Effect of cytochrome P450 induction on the metabolism and toxicity of ochratoxin A.
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 (4R), the major metabolite, and 4(S)-4-hydroxyochratoxin A (4S), the minor metabolite. Pretreatment of rats with phenobarbital (PB), dexamethasone (DXM), 3-methylcolcanthrene (3MC) and isosafrole (ISF) greatly induced 4R formation. PB, DXM, 3MC, clofibrate (CLF) and ISF treatments also induced 4S formation. Isoniazid (INH) pretreatment primarily induced 4S formation. The pH optimum for 4R formation was found to be 6.0 with 3MC microsomes, and 6.5 with PB and DXM microsomes. For 4S formation, the pH optimum was 7.0. At the optimum pH (compared with pH 7.4), 4R formation increased 40-50% with PB and DXM microsomes but 8.0-fold with 3MC microsomes. Studies using the inhibitors metyrapone and alpha-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 4R formation. Using urinary excretion of the enzymes alkaline phosphatase and gamma-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.
Omar
R F
RF
Biochemistry Department, Memorial University of Newfoundland, St. John's, Canada.
Gelboin
H V
HV
Rahimtula
A D
AD
D000469:Alkaline Phosphatase / Q000652:urine; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009183:Mycotoxins / Q000633:toxicity*; D009793:Ochratoxins / Q000378:metabolism / Q000633:toxicity*; D010634:Phenobarbital / Q000008:administration & dosage; D011524:Protoporphyrins / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000652:urine
D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D009183:Mycotoxins; D009793:Ochratoxins; D011524:Protoporphyrins; C025589:ochratoxin A; C007095:cobaltiprotoporphyrin; D003577:Cytochrome P-450 Enzyme System; D005723:gamma-Glutamyltransferase; D000469:Alkaline Phosphatase; D010634:Phenobarbital