Cyclopiazonic Acid

/AQUATIC SPECIES/ ...The acute effects of /cyclopiazonic acid (CPA) injected ip into channel catfish (Ictalurus punctatus)/ were characteristic of a neurotoxin. Some fish injected with CPA doses of 2.40 mg/kg bw or higher showed severe convulsions, tetany, and death within 30 min postinjection. There were no lesions in the organs of the moribund fish examined grossly and histologically. Cyclopiazonic acid fed for 10 weeks at a concentration of 100 ug/kg of diet had a growth-suppressing effect (P<0.05) on channel catfish (average weight, 7.5 g), and a concentration of 10,000 ug/kg caused accumulation of proteinaceous granules in renal tubular epithelium and necrosis of gastric glands. Cyclopiazonic acid had no effects on hematocrit, hemoglobin concentration, and erythrocyte and leukocyte counts (P>0.05).

The mycotoxin cyclopiazonic acid (CPA) was detected in the milk from ewes and the eggs from chickens that were given oral doses of the toxin. Three lactating ewes were given CPA for 2 days at a rate of 5 mg/kg of live weight. Thin-layer chromatographic analyses of dried, defatted milk samples showed that CPA was present in milk at an average concentration of 236 ng/g within 24 h of the first dose. The concentration of CPA reached a high of 568 ng/g, but none was detectable by the ninth day after the first dose. ...

...More than one mold can produce the same mycotoxin (e.g., both Aspergillus and Penicillium may produce the mycotoxin cyclopiazonic acid).

Cyclopiazonic acid (CPA) is an indole tetramic acid produced by Aspergillus flavus, A. oryzae, Penicillium cyclopium and P. camemberti.

/LABORATORY ANIMALS: Acute Exposure/ Chickens dosed (per os) with cyclopiazonic acid (CPA) at 0.5, 5.0, and 10 mg/kg body weight showed significant (P less than or equal to 0.05) increases in brain dopamine and serotonin concentrations 96 hr after dosing. The increases coincide with significant decreases in homovanillic acid and subtle increases of dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid concentrations. The elevated dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid concentrations may be related to the elevated concentrations of dopamine and serotonin, respectively. The observed changes in neurotransmitter/metabolite concentrations 96 hr after dosing parallel elimination of CPA from the birds skeletal muscles; however, they do not correlate with the significant weight losses in these birds at 48 and 96 hr after dosing. The brain weights of the treated birds were statistically insignificant from their respective controls, although increases in brain weight-body weight ratio within treatments and with time correlated with CPA toxicity. No significant changes were observed in dopamine, dihydroxyphenylacetic acid, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid concentrations among the treatments at 3, 24, and/or 48 hr after dosing.

/LABORATORY ANIMALS: Acute Exposure/ The oral LD50 value for CPA in nonpregnant mice was 64 +/- 4.4 mg/kg, and the toxicity signs were ptosis, hypokinesia, hypothermia, action tremor, cessation of food and water intake and resulting cachexia. The duration and intensity of these toxic signs were dose dependent.

/LABORATORY ANIMALS: Acute Exposure/ Cyclopiazonic acid (CPA) was found to have many pharmacological properties in common with the antipsychotic drugs chlorpromazine and reserpine. Thus, in mice CPA at ip doses of 5-14 mg/kg body weight produced hypokinesia, hypothermia, catalepsy, ptosis, sedation without loss of righting reflex, tremor, gait disturbance, dyspnoea, opisthotonus, atypical convulsion and prolonged barbiturate-induced sleep. ... The tremors induced by near-lethal doses of CPA were associated with voluntary or forced movements (action tremors); they worsened during the days following treatment, but they were weak compared with the exhausting and continuous tremors of the whole body caused by 20 mg tremorine/kg (used for comparison). When death occurred only 24-259 min after administration of CPA (11-14 mg/kg), it was preceded by dypsnoea, cyanosis, opisthotonus and clonic leg movements and tonic extension of hind legs (convulsions). When death was delayed (2-6 days after CPA administration), it was preceded by prostration, ptosis, hypothermia, tremor and cessation of food and water intake resulting in cachexia; convulsions were not seen in this group of mice. CPA did not affect the rate of convulsion or death caused by either maximal electroshock or metrazol administration but it did delay the onset of metrazol-induced seizures. In rabbits, 10 mg CPA/kg body weight initially produced tachycardia, tachypnoea and sedation with an activated electroencephalogram. Of three rabbits given 10 mg CPA/kg one died, and in this rabbit slow delta waves were seen just before and during a brief period with clonic leg movements. In this animal death was accompanied by tonic extension of the hind legs, respiratory arrest and cardiac fibrillation; and epileptiform EEG was not seen at any time. The unexpected EEG activation with sedation in rabbits treated with CPA was similar to the effect of reserpine on EEG.

