N-{[(3RS)-8-hydroxy-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-7-yl]-carbonyl}-L-phenylalanine

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 赭曲霉毒素及相关物质
• 英文名称: N-{[(3RS)-8-hydroxy-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-7-yl]-carbonyl}-L-phenylalanine
• 英文别名: ochratoxin B；8-hydroxy-3-methyl-1-oxo-isochroman-7-carboxylic acid L-phenyl alanine amide；(8-hydroxy-3-methyl-1-oxoisochromane-7-carbonyl)-L-phenylalanine；(2S)-2-[(8-hydroxy-3-methyl-1-oxo-3,4-dihydroisochromene-7-carbonyl)amino]-3-phenylpropanoic acid
• 化学式: C₂₀H₁₉NO₆
• 分子量: 369.374
• InChiKey: DAEYIVCTQUFNTM-MHTVFEQDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  113
• 氢给体数：
  3
• 氢受体数：
  6

ADMET

代谢

由于对OTB的生物转化了解不多，因此本研究的目的是调查大鼠体内OTB的生物转化情况。给F344雄性大鼠单次给药OTB（10 mg/kg bw）或重复给药（2 mg/kg bw，每周5天，持续2周），并在最后一次给药后72小时处死。使用高效液相色谱（HPLC）配合荧光检测和液相色谱-串联质谱（LC-MS/MS）分析尿和粪便中OTB及其代谢物的排泄情况。奥克特菌素β是通过肽键断裂产生的主要代谢物，除了少量4-羟基-OTB外，主要随尿液排出。在单次给药后72小时内，总共有19%的给药剂量以OTB和奥克特菌素β的形式在尿液和粪便中被回收。与OTA不同，OTB在单次和重复给药后没有明显的组织特异性蓄积。OTB比OTA更广泛地被代谢并且更快速地被消除。

... Since little is known regarding biotransformation ... of OTB, the aim of this study was to investigate biotransformation of OTB in rats... Male F344 rats were administered either a single dose of OTB (10 mg/kg bw) or repeated doses (2 mg/kg bw, 5 days/week for 2 weeks) and euthanized 72 hr after the last dosing. ... Excretion of OTB and metabolites in urine and feces was analyzed using both HPLC with fluorescence detection and LC-MS/MS. Ochratoxin beta, which results from cleavage of the peptide bond, was the major metabolite excreted in urine in addition to small amounts of 4-hydroxy-OTB. In total, 19% of the administered dose was recovered as OTB and ochratoxin beta in urine and feces within 72 hr after a single dose. In contrast to OTA, no tissue-specific retention of OTB was evident after single and repeated administration. ... OTB is more extensively metabolized and more rapidly eliminated than OTA. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

每天给猪喂食0.13毫克/千克体重的赭曲霉毒素B，连续8天后，赭曲霉毒素B被完全水解为赭曲霉毒素β。

Ochratoxin B (0.13 mg/kg body wt) fed to pigs daily for 8 days was completely hydrolyzed to ochratoxin beta.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在大鼠肝脏微粒体组分和NADPH的存在下，ochratoxin B形成了一种代谢产物。通过提取、薄层色谱、高压液相色谱和结晶，该产物从培养混合物中被分离出来。基于质谱和核磁共振光谱，推测其结构为4-羟基ochratoxin B。确定了形成4-羟基ochratoxin B的Km值，并且ochratoxin B的存在并不改变ochratoxin A的羟基化。大鼠通过腹腔注射ochratoxin A或B，或两者的混合物。在ochratoxin B存在的情况下，尿液中排出的三种代谢物，ochratoxin A、(4R)-4-羟基ochratoxin A和ochratoxin alpha的比例没有变化。Ochratoxin B被代谢为4-羟基ochratoxin B和ochratoxin beta，但比例与ochratoxin A的代谢物不同。当通过腹腔注射时，ochratoxin beta在24小时内被排出。单独使用ochratoxin A处理的大鼠，食物摄入量减少了50%，在近端小管中观察到严重的病变、变性和坏死。当ochratoxin A和B联合给药时，动物临床上未受影响，组织学上仅观察到近端小管的轻微损伤。这些观察表明ochratoxin B显著减少了ochratoxin A的毒性效应。

