Absorption, Distribution and Excretion
AFTER ADMIN OF SKATOLE TO CATTLE IN A DOSE OF 0.1-0.2 G SKATOLE/KG INTRARUMINALLY OR 0.06 G/KG BY JUGULAR INFUSION, THE MEAN PLASMA CONCN OF SKATOLE BECAME MAXIMAL AT 3 AND 9 HR, RESPECTIVELY.
GOATS WERE GIVEN A 2 HR JUGULAR INFUSION OF 3-METHYLINDOLE (3MI) CONTAINING (14)C-3MI USING PROPYLENE GLYCOL AS THE VEHICLE. 3MI WAS RAPIDLY CLEARED FROM BLOOD PLASMA AND TISSUES AFTER INFUSION, AND 81% OF THE RADIOACTIVITY WAS EXCRETED IN THE URINE BY 24 HR. MAX CONCN OF UNMETABOLIZED 3MI IN THE TISSUES RANGED FROM 2.6 TO 15 UG 3MI/G, INCL 7.5 UG 3MI/G IN THE LUNG. THE LUNG CONTAINED THE HIGHEST PROPORTION OF METABOLITES. THE DATA DEMONSTRATE THAT 3MI DOES NOT SELECTIVELY CONCENTRATE IN THE LUNG AND THAT THE CONCN ARE LOWER THAN THOSE USUALLY ASSOC WITH DIRECT MEMBRANE DAMAGE.

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Metabolism / Metabolites
SKATOLE IS PRODUCED IN THE GI TRACT (SMALL INTESTINE AND RUMEN) BY THE BACTERIAL DEGRADATION OF DIETARY TRYPTOPHAN RESIDUES...
MATURE BEEF COWS GRAZING ON DRY SUMMER RANGE WERE MOVED TO LUSH GREEN PASTURE TO INDUCE ACUTE BOVINE PULMONARY EDEMA AND EMPHYSEMA (ABPE) AND TO DETERMINE WHETHER PLASMA AND RUMINAL FLUID 3-METHYLINDOLE (3MI) CONCN ARE RELATED TO THE DEVELOPMENT OF ABPE. IN VITRO PRODN OF 3MI WAS OBSERVED IN CULTURE MEDIA INOCULATED WITH RUMINAL FLUID, DEMONSTRATING THAT MICROORGANISMS CAPABLE OF PRODUCING 3MI WERE IN THE RUMEN. APPARENTLY RUMINAL MICROORGANISMS OF CATTLE CONVERT TRYPTOPHAN (CONTAINED IN LUSH FORAGE) TO 3MI, WHICH UPON ABSORPTION BY THE ANIMAL MAY RESULT IN THE ONSET OF ABPE.
FORMED FROM INDOLE-3-ACETIC ACID. YIELDS O-FORMAMIDOACETOPHENONE IN RAT, WHEAT; FRYDMAN RB ET AL; FEBS LETTERS 17: 273 (1971). YIELDS 5-HYDROXYSKATOLE, 7-HYDROXYSKATOLE IN RAT; DALGLIESH CE ET AL; BIOCHEM J 70: 13P (1958). YIELDS 6-HYDROXYSKATOLE IN RABBIT; JEPSON JB ET AL; BIOCHIM BIOPHYS ACTA 62: 91 (1962). YIELDS SALICYLIC ACID IN PSEUDOMONAS; PROCTOR MM; NATURE (LONDON) 181: 1345 (1958). /FROM TABLE/
GOATS WERE GIVEN JUGULAR INFUSIONS OF (14)C-3-METHYLINDOLE (3MI). A MAJOR ROUTE OF METABOLISM INVOLVED FORMATION OF 3-METHYLOXINDOLE AND SUGGESTS THAT A MIXED FUNCTION OXIDASE, PYRROLOOXYGENASE, MAY BE THE MAJOR METABOLIC SYSTEM INVOLVED. A MINOR ROUTE OF METABOLISM INVOLVED OXIDATION OF THE METHYL CARBON OF 3MI.
For more Metabolism/Metabolites (Complete) data for 3-METHYLINDOLE (6 total), please visit the HSDB record page.
3-methylindole has known human metabolites that include 3-methylindole-2,3-epoxide and 3-methyleneindolenine.

Skatole regulates intestinal epithelial cellular functions through activating aryl hydrocarbon receptors and p38. Biochem Biophys Res Commun. 2019 Mar 19;510(4):649-655.

Skatole is a methylindole carrying a methyl substituent at position 3. It is produced during the anoxic metabolism of L-tryptophan in the mammalian digestive tract. It has a role as a mammalian metabolite and a human metabolite.
3-Methylindole has been reported in Tachigali glauca, Tecoma stans, and other organisms with data available.
See also: ... View More ...

