Institute of Applied Biosciences, Chair of Food Chemistry, Karisruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany.
Mycotoxin Res. 2008 Sep;24(3):117-23. doi: 10.1007/BF03032337.
TheAlternaria toxins alternariol (AOH), alternariol-9-methyl ether (AME), altenuene (ALT) and isoaltenuene (iALT) undergo extensive oxidative metabolism, but the cytochrome P450 (CYP) isoforms responsible for the reported hydroxylation reactions are yet unknown. In the present study, the activities of twelve human CYP isoforms for the hydroxylation of AOH, AME, ALT and iALT at different positions have been determined. The most active monooxygenase for AOH and AME was CYP1A1, and lower activities were observed for CYP1A2, 2C19 and 3A4. Hydroxylation at C-2 of AOH and AME was the preferred reaction of most isoforms. For ALT and iALT, CYP2C19 had the highest activity, followed by 2C9 and 2D6. The dominating metabolite of all active isoforms was the 8-hydroxylated ALT and iALT. The activities of the CYP isoforms are consistent with the pattern of metabolites of theAlternaria toxins obtained with pooled human hepatic microsomes. Based on the activities of the CYP isoforms, a significant extrahepatic hydroxylation must be expectede.g. in the lung and esophagus for AOH and AME, and in the intestine and ovaries for ALT and iALT. As all major hydroxylation products are catechols, the extrahepatic metabolism ofAlternaria toxins may be of toxicological relevance.
链格孢菌毒素交链孢酚（AOH）、交链孢酚-9-甲醚（AME）、altenuene（ALT）和异altenuene（iALT）经历广泛的氧化代谢，但负责报道的羟基化反应的细胞色素 P450（CYP）同工酶仍不清楚。在本研究中，测定了十二个人类 CYP 同工酶对 AOH、AME、ALT 和 iALT 不同位置羟基化的活性。AOH 和 AME 最活跃的单加氧酶是 CYP1A1，而 CYP1A2、2C19 和 3A4 的活性较低。AOH 和 AME 的 C-2 羟基化是大多数同工酶的首选反应。对于 ALT 和 iALT，CYP2C19 的活性最高，其次是 2C9 和 2D6。所有活性同工酶的主要代谢物是 8-羟基化的 ALT 和 iALT。CYP 同工酶的活性与用混合人肝微粒体获得的链格孢菌毒素代谢物模式一致。基于 CYP 同工酶的活性，可以预期在肺和食道中对 AOH 和 AME 进行明显的肝外羟基化，在肠道和卵巢中对 ALT 和 iALT 进行明显的肝外羟基化。由于所有主要的羟基化产物都是儿茶酚，链格孢菌毒素的肝外代谢可能具有毒理学意义。
