Rubratoxin A

Rubratoxin A is a potent inhibitor of protein phosphatase 2A, exerting antitumor and antimetastatic effects. Inhibition may cause the phosphorylation of CREB and subsequent activation of natural killer cells via the stimulation of interleukin-2 release from T cells, contributing to antimetastatic effects. Focal adhesion kinase phosphorylation and paxillin phosphorylation that interfere with cell adhesion could be another antimetastatic effect. Rubratoxin A has also been shown to inhibit Na+/K+-transporting ATPases. (A2987, A2988)

RUBRATOXINS A & B ARE HEPATOTOXIC METABOLITES PRODUCED BY THE MOLDS PENICILLIUM RUBRUM & P PURPUROGENUM. THESE MOLDS OFTEN GROW IN FEEDSTUFFS ALONG WITH ASPERGILLUS SP; RUBRATOXINS & AFLATOXINS MAY COEXIST IN THE GRAIN OR FEED PRODUCT. THIS MEANS THAT AFLATOXICOSIS MAY BE COMPLICATED BY RUBRATOXINS & THAT THE CONDITIONS FAVORING AFLATOXIN PRODUCTION IN STORED FEEDS CAN ALSO FAVOR RUBRATOXIN.

/LABORATORY ANIMALS: Acute Exposure/ CLINICAL SIGNS INCL ANOREXIA, DEHYDRATION, DEPRESSION, DIARRHEA, JAUNDICE, & WT LOSS. SWINE MAY MANIFEST HEAD PRESSING, COLIC, & VENTRAL ERYTHEMA. HORSES MAY BECOME INCOORDINATED. DEATH OCCURS IN AS FEW AS 12 HR. IN MICE THERE ARE FETAL DEATHS OR STUNTED OR DEFORMED FETUSES. GENERAL IMPRESSION IS OF A SEVERE HEMORRHAGIC NECROTIZING HEPATITIS WITH HEMORRHAGES IN VARIOUS ORGANS. THE SPLEEN ALSO MAY BE NECROTIC. ... IN CATS THERE IS EDEMA OF THE WALL OF THE GALLBLADDER & MASSIVE ASCITES. IN HORSES THERE MAY BE BRAIN HEMORRHAGES. /RUBRATOXINS/

/LABORATORY ANIMALS: Acute Exposure/ RUBRATOXICOSIS IS NOT PRESENTLY A SEPARATE ENTITY IN VETERINARY TOXICOLOGY BECAUSE THERE ARE NO DOCUMENTED CASES OF AN UNCOMPLICATED FORM. OTHER MOLD TOXINS, PARTICULARLY AFLATOXINS, HAVE ALWAYS BEEN PRESENT IN CASES WHERE RUBRATOXINS WERE PRESENT IN MOLDY FEED. /RUBRATOXINS/

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ IT IS IMPORTANT TO NOTE THAT RUBRATOXINS ARE MUCH LESS TOXIC THAN AFLATOXINS ON AN EQUAL WT BASIS. RUBRATOXINS ARE TERATOGENIC, EMBRYOCIDAL, & GROWTH SUPPRESSANT IN MICE, BUT THEY ARE NOT CARCINOGENIC. CHRONIC INGESTION OF SMALL AMT OF RUBRATOXIN MAY BE WITHOUT EFFECT. ON THE OTHER HAND, RATS MAY INGEST SMALL CONCN OF TOXIN FOR MANY WK & THEN SUDDENLY BECOME ILL & DIE IN 3 DAYS. THUS THERE SEEMS TO BE A THRESHOLD OF TOLERANCE FOR RUBRATOXINS. /RUBRATOXINS/

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ RUBRATOXIN (0.8 TO 1.0 MG/KG) WAS ADMIN TO PREGNANT RATS ON GESTATIONAL DAYS 7 THROUGH 15. FETAL DEATH & MALFORMATIONS WERE INDUCED WITH GREATEST FREQUENCY FOLLOWING TREATMENT ON GESTATIONAL DAYS 9 THROUGH 11. /RUBRATOXINS/

/SRP:/ Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison 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 respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

A STERILE GLUCOSE-MINERAL SALTS BROTH WAS INOCULATED WITH SPORE SUSPENSIONS OR MYCELIAL PELLETS OF PENICILLIUM RUBRUM AND INCUBATED QUIESCENTLY FOR 14 DAYS. RUBRATOXINS WERE RECOVERED FROM CULTURE FILTRATES BY ETHER EXTRACTION AND RESOLVED BY TLC. TOXIN FORMATION WAS ENHANCED BY MALONATE BUT WAS NOT MARKEDLY AFFECTED BY ETHYL MALONATE, SHIKIMATE, AND ACETATE OR BY ISOCITRATE OR OXALOACETATE ADDED IN THE PRESENCE OF MALONATE. CITRATE, CIS-ACONITATE, ALPHA-KETOGLUTARATE, SUCCINATE, FUMARATE AND MALONATE WHEN PRESENT IN THE MEDIUM ALONE OR IN CONJUNCTION WITH MALONATE CAUSED A 15-50% REDUCTION IN RUBRATOXIN FORMATION. ACETYL-COA (10-15 MOL/FLAS) CAUSED AN 80% INCREASE IN TOXIN YIELD. AT 10-3 MOLAR, CITRATE STIMULATED RUBRATOXIN A PRODUCTION BY AS MUCH AS 100%. ABOVE 10-3 MOLAR, CITRATE INHIBITED TOXIN PRODUCTION. INCORPORATION OF (2-14)C-ACETATE INTO RUBRATOXIN WAS ENHANCED BY MALONATE AND FUMARATE + MALONATE. PYRUVATE + MALONATE PRODUCED A 40% INCREASE IN (2-14)C-ACETATE INCORPORATION INTO RUBRATOXIN. THE HIGHEST REDUCTION OF LABELED ACETATE INCORPORATION (36%) WAS CAUSED BY SUCCINATE OR ALPHA-KETOGLUTARATE COMBINED WITH MALONATE.