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Penicillic acid is a novel and potent polyketide mycotoxin with antibiotic and carcinogenic activity was isolated from various Aspergillus and Penicillium species. In vitro tests on rat alveolar macrophages (AM) reveal cytotoxicity. Penicillic acid prevents caspase-8 from processing itself, thereby inhibiting the apoptosis brought on by Fas ligands.
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
IN VIVO AND IN VITRO STUDIES SHOWED SIGNIFICANT UPTAKE OF (14)C-PENICILLIC ACID BY RED BLOOD CELLS AND A SIGNIFICANT INCREASE IN RADIOACTIVITY ASSOCIATED WITH THE MEMBRANE FRACTION WITH TIME (1-4 HOURS). HOWEVER, THE MAJORITY OF THE BLOOD CELL ACTIVITY WAS INTRACELLULAR. THE (14)C-RADIOACTIVITY CONCENTRATION IN LIVER FRACTIONS (1.5% OF THE RNA-DNA AND PROTEIN FRACTIONS. THE LEVEL OF THE (14)C ACTIVITY ASSOCIATED WITH THESE FRACTIONS INCREASED WITH TIME (24 HR). STUDIES OF THE IN VIVO METABOLISM OF [(14)C] PENICILLIC ACID BY RATS SHOWED THAT A SIGNIFICANT AMOUNT OF RADIOACTIVITY WAS EXCRETED IN THE URINE (82% OF THE ADMINISTERED DOSE AFTER 7 DAYS). BILIARY METABOLITES ACCOUNTED FOR 10% OF ADMINISTERED DOSE 2 HOURS AFTER ADMINISTRATION. Metabolism / Metabolites PENICILLIC ACID IS A KNOWN METABOLITE OF STRAINS OF PENICILLIUM ROQUEFORTI ASSOCIATED WITH BLUE-VEINED CHEESES. TEN PERCENT OF PENICILLIC ACID METABOLITES IN MALE MICE WERE DETECTED AS GLUCURONIDE CONJUGATES. ALL METABOLITES IN URINE, PLASMA AND BILE WERE MORE POLAR THAN THE PARENT COMPOUND. THE MAJOR METABOLITES WERE CONJUGATES OR DERIVATIVES OF GLUTATHIONE OR CYSTEINE. IN SUBCELLULAR FRACTIONS OF MOUSE LIVER HOMOGENATES, PENICILLIC ACID REACTS WITH GLUTATHIONE BOTH ENZYMICALLY AND NONENZYMICALLY; EACH REACTION WAS OF EQUAL IMPORTANCE. METABOLISM BY VARIOUS HEPATIC SUBCELLULAR FRACTIONS WAS ESSENTIALLY NONENZYMIC WHEN GLUTATHIONE WAS ABSENT, BUT METABOLISM WAS INCREASED WHEN GLUTATHIONE WAS AVAILABLE. IN THE PRESENCE OF GLUTATHIONE, 75% OF ADDED PENICILLIC ACID WAS BIOTRANSFORMED WITHIN 30 MINUTES TO METABOLITES NOT EXTRACTABLE WITH ORGANIC SOLVENTS AND MORE POLAR THAN PENICILLIC ACID. Penicillic acid is rapidly absorbed and extensively metabolized in the liver. Detoxification occurs via interactions with glutathione S-transferases and metabolites are excreted mainly in the urine. (A3011, A3013) |
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| Toxicity/Toxicokinetics |
Toxicity Summary
Penicillic acid has been shown to inhibit alcohol and lactate dehydrogenases by forming covalent adducts with either cysteine or lysine residues at the enzyme active sites. Penicillic acid also binds directly to the active center cysteine in the large subunit of caspase-8, thus inhibiting FasL-induced apoptosis by targeting self-processing of caspase-8. Penicillic acid is also mutagenic and can cause DNA single-strand breaks, chromosome aberrations, and inhibition of DNA synthesis. Mycotoxins are often able to enter the liver and kidney by human organic anion transporters (hOATs) and human organic cation transporters (hOCTs). They can also inhibit uptake of anions and cations by these transporters, interefering with the secretion of endogenous metabolites, drugs, and xenobiotics including themselves. This results in increased cellular accumulation of toxic compounds causing nephro- and hepatotoxicity. (A2957, A3007, A3008, A3010, A3012, A3014) Toxicity Data LD50: 600 mg/kg (Oral, Mouse) (A3013) LD50: 250 mg/kg (Intravenous, Mouse) (A3013) LD50: 90 mg/kg (Intraperitoneal, Mouse) (A3013) Interactions PENICILLIC ACID AND OCHRATOXIN A ARE SYNERGISTIC TOXIC FUNGAL METABOLITES. THE EFFECT OF PENICILLIC ACID ON THE PANCREATIC ENZYME CARBOXYPEPTIDASE A IN VITRO WAS DECREASED CONVERSION OF PARENT OCHRATOXIN A TO ALPHA-OCHRATOXIN, A NON-TOXIC METABOLITE. IN VIVO, PENICILLIC