A metabolic product was formed from ochratoxin B by rat liver microsomal fractions in the presence of NADPH. It was isolated from the incubation mixture by extraction, thin-layer chromatography, high-pressure liquid chromatography, and crystallization. On the basis of mass and nuclear magnetic resonance spectroscopy, the structure is suggested to be 4-hydroxyochratoxin B. The Km for the formation of 4-hydroxyochratoxin B was determined, and the hydroxylation of ochratoxin A was not altered by the presence of ochratoxin B. Rats were given ochratoxin A or B, or a mixture of both intraperitoneally. The ratios of the three metabolites, ochratoxin A, (4R)-4-hydroxyochratoxin A, and ochratoxin alpha, excreted in the urine did not change in the presence of ochratoxin B. Ochratoxin B was metabolized to 4-hydroxyochratoxin B and ochratoxin beta, but in a different ratio than for the ochratoxin A metabolites. When given intraperitoneally, ochratoxin beta was excreted within 24 hr. In rats treated with ochratoxin A alone, the food intake was reduced by 50%, and histologically severe lesions, degeneration, and necrosis were observed in the proximal tubules. When ochratoxin A and B given in combination, the animals were clinically unaffected and histologically there was only slight damage of proximal tubules. These observations indicate that ochratoxin B considerably reduces the toxic effects of ochratoxin A.

来源:Hazardous Substances Data Bank (HSDB)

代谢

这项研究的目标是开发和评估用于确认赭曲霉毒素A（OA）、开环赭曲霉毒素A（OP-OA）、赭曲霉毒素B（OB）、羟基赭曲霉毒素A（OA-OH）和赭曲霉毒素α（OAlpha）及其在大鼠体内由这些毒素形成的新陈代谢产物的程序，并证明在大鼠注射不同赭曲霉毒素后，可以在大鼠的胆汁和尿液中识别出许多赭曲霉毒素代谢物。在酸化甲醇中的酯化程序和强碱中的内酯水解程序产生了大多数不同赭曲霉毒素的另外两种形式。酯化程序为确认赭曲霉毒素提供了一种简单、快速且可靠的方法。在大鼠的尿液和胆汁中总共检测到20种不同的OA、OP-OA、OB、OA-OH和OAlpha的代谢物，其中几种被鉴定出来。在这些代谢物中，OA和最近发现的有毒形式OP-OA在注射任一种时都会在体内迅速形成。本研究中开发的程序可以用于确认和分离生物样本中的赭曲霉毒素，并表明除了OA和相关的赭曲霉毒素在体内形成了新的OA形式（OP-OA）之外，还形成了许多其他代谢物。

