T3D0170

171 T3D0170

p-Cresol

p-Cresol (4-methylphenol), a 108.1 Da volatile low-molecular-weight compound, is a phenol. It is a partially lipophilic moiety which strongly binds to plasma protein (close to 100%) under normal conditions. p-Cresol is metabolized through conjugation, mainly sulphation and glucuronization, but removal of the unconjugated p-cresol is, at least in part, via the urine. Therefore it is not surprising that this compound, together with several other phenoles, is retained when the kidneys fail. P-Cresol is an end-product of protein breakdown, and an increase of the nutritional protein load in healthy individuals results in enhanced generation and urinary excretion. The serum p-cresol concentration in uremic patients can be decreased by changing to a low-protein diet. p-Cresol is one of the metabolites of the amino acid tyrosine, and to a certain extent also of phenylalanine, which are converted to 4-hydroxyphenylacetic acid by intestinal bacteria, before being decarboxylated to p-cresol (putrefaction). The main contributing bacteria are aerobes (mainly enterobacteria), but to a certain extent also anaerobes play a role (mainly Clostridium perfringens). In uremia, modifications in the intestinal flora result in the specific overgrowth of bacteria that are specific p-cresol producers. The administration of antibiotics reduces urinary excretion of p-cresol, as a result of the liquidation of the producing bacteria. Environmental factors might also contribute. The liver cytochrome P450 metabolizes toluene to benzyl alcohol, but also to o-cresol and p-cresol. Toluene is not only used industrially, but it is also the most widely abusively inhaled solvent. Furthermore, p-cresol is a metabolite of menthofuran, one of the metabolites of R-(+)-pulegone, which is found in extracts from the plants Mentha pulegium and Hedeoma pulegioides, commonly known as pennyroyal oil and pennyroyal tea. These extracts are popular as unconventional herbal therapeutic agents and are applied as abortiva, diaphoretics, emmenagogues, and psychedelic drugs. Pennyroyal oil is extensively used for its pleasant mint-like smell in the flavoring industry. The toxicity of pennyroyal oil and menthofuran is well known. Another compound used in traditional medicine, especially in Japan, which is a precursor of p-cresol is wood tar creosote. p-Cresol has been reported to affect several biochemical, biological and physiological functions: (i) it diminishes the oxygen uptake of rat cerebral cortex slices; (ii) it increases the free active drug concentration of warfarin and diazepam; (iii) it has been related to growth retardation in the weanling pig; (iv) it alters cell membrane permeability, at least in bacteria; (v) it induces LDH leakage from rat liver slices; (vi) it induces susceptibility to auditive epileptic crises; and (vii) it blocks cell K+ channels. (A7723). p-Cresol is a uremic toxin that is at least partially removed by peritoneal dialysis in haemodialysis patients, and has been involved in the progression of renal failure. (MID: 11169029). At concentrations encountered during uremia, p-cresol inhibits phagocyte function and decreases leukocyte adhesion to cytokine-stimulated endothelial cells. (A3274). 106-44-5

2879

C7H8O

108.057510 Colorless solids or liquids.

35.5°C

21.5 mg/mL at 25°C

Inhalation (L528) ; dermal (L528) ; oral (L528)

p-Cresol is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.

Cresols can be absorbed following inhalation, oral, and dermal exposure. Once in the body they can distribute rapidly into many organs and tissues. Cresols undergo oxidative metabolism in the liver and are rapidly eliminated, mostly in the urine, as sulfate or glucuronide conjugates. The activation of cresols by oxidation involves tyrosinase and thyroid peroxidase, forming a reactive quinone methide. Experiments with recombinant P-450s demonstrated cresol metabolism was mediated by several P-450s including CYP2D6, 2C19, 1A2, 1A1, and 2E1. (L528, A197, L529, A198) LD50: 207 mg/kg (Oral, Rat) (T13) LD50: 301 mg/kg (Dermal, Rabbit) (T13) LD50: 25 mg/kg (Intraperitoneal, Mouse) (T13) No indication of carcinogenicity to humans (not listed by IARC).

Cresols are used as solvents, disinfectants and deodorizers, as well as to make other chemicals. They may be formed normally in the body from other compounds. Cresols are found in many foods and in wood and tobacco smoke, crude oil, coal tar, and in chemical mixtures used as wood preservatives. Small organisms in soil and water produce cresols when they break down materials in the environment. Breathing air containing cresols is the primary source of exposure. Exposure may also result from drinking contaminated water, eating contaminated food and coming into contact with liquids containing cresols. (L528)

Intermediate Oral: 0.1 mg/kg/day (L134) Chronic Oral: 0.1 mg/kg/day (L134)

Acute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.

Ingestion of p-cresol results in burning of the mouth and throat, abdominal pain, and vomiting. Inhalation or dermal exposure of animals to p-cresol can produce irritation and corrosion at the site of contact. (L482) If the compound has been ingested, rapid gastric lavage should be performed using 5% sodium bicarbonate. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. In serious cases, atropine and/or pralidoxime should be administered. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of '-oximes' has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally.

2009-03-06T18:58:12Z

2014-12-24T20:21:15Z

Cytochrome P450 1A1 (P04798) Cytochrome P450 1A2 (P05177) Cytochrome P450 2C19 (P33261) Cytochrome P450 2D6 (P10635) Cytochrome P450 2E1 (P05181) Tyrosinase (P14679) Thyroid peroxidase (P07202) (L528)

http://en.wikipedia.org/wiki/p-Cresol

C01468

17847

CPD-108

C032538

Cresol, para-

DB01688

PCR

1807

true

CC1=CC=C(O)C=C1

C7H8O

InChI=1S/C7H8O/c1-6-2-4-7(8)5-3-6/h2-5,8H,1H3

InChIKey=IWDCLRJOBJJRNH-UHFFFAOYSA-N

108.1378

108.057514878

Endogenous Solid 1.94

HMDB01858

CHEMBL16645

13839082

Heliodoro Monroy, “Process of recovering BHT values from mother liquors of the crystallization of BHT obtained by alkylating p-cresol with isobutylene.” U.S. Patent US3940451, issued January, 1956.