ACID INHIBITED MOUSE AND CHICKEN PANCREATIC CARBOXYPEPTIDASE A AFTER MULTIPLE ORAL EXPOSURE. THE MODE OF TOXIC INTERACTION OF THE 2 MYCOTOXINS MAY HAVE BEEN DUE TO IMPAIRED DETOXIFICATION OF OCHRATOXIN A THROUGH PENICILLIC ACID DEPLETION OF CARBOXYPEPTIDASE A ACTIVITY. ACUTE CYTOTOXICITY OF PENICILLIC ACID IN MICE WAS INCREASED BY PENTOBARBITAL AND 3-METHYLCHOLANTHRENE PRETREATMENT BUT DECREASED BY SKF-525A. CYSTEINE, WHEN GIVEN 5 MINUTES BEFORE BUT NOT 20 MINUTES AFTER PENICILLIC ACID ADMINISTRATION, PROTECTED THE MICE AGAINST TOXICITY, WHILE DIETHYL MALEATE PRETREATMENT INCREASED PENICILLIC ACID TOXICITY IN THE MOUSE. |
| References | |
| Additional Infomation |
3-Methoxy-5-methyl-4-oxo-2,5-hexadienoic acid has been reported in Exophiala and Aspergillus melleus with data available.
Penicillic acid is a mycotoxin produced by several species of Aspergillus and Penicillium. It has antibiotic activity and is cytotoxic, hepatotoxic, and carcinogenic. Penicillic acid is a human health hazard because it can be found on contaminated crops such as corn. (A2957, A3013) A mycotoxin with antibiotic and carcinogenic activity produced by various strains of PENICILLIUM and ASPERGILLUS. It has been found in tobacco, sausages, and corn. Mechanism of Action HAS CARCINOGENIC ACTIVITY ATTRIBUTABLE TO ALPHA,BETA-UNSATURATION TOGETHER WITH AN EXTERNAL CONJUGATED DOUBLE BOND ATTACHED TO THE 4 POSITION OF THE GAMMA LACTONE RING... The effect of penicillic acid on isolated frog's heart has been studied along with ions of Na(+), K(+), and Ca(2+). Penicillic acid has been found to inhibit the entry of these ions into cardiac tissue thereby arresting the action of the heart. The blockage can be washed away by perfusion with Ringer's solution. |
| Molecular Formula |
C8H10O4
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|---|---|
| Molecular Weight |
170.16300
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| Exact Mass |
170.057
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| Elemental Analysis |
C, 56.47; H, 5.92; O, 37.61
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| CAS # |
90-65-3
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| Related CAS # |
90-65-3
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| PubChem CID |
5385314
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
285.7±35.0 °C at 760 mmHg
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| Melting Point |
83-87ºC
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| Flash Point |
113.5±19.4 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.482
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| LogP |
0.84
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
12
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| Complexity |
250
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C=C(C(C(C)=C)=O)OC)O
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| InChi Key |
VOUGEZYPVGAPBB-XQRVVYSFSA-N
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| InChi Code |
InChI=1S/C8H10O4/c1-5(2)8(11)6(12-3)4-7(9)10/h4H,1H2,2-3H3,(H,9,10)/b6-4-
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| Chemical Name |
(2Z)-3-methoxy-5-methyl-4-oxohexa-2,5-dienoic acid
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| Synonyms |
Penicillic acid
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~587.7 mM)
H2O: ~25 mg/mL (~146.9 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (14.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (14.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (14.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 5.8768 mL | 29.3841 mL | 58.7682 mL | |
| 5 mM | 1.1754 mL | 5.8768 mL | 11.7536 mL | |
| 10 mM | 0.5877 mL | 2.9384 mL | 5.8768 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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