The objectives of this study were to develop and evaluate procedures for the confirmation of ochratoxin A (OA), lactone opened OA (OP-OA), ochratoxin B (OB), hydroxy OA (OA-OH) and ochratoxin alpha (Oalpha) and metabolites formed in the rats from these toxins, and to demonstrate that many ochratoxin metabolites can be identified in the bile and urine of rats injected with the different ochratoxins. An esterification procedure in acidified methanol and a lactone hydrolysis procedure in strong base yielded two additional forms of most of the different ochratoxins. The esterification procedure provided a simple, fast and reliable method for the confirmation of the ochratoxins. A total of 20 different metabolites of OA, OP-OA, OB, OA-OH and Oalpha were detected in the urine and the bile of rats of which several were identified. Among these, OA and the recently discovered and toxic form of OA (OP-OA) were readily formed in vivo when either were injected. Procedures developed in this study can be used to confirm and isolate ochratoxins in biological samples and have shown that a new form of OA (OP-OA) along with many other metabolites are formed from OA and related ochratoxins in vivo.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗救助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。 /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/遗传毒性/ 为了阐明三种结构相关的真菌毒素，即赭曲霉毒素A（OTA）、赭曲霉毒素B（OTB）和桔霉素（CIT）对人类健康的影响，研究者们调查了它们在人类肝脏细胞系（HepG2）中的急性毒性、促有丝分裂性和遗传毒性效应。这些化合物在肾病的流行地区发霉的食物中被发现，与尿路癌症有关。与之前的实验一致，研究者们发现OTA能剂量依赖性地诱导微核（MN）和单细胞凝胶电泳（SCGE）试验中的DNA迁移，在浓度大于或等于5微克/毫升时具有统计学意义。相比之下，OTB在相同条件下没有遗传毒性活动，但该化合物即使在低于OTA的剂量（10微克/毫升）下也能显著抑制细胞分裂。CIT在MN试验中引起与OTA相似的效果（在剂量水平大于或等于2.5微克/毫升时显著），但在SCGE试验中为阴性。所有化合物在添加了HepG2来源的酶匀浆（S9混合物）后，在TA98和TA100菌株中未能诱导突变。通过使用DNA-着丝粒探针，研究者们发现OTA诱导的MN涉及染色体断裂效应（55-60%的MN为着丝粒阴性），而CIT诱导的MN主要 为着丝粒阳性（78-82%）。这些发现表明OTB在人类来源的细胞中不具有遗传毒性活性，因此可能不是人类的遗传毒性致癌物。相比之下，CIT在HepG2细胞中是诱导MN的同等有效剂，但这种效果是由不同的机制引起的，即非整倍体。

/GENOTOXICITY/ To elucidate the effects of three structurally related mycotoxins, namely, ochratoxin A (OTA), ochratoxin B (OTB), and citrinin (CIT), on human health, ...their acute toxic, mitogenic, and genotoxic effects in the human-derived liver cell line (HepG2) /were investigated/. These compounds are found in moldy foods in endemic areas of nephropathy, which is associated with urinary tract cancers. In agreement with previous experiments, /investigators/ found that OTA causes a dose-dependent induction of micronuclei (MN) and DNA migration in the single-cell gel electrophoresis (SCGE) assay, which was statistically significant at concentrations of > or =5 ug/mL. In contrast, OTB was devoid of genotoxic activity under identical conditions, but the compound caused pronounced inhibition of cell division even at doses lower than OTA (10 ug/mL). CIT caused an effect similar to that of OTA in MN assays (significant at dose levels of > or =2.5 ug/mL) but was negative in the SCGE test. All compounds failed to induce mutations in Salmonella/microsome assays in strains TA98 and TA100 after addition of HepG2-derived enzyme homogenate (S9-mix). By use of DNA-centromeric probes /investigators/ found that induction of MN by OTA involves chromosome breaking effects (55-60% of the MN were centromere negative), whereas CIT-induced MN were predominantly centromere positive (78-82%). /These/ findings indicate that OTB is devoid of genotoxic activity in human-derived cells and therefore probably not a genotoxic carcinogen in humans. In contrast, CIT was an equally potent inducer of MN in HepG2 cells as OTA, but this effect is caused by a different mechanism, namely, aneuploidy.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：急性暴露/在1日龄小鸡中，从曲霉中分离出的赭曲霉毒素B的毒性与大环内酯环中酚羟基的酸解离常数密切相关。

/LABORATORY ANIMALS: Acute Exposure/ In day-old chicks, the toxicity of ochratoxin B isolated from Aspergillus was closely related to the acid dissociation constant of the phenolic hydroxyl group in the dihydroisocoumarin ring.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

描述了标记性赭曲霉毒素A和B的制备方法。标记性赭曲霉毒素B的制备方法涉及通过混合酐合成赭曲霉毒素β的叠氮化物，然后与标记的苯丙氨酸进行偶联，以产生(14)C-赭曲霉毒素B。将标记的赭曲霉毒素注入雄性Wistar大鼠体内，在不同存活时间后处死，并进行全身自动放射性显影。赭曲霉毒素A在大鼠体内的分布模式与之前在鼠标体内记录的模式没有差异。因此，大鼠（而不是小鼠）对赭曲霉毒素A诱导癌症的高度易感性不能通过毒素在特定细胞或器官的积累来解释。赭曲霉毒素A和B的分布模式几乎一致——唯一明显的区别是标记性赭曲霉毒素A在血液中的保留时间比赭曲霉毒素B长得多，后者更快地被排出。当分析组织提取物中的标记代谢物时，只有在注入赭曲霉毒素B的大鼠的提取物中发现含有易于检测的浓度，而赭曲霉毒素A的代谢物未见。

