our results suggest that at least P450IIB1-dependent metabolism of OTA leads to its detoxication and that OTA itself may be toxic in some circumstances or that other pathways are responsible for its activation.