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Mechanism of Action
NUCLEOPHILIC THIOL AGENTS, GLUTATHIONE, L-CYSTEINE AND N-ACETYL-L-CYSTEINE, PROTECTED MICROSOMAL PROTEINS AGAINST ALKYLATION BY THE REACTIVE METABOLITE OF 3-METHYLINDOLE. THE CYTOSOL FRACTION FROM THE LUNGS OF CATTLE INCR THE PROTECTIVE EFFECT OF THESE THIOL AGENTS. PRETREATMENT OF SHEEP WITH DIETHYLMALEATE, WHICH DEPLETES GLUTATHIONE, INCR THE SEVERITY OF THE PNEUMOTOXIC EFFECT OF 3-METHYLINDOLE, WHEREAS PRETREATMENT WITH L-CYSTEINE DECR THE SEVERITY OF THIS EFFECT. THESE FINDINGS ARE CONSISTENT WITH A HYPOTHESIS THAT AN ELECTROPHILIC REACTIVE METABOLITE OF 3-METHYLINDOLE IS RESPONSIBLE FOR ITS PNEUMOTOXIC EFFECT AND IMPLIES THAT GLUTATHIONE AND GLUTATHIONE S-TRANSFERASES ARE INVOLVED IN THE DETOXIFICATION OF THIS REACTIVE METABOLITE.
INCUBATION OF VARIOUS INDOLIC COMPD WITH GOAT LUNG MICROSOMES SHOWED THAT ONLY 3-METHYLINDOLE WAS ABLE TO GENERATE A FREE RADICAL IN THE NADPH-DEPENDENT MICROSOMAL SYSTEM, AS TESTED BY SPIN-TRAPPING. ENZYMIC RADICAL FORMATION FROM 3-METHYLINDOLE SUGGESTS A MICROSOMAL-ACTIVATED FREE RADICAL MECHANISM FOR THE SPECIFICITY OF 3-METHYLINDOLE-INDUCED PULMONARY TOXICITY.
Bioactivation of 3-methylindole (3MI), a highly selective pneumotoxin in goats, was investigated in human lung and liver tissues in order to provide information about the susceptibility of humans to 3MI toxicity. Human lung microsomes were prepared from eight organ transplantation donors and liver microsomes from one of the donors were /selected/. The 3MI turnover rate with human lung microsomes was 0.23 +/- 0.06 nmol/mg/min, which was lower than the rate with the human liver microsomes (7.40 mnol/mg/min). The activities were NADPH dependent and inhibited by l-aminobenzotriazole, a potent cytochrome p450 suicide substrate inhibitor. Covalent binding of 3MI reactive intermediates to human tissues was determined by incubation of (14)C-3MI and NADPH with human lung and liver microsomal proteins. Although human lung microsomes displayed measurable covalent binding activity (2.74 +/- 2.57 pmol/mg/min), the magnitude of this reaction was only 4% as large as that seen with human liver microsomes and also was inhibited by l-aminobenzotriazole. Therefore, the bioactivation of 3MI to covalently binding intermediates is catalyzed by cytochrome p450 in human pulmonary tissues. These activities were compared to those activities measured with tissues from goats. Proteins from goat and human pulmonary and hepatic microsomal incubations were incubated with radioactive 3MI, and radioactive proteins were analyzed by SDS-PAGE and HPLC and visualized by autoradiography and radiochromatography, respectively. The results showed that a 57-kDa protein was clearly the most prominently alkylated target associated with 3MI reactive intermediates. These data suggest that humans may be susceptible to 3MI mediated toxicities and that the specificity of covalent binding and the extent of binding to target proteins may play important roles in organ and species selective susceptibilities to 3MI pneumotoxicity.

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Therapeutic Uses
EXPTL USE: MEDICATION (VET): INJECTED IM FOR 15 CONSECUTIVE DAYS TO INFECTED GUINEA-PIGS WEIGHING 200-300 G, 5 MG SKATOLE/DAY EXHIBITED TUBERCULOSTATIC ACTIVITY AGAINST MYCOBACTERIUM TUBERCULOSIS HOMINIS.

C9H9N

131.17446

131.073

83-34-1

Skatole-d3;111399-60-1;Skatole-d8;697807-03-7

6736

Off-white to gray solid powder

1.1±0.1 g/cm3

265.1±9.0 °C at 760 mmHg

92-97 °C(lit.)

112.5±11.3 °C

0.0±0.5 mmHg at 25°C

1.655

2.6

1

0

0

10

122

0

ZFRKQXVRDFCRJG-UHFFFAOYSA-N

InChI=1S/C9H9N/c1-7-6-10-9-5-3-2-4-8(7)9/h2-6,10H,1H3

3-methyl-1H-indole

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~762.37 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (19.06 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (19.06 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (19.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)