The ... m-cresols /is/ ... ring-hydroxylated to a small extent ... 2,5-Dihydroxytoluene has been isolated from the urine of rabbits fed ... m-cresols ...
Ten healthy men were exposed to approximately 200 ppm toluene for 4 hr. Urinary m-cresol concentration was 0.570 mg/L at the end of the exposure, 0.599 mg/L 4 hr after exposure, and 0.527 mg/L 20 hr after exposure.
The urinary & biliary excretion of (14)C-labeled m-cresol was investigated in 12 species of freshwater fish when immersed in sublethal concn in the aquarium water for 48 hr. The oxidation product, m-hydroxybenzoic acid & the m-cresol sulfate conjugate were excreted into the aquarium water by all species except the guppy, which did not excrete m-hydroxybenzoic acid. In addition to these two metabolites, the m-cresol glucuronic acid conjugate was found in the bile of all species, except the guppy.
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)
IDENTIFICATION AND USE: m-Cresol is colorless, yellowish liquid. It is used as a bactericide for control of crown gall and olive knot on certain fruit and nut trees and ornamentals and the genetic/physiological disorder burr knot on apples. Currently, one product is registered which contains both m-cresol and xylenol. Used as disinfectant/bacteriocide/germicide for animal pathogenic bacteria (G- and G+ vegetative) in households, sickrooms, hospitals, veterinary clinics, and veterinary hospitals; on surgical instruments, diagnostic instruments/equipment and on hospital critical rubber/plastic items. Used as an insecticide and miticide on dogs for treatment of lice and fleas. It is also used for making synthetic resins; in photographic developers, explosives. Additionally, m-cresol is chemical intermediate for thymol used in cough/cold medicinals, synthetic pyrethroid insecticides, 3-methyl-6-t-butylphenol, trinitro-m-cresol for explosives, and phenolic resins; disinfectant ingredient; ore flotation agent; solvent. m-Cresol, either pure or mixed with p-cresol, is important in the production of contact herbicides. m-Cresol is also a precursor to the pyrethroid insecticides. Furthermore, many flavor and fragrance compounds, such as (-)-methanol and musk ambrette, are derived from m-cresol. Several important antioxidants including synthetic vitamin E are produced from m-cresol. Finally, m-cresol is used as a topical dental antiseptic, and it is also used in insulin preparations. HUMAN EXPOSURE AND TOXICITY: o-Cresol, m-Cresol, and p-Cresol are metabolites of toluene and urinary levels are often used to monitor exposure to and metabolism of toluene. m-Cresol, o-Cresol, and p-Cresol are biomarkers for phenol exposure. The ability of m-Cresol to increase the permeability of human lung fibroblast membranes was reported. m-Cresol is used for endodontic treatments in dentistry and is cytotoxic to human dental pulp cells (D824 cells). ANIMAL STUDIES: In an acute dermal toxicity study, technical grade m-cresol caused severe skin damage on at least 2/6 shaved, female, albino rabbits within 4 hours of application of 2830 mg/kg . m-Cresol, undiluted and in solution, can cause severe local irritation and corrosion following dermal and ocular exposure. Eye irritation can be severe and include corneal opacity. In other experiment, 215-464 mg/kg of m-cresol was given orally to rats in a single dose orally and resulted in hypoactivity, convulsions, GI tract inflammation, hyperemia, and death. 1,400-2,100 mg/kg of m-cresol was given to rabbits in a single dose orally and resulted in convulsions, coma, and death. 280-420 mg/kg of m-cresol was given to rabbits in a single dose iv and resulted in convulsions, coma and death. In a 28-day study, rats and mice of both sexes were given m-cresol at concentrations of from 300 to 30,000 ppm in the diet. All rats survived until study termination; some mice died at the 10,000 and 30,000 ppm dietary levels. Increased liver weights and kidney weights were noted in both species at doses as low as 3000 ppm. Bone marrow hyperplasia and atrophy of the uterus, ovary, and mammary gland were seen occasionally in both the 10,000- and 30,000-ppm groups. Groups of 10 rats of each sex were treated with m-cresol (0, 50, 150 or 450 mg/kg) in corn oil by gavage daily for 13 weeks. Convulsions were seen only in the groups treated with > 450 