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首页> 外文期刊>Mycotoxin Research >Genotoxicity and inactivation of catechol metabolites of the mycotoxin zearalenone
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Genotoxicity and inactivation of catechol metabolites of the mycotoxin zearalenone

机译：霉菌毒素玉米赤霉烯酮儿茶酚代谢产物的遗传毒性和灭活

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Zearalenone (ZEN) is a highly estrogenic mycotoxin produced by Fusarium species. The adverse effects of ZEN and its reductive metabolite α-zearalenol (α-ZEL) are often compared to those of 17β-estradiol (E2) and estrone (E1). These endogenous steroidal estrogens are associated with an increased risk for cancer, which may be mediated by two mechanisms, i.e. (1) hormonal activity and (2) genotoxic effects after cytochrome P450-catalyzed metabolic activation to catechols. Like E1 and E2, ZEN and α-ZEL exhibit marked estrogenicity and also undergo aromatic hydroxylation to catechol metabolites. The subsequent methylation of catechols by catechol-O-methyltransferase (COMT) is generally considered as a detoxifying pathway. Imbalances between the activation and inactivation reactions can lead to the formation of reactive semiquinones and quinones, which can alkylate DNA or produce reactive oxygen species by redox cycling. In the present study, the genotoxicity of the catechol metabolites of ZEN, α-ZEL, E1 and E2 was determined in a cell-free system by measuring 8-oxo-2′-deoxyguanosine using a LC-DAD-MS2 method. Each of the individual catechols of ZEN, α-ZEL, E1 and E2 induced oxidative DNA damage in calf thymus DNA. The ranking order of the DNA damaging activity was 15-hydroxy-ZEN/α-ZEL ≈ 2/4-hydroxy-E1/E2 13-hydroxy-ZEN/α-ZEL. When hepatic microsomes from different species were incubated with ZEN, the rat had the highest activity for catechol formation, followed by human, mouse, pig and steer. The amount of catechol metabolites correlated directly with the amount of oxidative damage in calf thymus DNA. The ranking order for the rate of methylation by human hepatic COMT was 2-hydroxy-E1/E2 4-hydroxy-E1/E2 13/15-hydroxy-ZEN/α-ZEL. Thus, the catechol metabolites of the mycoestrogen ZEN and its reductive metabolite α-ZEL exhibit a DNA-damaging potential comparable to that of the catechol metabolites of E1 and E2, but are much poorer substrates for inactivation by human COMT.
机译：玉米赤霉烯酮（ZEN）是由镰刀菌属物种产生的高度雌激素性霉菌毒素。通常将ZEN及其还原性代谢物α-玉米赤霉烯醇（α-ZEL）与17β-雌二醇（E2）和雌酮（E1）的不良反应进行比较。这些内源性甾体雌激素与癌症风险增加有关，其可能由两种机制介导，即（1）激素活性和（2）细胞色素P450催化的代谢活化为儿茶酚后的遗传毒性作用。像E1和E2一样，ZEN和α-ZEL表现出显着的雌激素性，并且也经历芳香族羟基化作用而生成儿茶酚代谢物。通常认为邻苯二酚被邻苯二酚-O-甲基转移酶（COMT）甲基化是一种解毒途径。活化和失活反应之间的不平衡会导致反应性半醌和醌的形成，它们可以使DNA烷基化或通过氧化还原循环产生反应性氧。在本研究中，通过使用LC-DAD-MS2测量8-oxo-2'-脱氧鸟苷，在无细胞系统中确定ZEN，α-ZEL，E1和E2的儿茶酚代谢物的遗传毒性。方法。 ZEN，α-ZEL，E1和E2的各个儿茶酚均会诱发小牛胸腺DNA中的氧化性DNA损伤。 DNA破坏活性的排序顺序为15-羟基-ZEN /α-ZEL≈2 / 4-羟基-E1 / E2> 13-羟基-ZEN /α-ZEL。当将不同物种的肝微粒体与ZEN孵育时，大鼠的儿茶酚形成活性最高，其次是人，小鼠，猪和ste牛。儿茶酚代谢产物的数量与小牛胸腺DNA中的氧化损伤数量直接相关。人肝COMT甲基化速率的排名顺序为2-羟基-E1 / E2 4-羟基-E1 / E2 13 / 15-羟基-ZEN /α-ZEL。因此，真菌雌激素ZEN及其还原性代谢物α-ZEL的儿茶酚代谢物具有与E1和E2的儿茶酚代谢物相当的DNA破坏潜能，但对于人COMT的灭活作用却是较差的底物。

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