/LABORATORY ANIMALS: Acute Exposure/ Groups of Sprague-Dawley rats were dosed per os for 4 consecutive days with 0.0, 0.2, 2.0 or 4.0 mg cyclopiazonic acid (CPA)/kg body weight/day, and killed on the fifth day. Sections of liver were prepared for electron microscopic examination. Dilatation of the rough endoplasmic reticulum was observed in all hepatocytes examined from the 2 highest dose groups, and in about 25% of liver cells from the 0.2 mg CPA/kg/day group. Vesiculation of the rough endoplasmic reticulum also occurred in these groups, an increasing amount of vesiculation being observed with increasing dosage. Control sections exhibited neither of these characteristics. No proliferation of smooth endoplasmic reticulum, or blockage of bile canaliculi was observed in any group. Lysing cells were present only in the 4.0 mg CPA/kg/day group; mitochondria in the 2.0 and 4.0 mg CPA/kg/day dose groups were swollen. Nuclei were ultrastructurally normal in all groups. The primary cellular effect of CPA was on the endoplasmic reticulum, even at relatively low doses.

For more Non-Human Toxicity Excerpts (Complete) data for CYCLOPIAZONIC ACID (26 total), please visit the HSDB record page.

LD50 Rat oral 36 mg/kg

LD50 Rat ip 2 mg/kg

LD50 Mouse oral 64 mg/kg

LD50 Mouse ip 13 mg/kg

Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Drugs used to cause dilation of the blood vessels.

Estimates of these pharmacokinetic parameters were supported by the achievement of steady-state plasma CPA levels within 6 d in pigs consuming a diet containing 10 ppm CPA, and by measured concentrations of CPA in plasma (410+/-44 ng/mL) and skeletal muscle (469+/-86 ng/ g).

The distribution of the mycotoxin, cyclopiazonic acid (CPA), in tissues and its excretion in urine and feces was studied in male Sprague-Dawley rats. Radiolabelled CPA was biosynthetically produced by cultures of Penicillium griseofulvum and was administered to rats either intraperitoneally (ip) or intragastrically (ig). Radiolabelled material was excreted in both urine and feces from rats dosed by either route. There was no excretion of radioactivity as expired 14CO2. Biliary excretion apparently had a major role in the disposition of CPA, since 38% of the dose of radioactivity was excreted in the feces of ip-dosed rats within 72 hr. Skeletal muscle tissue contained 48% of the radioactive dose 6 hr after either ip or ig administration. At 72 hr, skeletal muscle of the ip-dosed rats contained 3% of the dose, whereas rats dosed ig retained 8% of the dose in muscle. Degeneration was observed in muscle from rats treated with 8 mg CPA/kg/day for 4 days. The results indicate that some of the toxic effects observed in animals exposed to CPA (hyperaesthesia, hypokinesis, abnormal posture, opisthotonos and convulsions) may be due in part to direct effects of the toxin on muscle.

The mycotoxin cyclopiazonic acid (CPA) was detected in the milk from ewes and the eggs from chickens that were given oral doses of the toxin. Three lactating ewes were given CPA for 2 days at a rate of 5 mg/kg of live weight. Thin-layer chromatographic analyses of dried, defatted milk samples showed that CPA was present in milk at an average concentration of 236 ng/g within 24 h of the first dose. The concentration of CPA reached a high of 568 ng/g, but none was detectable by the ninth day after the first dose. Laying hens were given oral doses of CPA in two separate studies: an acute study over 9 days with dose groups of 0.0, 2.5, 5.0, and 10.0 mg/kg of live weight and a chronic study over 4 weeks with dose groups of 0.0, 1.25, and 2.5 mg/kg of live weight. Eggs from birds in all dose groups throughout both studies contained CPA. The concentrations of CPA were much higher in egg whites than in egg yolks, averaging approximately 100 and 10 ng/g, respectively,