Methods for preparation of labelled ochratoxin A and B are described. The method for preparation of labelled ochratoxin B involves the synthesis of the azide of ochratoxin beta via the mixed anhydride and subsequent conjugation to labelled phenylalanine to yield (14)C-ochratoxin B. The labelled ochratoxins were injected into male Wistar rats and after different survival times they were sacrificed and subjected to whole body autoradiography. The distribution pattern of ochratoxin A in the rat did not differ from that earlier registered for mouse. The previously known, high susceptibility of rats (and not mice) to ochratoxin A-induced cancer could thus not be explained by an accumulation of the toxin in specific cells or organs. The distribution patterns of ochratoxin A and B were almost congruent--the only apparent difference being a much longer retention of the labelled ochratoxin A in the blood compared to ochratoxin B, which was much faster excreted. When analyzing tissue extracts for labelled metabolites only the extracts from the rats injected with ochratoxin B were found to contain easily detectable concentrations, while no metabolites of ochratoxin A were seen.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

A和B混合物（0.38和0.13毫克/千克体重）在怀孕早期每天喂给猪8天。B型 ochratoxin吸收不良，在肠道中优先水解。

Mixture of ochratoxins A and B (0.38 and 0.13 mg/kg body wt) was fed to pigs daily for 8 days during early pregnancy. Ochratoxin B was poorly absorbed and preferentially hydrolyzed in intestinal tract.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

由于对OTB的生物转化了解甚少，本研究旨在探讨大鼠体内OTB的生物转化过程。雄性F344大鼠接受单次剂量的OTB（10 mg/kg体重）或多次剂量（2 mg/kg体重，每周5天，持续2周）的处理，并在最后一次给药后72小时处死。通过高效液相色谱（HPLC）结合荧光检测和液相色谱-串联质谱（LC-MS/MS）分析尿液和粪便中OTB及其代谢物的排泄情况。结果显示，OTB的主要代谢物是ochratoxin beTA，这是由肽键断裂产生的，此外还有少量的4-羟基-OTB。在单次给药后72小时内，尿液和粪便中回收了相当于给药量的19%的OTB和ochratoxin beTA。与OTA不同，OTB在单次和多次给药后没有明显的组织特异性蓄积。OTB比OTA更广泛地被代谢并且更快速地被消除。

... Since little is known regarding biotransformation ... of OTB, the aim of this study was to investigate biotransformation of OTB in rats... Male F344 rats were administered either a single dose of OTB (10 mg/kg bw) or repeated doses (2 mg/kg bw, 5 days/week for 2 weeks) and euthanized 72 hr after the last dosing. ... Excretion of OTB and metabolites in urine and feces was analyzed using both HPLC with fluorescence detection and LC-MS/MS. Ochratoxin beta, which results from cleavage of the peptide bond, was the major metabolite excreted in urine in addition to small amounts of 4-hydroxy-OTB. In total, 19% of the administered dose was recovered as OTB and ochratoxin beta in urine and feces within 72 hr after a single dose. In contrast to OTA, no tissue-specific retention of OTB was evident after single and repeated administration. ... OTB is more extensively metabolized and more rapidly eliminated than OTA. ...

