Omar R F, Gelboin H V, Rahimtula A D
Biochemistry Department, Memorial University of Newfoundland, St. John's, Canada.
Biochem Pharmacol. 1996 Feb 9;51(3):207-16. doi: 10.1016/0006-2952(95)02194-9.
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.
对用各种细胞色素P450诱导剂处理过的大鼠的肝微粒体进行检测，以考察其将霉菌毒素赭曲霉毒素A（OTA）代谢为主要代谢产物4（R）-4-羟基赭曲霉毒素A（4R）和次要代谢产物4（S）-4-羟基赭曲霉毒素A（4S）的能力。用苯巴比妥（PB）、地塞米松（DXM）、3-甲基胆蒽（3MC）和异黄樟素（ISF）对大鼠进行预处理可极大地诱导4R的形成。PB、DXM、3MC、氯贝丁酯（CLF）和ISF处理也可诱导4S的形成。异烟肼（INH）预处理主要诱导4S的形成。发现用3MC微粒体时，4R形成的最适pH为6.0，用PB和DXM微粒体时为6.5。对于4S的形成，最适pH为7.0。在最适pH下（与pH 7.4相比），用PB和DXM微粒体时4R的形成增加40 - 50%，而用3MC微粒体时增加8.0倍。使用抑制剂美替拉酮和α-萘黄酮以及针对各种细胞色素P450的单克隆抗体进行的研究表明，至少细胞色素P450同工酶IA1/IA2、IIB1和IIIA1/IIIA2参与4R的形成。以碱性磷酸酶和γ-谷氨酰转移酶的尿排泄作为肾损伤指标，我们观察到用PB对大鼠进行预处理可诱导肝细胞色素P450（P450II2B1），从而预防OTA肾毒性，而用钴原卟啉IX预处理可降低细胞色素P450水平，加剧OTA肾毒性。我们的结果表明，至少OTA的P450IIB1依赖性代谢导致其解毒，并且OTA本身在某些情况下可能有毒，或者其他途径负责其激活。