mg/kg. Hypoactivity, rapid labored respiration and excessive salivation were observed sporadically at doses of > 50 mg/kg. In spite of the observed clinical signs, few significant changes were found in rats performance on neurobehavioral test batteries, no brain weight changes were noted, and no gross or histopathological lesions in the brain or other nervous tissues were found. In developmental studies, m-Cresol caused maternal toxicity in rats and rabbits, but it caused no effects on the developing embryos at any dose. All three isomers of cresol are capable of promoting skin tumors initiated by a single dermal application of 9,10-dimethyl-1,2-benzanthracene (DMBA). m-Cresol did induce unscheduled DNA synthesis with metabolic activation, but not without. The results of SCE production, chromosome aberration, forward mutation, and dominant lethal mutation assays indicated no genotoxicity. m-Cresol was tested for ability to induce chromosomal aberrations in mouse bone marrow in vivo. No effect on chromosomal aberrations was found. ECOTOXICITY STUDIES: The acute toxicity of the three disinfectants to young daphnids and embryos were hypochlorite > formaldehyde > m-cresol. The effects on growth mostly occurred in the late stages of organogenesis. Growth studies have shown that m-cresol is moderately toxic to aquatic bacteria, cyanobacteria (blue-green algae) and protozoa.
m-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.
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌性证据
癌症分类：C组可能的人类致癌物
Cancer Classification: Group C Possible Human Carcinogen
CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Based on an increased incidence of skin papillomas in mice in an initiation-promotion study. The three cresol isomers produced positive results in genetic toxicity studies both alone and in combination. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Limited.
... m-Cresol (in NaHCO2) /was administered/ to rabbits by gavage. Urinary metabolites were evaluated after administration of 500 mg of m-Cresol. Ten percent of the dose was excreted as ethereal sulfate, 60% as ether glucuronide, 1% as the free cresol, about 3% as 2,5-dihydroxytoluene, and a trace amount as 3,4-dihydroxytoluene.
/It has been/ reported that 22% of the sulfate conjugate of m-Cresol (in water) was excreted after 290 mg/kg m-Cresol was administered to rabbits by gavage.
Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
申请人：Vertex Pharmaceuticals Incorporated
公开号：US20150231142A1
公开（公告）日：2015-08-20
The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
A simple and direct method for converting thioamides into thioesters
作者：David C Harrowven、Matthew C Lucas、Peter D Howes
DOI：10.1016/s0040-4020(98)01096-5
日期：1999.1
Thioamides may be transformed into thioesters through the simple expedient of warming them in an aqueous THF solution containing an alkylating agent. Reactions proceed in high yield and are amenable to multi-gram scale.
[EN] CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF<br/>[FR] MODULATEURS DE CALPAÏNE ET LEURS UTILISATIONS THÉRAPEUTIQUES
申请人：BLADE THERAPEUTICS INC
公开号：WO2019190885A1
公开（公告）日：2019-10-03
Small molecule calpain modulator compounds, including their pharmaceutically acceptable salts, can be included in pharmaceutical compositions. The compounds can be useful in inhibiting calpain, or competitive binding with calpastatin, by contacting them with CAPN1, CAPN2, and/or CAPN9 enzymes residing inside a subject. The compounds and composition can also be administered to a subject in order to treat a fibrotic disease or a secondary disease state or condition of a fibrotic disease.
[EN] PREPARATION AND USES OF REACTIVE OXYGEN SPECIES SCAVENGER DERIVATIVES<br/>[FR] PRÉPARATION ET UTILISATIONS DE DÉRIVÉS PIÉGEURS D'ESPÈCES RÉACTIVES DE L'OXYGÈNE
申请人：XW LAB INC
公开号：WO2019033330A1
公开（公告）日：2019-02-21
Compounds of Formula (I) a or (I) b: including certain quinone derivatives, and the corresponding pharmaceutical compositions, which may serve to modulate ferroptosis in a subject. Also disclosed herein are the preparations of these compounds and pharmaceutical compositions and their potential uses in the manufacture of a medicament in reducing reactive oxygen species (ROS) in a cell and for preventing, treating, ameliorating certain related disorder or a disease.
