Norred W P, Plattner R D, Dombrink-Kurtzman M A, Meredith F I, Riley R T
Richard B. Russell Agricultural Research Center, ARS/USDA, Athens, Georgia 30604-5677, USA.
Toxicol Appl Pharmacol. 1997 Nov;147(1):63-70. doi: 10.1006/taap.1997.8272.
Fumonisin B1 (FB1) is the predominant member of a family of toxic metabolites produced by several species of Fusarium and is commonly found on corn. FB1 is a potent competitive inhibitor of ceramide synthase, which catalyzes the conversion of sphinganine and sphingosine to ceramide. The resultant accumulation of free sphingoid bases and the disruption of sphingolipid metabolism is believed to be the mechanism of toxicity of the fumonisins. The objectives of this study were to determine the relative potency of analogs of FB1 to inhibit ceramide synthase and to determine whether the inhibition is specific to mycotoxins with fumonisin-like structures. Fumonisins B1, B2, B3, B4, C4, and TA toxin (a structurally similar mycotoxin produced by the tomato pathogen, Alternaria alternata f. sp. lycopersici) were approximately equipotent inhibitors. Hydrolyzed fumonisins B1, B2, and B3, which lack the tricarballylic side chains, were only 30-40% as potent as the parent toxins. N-acetylated FB1 (FA1) did not block ceramide synthase, suggesting that FA1 is nontoxic. Inhibition of ceramide synthase by fumonisin analogs did not appear to be related to the lipophilicity of the compounds, as determined by computer estimation of log P values. The ability of relatively high (10 and 100 microm) doses of other mycotoxins that bear no structural similarity to fumonisins, including aflatoxin B1, cyclopiazonic acid, beauvericin, T-2 toxin, sterigmatocystin, luteoskyrin, verrucarin A, scirpentriol, and zearalenone, to block ceramide synthase was also determined. All of the toxins tested were negative in the bioassay with the exception of fumonisins, indicating that disruption of sphingolipid metabolism is a specific cytotoxic response.
伏马菌素B1（FB1）是几种镰刀菌产生的一系列有毒代谢产物中的主要成分，常见于玉米中。FB1是神经酰胺合酶的强效竞争性抑制剂，神经酰胺合酶催化鞘氨醇和鞘氨醇转化为神经酰胺。游离鞘氨醇碱的积累以及鞘脂代谢的紊乱被认为是伏马菌素的毒性机制。本研究的目的是确定FB1类似物抑制神经酰胺合酶的相对效力，并确定这种抑制是否对具有伏马菌素样结构的霉菌毒素具有特异性。伏马菌素B1、B2、B3、B4、C4和TA毒素（由番茄病原菌链格孢菌番茄专化型产生的一种结构相似的霉菌毒素）是大致等效的抑制剂。缺乏三羧酸侧链的水解伏马菌素B1、B2和B3的效力仅为母体毒素的30 - 40%。N - 乙酰化FB1（FA1）不阻断神经酰胺合酶，表明FA1无毒。通过计算机估算log P值确定，伏马菌素类似物对神经酰胺合酶的抑制作用似乎与化合物的亲脂性无关。还测定了相对高剂量（10和100微摩尔）的其他与伏马菌素无结构相似性的霉菌毒素，包括黄曲霉毒素B1、环匹阿尼酸、白僵菌素、T - 2毒素、杂色曲霉素、藤黄绿菌素、疣孢菌素A、蛇形菌素和玉米赤霉烯酮阻断神经酰胺合酶的能力。除伏马菌素外，所有测试毒素在生物测定中均为阴性，表明鞘脂代谢的破坏是一种特异性细胞毒性反应。
