HEPATOTOXIC SUBSTANCE FROM PENICILLIUM RUBRUM
HEPATOTOXIC SUBSTANCE FROM PENICILLIUM RUBRUM
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红色青霉的肝毒性物质
DOI：
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发表时间：
1962
影响因子：
3.2
通讯作者：
C. H. Wilson
中科院分区：
文献类型：
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作者：
B. J. Wilson;C. H. Wilson
伯恩赛德等人（美国《动物学杂志》（Am. J. Vet. Research 18：817，1957）和Forgacs等人（Am. J. Vet. Research 19：744，1958）。Bailey和Groth（J. Am. Vet. Med. Assoc.134：514，1959），而且得出结论，最近描述的犬科疾病X型肝炎和与红色青霉菌和其它真菌的培养物相关的猪的霉玉米中毒是由相同的病原体引起的。该真菌的一个菌株P-13（由Dennis N.考克斯，格鲁吉亚沿海平原实验站，蒂夫顿，佐治亚州），在我们的实验室中受到特别的关注，因为它在潮湿的水稻、梯牧草、燕麦、黑麦和玉米上生长时具有特殊的促生长性。从该菌株在1%蔗糖润湿的破碎硬玉米培养基上生长2至3周的培养物中提取了一种未确定纯度的肝毒性酸性产物。用无水甲醇完成萃取。通过在极性溶剂中的选择性溶解度实现活性成分的浓缩，以消除无毒物质。最终产品是一种热稳定、不挥发的棕色残留物，在室温下容易研磨成粉末。在化学上，它是一种有机酸，可溶于5%碳酸氢钠和几种极性溶剂。莫利施和本尼迪克特的测试都是阴性。毒性提取物在足够的剂量下对狗、兔子、豚鼠和小鼠是致命的。大多数毒性研究是在白色小鼠中进行的，这些小鼠对胃内、腹膜内和静脉内注射溶于丙二醇的毒素或溶于水溶液的中和毒素反应一致且具有特征性。白色小鼠的LD 5为0.2 - 0.4 mg（静脉注射）和0.1 - 0.2 mg（腹腔注射）。小鼠的急性反应在毒素给药后1至2小时内开始，包括抑郁和腹部不适的迹象，随后是不协调、步态摇摆和死亡前虚脱。肝脏充血，沿着充血或肠道出血，是显著的大体反应。在不太急性的反应中，流泪和渗出将眼睑密封在一起。注射后10小时或更长时间死亡的动物通常显示均匀苍白或斑驳的肝脏（有时为黄色），偶尔出现肾脏增大、苍白。除了肠道出血或充血外，腋窝和腹股沟区的皮下血管经常扩张和充血。在肝脏中显微镜下观察到最明显的病变，其中观察到极度充血、出血和细胞变性，伴有极轻微至中度脂肪变化。初步研究的结果，使用重复静脉注射毒素的狗，表明这种物质可能是一种病原体的肝炎x。在这种和其他宿主中的详细病理反应结果将在后面报告。从P-13菌株的培养物或提取物中没有明显的抗生素作用。将毒素局部应用于家兔剪下的皮肤，未能诱导任何炎症反应。目前正在进行的化学和病理学研究应能取得成果，揭示更多关于有毒物质的化学性质及其在各种易感动物中的作用机制的数据。
Penicillium rubrum cultures, and feed infected with this organism, were shown to be toxic for several animals by Burnside et al. (Am. J. Vet. Research 18:817, 1957) and Forgacs et al. (Am. J. Vet. Research 19:744, 1958). Bailey and Groth (J. Am. Vet. Med. Assoc. 134:514, 1959), moreover, concluded that hepatitis x, a recently described canine disease, and moldy-corn poisoning of swine, with which cultures of P. rubrum and other fungi were associated, are caused by the same etiological agent. One strain of this fungus, P-13 (Kindly supplied by Dennis N. Cox, Georgia Coastal Plain Experiment Station, Tifton, Ga.), has received particular attention in our laboratory because of its exceptional toxigenicity when grown on moistened rice, timothy hay, oats, rye, and corn. A hepatotoxic acidic product of undetermined purity was extracted from cultures of this strain grown for 2 to 3 weeks on a medium of cracked, hard corn moistened with 1% sucrose. Extraction was accomplished with anhydrous methanol. Concentration of the active principle, to eliminate nontoxic substances, was accomplished through selective solubility in polar solvents. The final product is a heat-stable, nonvolatile, brown residue, easily ground to a powder at room temperature. Chemically, it is an organic acid, soluble in 5% sodium bicarbonate and several polar solvents. Molisch and Benedict tests are negative. The toxic extract is lethal, in adequate dosage, for dogs, rabbits, guinea pigs, and mice. Most toxicity studies were made on white mice, which reacted consistently and characteristically to intragastric, intraperitoneal, and intravenous injections of toxin in propylene glycol or neutralized toxin in aqueous solution. The LD5 for white mice is 0.2 to 0.4 mg (intravenously), and 0.1 to 0.2 mg (intraperitoneally). Acute reactions in mice, beginning within 1 to 2 hr after toxin administration, consisted of depression and evidence of abdominal distress, followed by incoordination, wobbling gait, and prostration prior to death. Engorgement of the liver, along with hyperemia or intestinal hemorrhage, were prominent gross reactions. In less acute responses, lacrimation and exudation sealed the eyelids together. Animals dying 10 hr or more after injection frequently showed a uniformly pale or mottled liver (sometimes yellow) and occasionally enlarged, pale kidneys. In addition to intestinal hemorrhage or congestion, subcutaneous blood vessels in the axillary and inguinal regions were frequently dilated and congested. The most pronounced lesions were seen microscopically in the liver, where extreme congestion, hemorrhage, and cellular degeneration, with minimal to moderate fatty changes, were observed. Results of preliminary studies, using repeated intravenous injections of toxin in dogs, suggest that this substance may be a causative agent of hepatitis x. Results of detailed pathological reactions in this and other hosts will be reported later. No significant antibiotic action has been evident from cultures or extracts of the P-13 strain. Topical application of the toxin to clipped skin of rabbits failed to induce any inflammatory reaction. Chemical and pathological studies now in progress should be fruitful in revealing more data on the chemical nature of the toxic substance and its mechanism of action in various susceptible animals.