Föllmann Wolfram, Behm Claudia, Degen Gisela H
Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystr. 67, 44139, Dortmund, Germany,
Arch Toxicol. 2014 May;88(5):1097-107. doi: 10.1007/s00204-014-1216-8. Epub 2014 Feb 28.
Citrinin (CIT) and ochratoxin A (OTA) are mycotoxins produced by several species of the genera Aspergillus, Penicillium and Monascus. Both can be present as contaminants in various food commodities and in animal feed. The occurrence and toxicity of OTA and human exposure have been intensively studied, but for CIT such data are scarce by comparison. Recently, dihydrocitrinone (DH-CIT) was detected as main metabolite of CIT in human urine, and co-occurrence of CIT and OTA was shown in human blood plasma (Blaszkewicz et al. in Arch Toxicol 87:1087-1094, 2013). In light of these new findings, we have now investigated the toxicity of the metabolite DH-CIT in comparison with CIT and analysed the effects of mixtures of CIT and OTA in vitro. The cytotoxic potency of DH-CIT (IC50 of 320/200 μM) was distinctly lower compared with CIT (IC50 of 70/62 μM) after treatment of V79 cells for 24 and 48 h. Whereas CIT induced a concentration-dependent increase in micronucleus frequencies at concentrations ≥30 μM, DH-CIT showed no genotoxic effect up to 300 μM. Thus, conversion of CIT to DH-CIT in humans can be regarded as a detoxification step. Mixtures of CIT and OTA exerted additive effects in cytotoxicity assays. The effect of CIT and OTA mixtures on induction of micronuclei varied dependent on the used concentrations between additive for low μM concentrations and more-than-additive for high μM concentrations. Effects on cell cycle were mostly triggered by OTA when both mycotoxins were used in combination. The implications of our and related in vitro studies are discussed with respect to in vivo concentrations of CIT and OTA, which are found in animals and in humans.
桔青霉素（CIT）和赭曲霉毒素A（OTA）是由曲霉属、青霉属和红曲霉属的几种菌种产生的霉菌毒素。二者均可作为污染物存在于各类食品及动物饲料中。OTA的存在、毒性及人体暴露情况已得到深入研究，但相比之下，关于CIT的此类数据却很匮乏。最近，在人类尿液中检测到二氢桔青霉素（DH-CIT）是CIT的主要代谢产物，并且在人类血浆中发现了CIT和OTA的共存情况（Blaszkewicz等人，《毒理学档案》87:1087 - 1094，2013年）。鉴于这些新发现，我们现在研究了代谢产物DH-CIT与CIT相比的毒性，并分析了CIT和OTA混合物在体外的作用。在用V79细胞处理24小时和48小时后，与CIT（IC50为70/62μM）相比，DH-CIT的细胞毒性效力（IC50为320/200μM）明显更低。当浓度≥30μM时，CIT会导致微核频率呈浓度依赖性增加，而DH-CIT在高达300μM时未显示出遗传毒性作用。因此，人体中CIT向DH-CIT的转化可被视为一个解毒步骤。在细胞毒性试验中，CIT和OTA的混合物表现出相加作用。CIT和OTA混合物对微核诱导的影响因所用浓度而异，低μM浓度时为相加作用，高μM浓度时为超相加作用。当两种霉菌毒素联合使用时，对细胞周期的影响主要由OTA引发。我们及相关体外研究的结果结合动物和人体中发现的CIT和OTA体内浓度进行了讨论。