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为产物：
  描述：

  3,4-二氢-8-羟基-3-甲基-1-氧代-1H-2-苯并吡喃-7-羧酸 在 吡啶 、 lithium hydroxide 、 磷酸 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 为溶剂， 反应 37.5h， 生成 N-{[(3RS)-8-hydroxy-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-7-yl]-carbonyl}-L-phenylalanine
  参考文献：
  名称：

  On the role of copper and iron in DNA cleavage by ochratoxin A. Structure-activity relationships in metal binding and copper-mediated DNA cleavage

  摘要：

  奥克拉毒素A（OTA，1：X = Cl）是一种真菌致癌物质，当在代谢活化时，它促进单链DNA断裂和DNA加合物的形成。为了确定氧化还原活性过渡金属是否诱导OTA介导的DNA损伤，我们研究了毒素在水介质中结合Cu（II）和Fe（III）的能力，并在它们的存在下利用琼脂糖凝胶电泳和超螺旋质粒DNA促进DNA断裂。利用荧光光谱，发现1在生理pH下能够很容易地结合Cu（II），而在酸性条件（pH 2.6）下用于研究Fe（III）结合，因为在较高pH值下会形成Fe-氧化物沉淀。利用1的合成衍生物进行结构活性关系研究表明，1通过其酚氧结合Cu（II）和Fe（III），而其苯丙氨酸部分的羧酸结合Cu（II），但在pH 2.6下似乎不参与Fe（III）的配位。在金属介导的DNA断裂方面，未发现1在Fe诱导的DNA链切断中起作用。对于Cu（II），只有通过添加适当的还原剂（抗坏血酸钠）才能启动1的1：1铜结合复合物引发的DNA断裂。然而，发现1能够通过1,10-邻菲啰啉（Cu（OP）2）的Cu（II）复合物促进DNA断裂；这是一种原型的Cu介导核酸酶系统，只有在外部还原剂的激活下才能切割DNA。通过缺乏氯原子的类似物进行结构活性关系研究，如奥克拉毒素B（2：X = H）和内酯（12），表明氯原子对于OTA在促进Cu（OP）2介导的DNA断裂中的活性是必不可少的。我们的研究结果对于1的遗传毒性特性的影响进行了讨论。关键词：奥克拉毒素，DNA断裂，铜，铁，1,10-邻菲啰啉。

  DOI：

  10.1139/v98-088

文献信息

• Structure–Activity Relationships Imply Different Mechanisms of Action for Ochratoxin A-Mediated Cytotoxicity and Genotoxicity
  作者：Kheira Hadjeba-Medjdoub、Mariana Tozlovanu、Annie Pfohl-Leszkowicz、Christine Frenette、Robert J. Paugh、Richard A. Manderville

  DOI：10.1021/tx200406c

  日期：2012.1.13

  Ochratoxin A (OTA) is a fungal toxin that is classified as a possible human carcinogen based on sufficient evidence for carcinogenicity in animal studies. The toxin is known to promote oxidative DNA damage through production of reactive oxygen species (ROS). The toxin also generates covalent DNA adducts, and it has been difficult to separate the biological effects caused by DNA adduction from that of ROS generation. In the current study, we have derived structure activity relationships (SAR) for the role of the C5 substituent of OTA (C5-X = Cl) by first comparing the ability of OTA, OTBr (C5-X = Br), OTB (C5-X = H), and OTHQ (C5-X = OH) to photochemically react with GSH and 2'-deoxyguanosine (dG). OTA, OTBr, and OTHQ react covalently with GSH and dG following photoirradiation, while the nonchlorinated OTB does not react photochemically with GSH and dG. These findings correlate with their ability to generate covalent DNA adducts (direct genotoxicity) in human bronchial epithelial cells (WI26) and human kidney (HK2) cells, as evidenced by the P-32-postlabeling technique. OTB lacks direct genotoxicity, while OTA, OTBr, and OTHQ act as direct genotoxins. In contrast, their cytotoxicity in opossum kidney epithelial cells (OK) and WI26 cells did not show a correlation with photoreactivity. In OK and WI26 cells, OTA, OTBr, and OTB are cytotoxic, while the hydroquinone OTHQ failed to exhibit cytotoxicity. Overall, our data show that the C5-Cl atom of OTA is critical for direct genotoxicity but plays a lesser role in OTA-mediated cytotoxicity. These SARs suggest different mechanisms of action (MOA) for OTA genotoxicity and cytotoxicity and are consistent with recent findings showing OTA mutagenicity to stem from direct genotoxicity, while cytotoxicity is derived from oxidative DNA damage.