... A larger percentage (71-73%) of MX-derived radioactivity was excreted in urine after an iv dose (0.2 mg/kg) in both female rats and male mice. Most MX-derived radioactivity was excreted within the first 24 hr postdosing. MX was transformed to urinary and biliary metabolites. A major extremely polar urinary metabolite was tentatively identified as 1-hydroxy-1,2,2-ethanetricarboxylic acid. This metabolite is likely transformed from the MX degradation product 2-hydroxy-3-formyl-4-oxo-2-butenoic acid.
... MX is extensively detoxified in vivo and is unlikely to cause genetic damage in systemic tissues except at relatively high doses where detoxification pathways become saturated...
There is inadequate evidence in humans for the carcinogenicity of MX. There is limited evidence in experimental animals for the carcinogenicity of MX. MX is a potent, direct-acting mutagen that induces primarily GC to TA transversions in both bacterial and mammalian cells. It induces DNA damage in bacterial and mammalian cells as well as in rodents in vivo. MX is a chromosomal mutagen in mammalian cells and in rats, and it induces mammalian cell transformation in vitro. The MX-associated thyroid gland tumors in rats are caused by mechanisms other than TSH-mediated hormonal promotion. Overall evaluation 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is possibly carcinogenic to humans (Group 2B).
Groups of male BALB/cABOM mice (initial numbers unspecified), 4 weeks of age, were administered an intraperitoneal injection of 7 mg/kg bw azoxymethane or 0.9% sodium chloride (vehicle control) once a week for 2 weeks. One week later, animals were administered 0 or 20 mg/kg bw MX (94% pure dissolved in sterile water at pH 3.4-4.0) intrarectally three times weekly for 6 weeks to give a total MX dose of 360 mg/kg or 40 mg/kg bw MX three times weekly over 4 weeks, giving a total MX dose of 480 mg/kg. All mice were killed 15 weeks after the start of the experiment, 6 or 8 weeks after the last dose. The small intestine, colon and cecum were removed. The colon and cecum were scored for altered crypt foci and small intestine, colon and cecum were scored for tumors ... . Neither dose of MX increased the incidence of aberrant crypt foci per colon when compared with sodium chloride or azoxymethane. ... Most mice in every treatment group, including the vehicle control, had small tumors (0.3-0.6 mm, 1-16 per small intestine). One mouse receiving azoxymethane and 40 mg/kg bw MX had a colon tumor ... . (The IARC Working Group noted the inadequacy of the strain and dose of azoxymethane.)
... Radioactivity was rapidly absorbed and excreted near equally in urine (42-54%) and feces (40-51%) 72 hr following oral administration of (14)C-labeled MX at single doses from 0.2 to 20 mg/kg to male and female mice and female rats. A larger percentage (71-73%) of MX-derived radioactivity was excreted in urine after an iv dose (0.2 mg/kg) in both female rats and male mice. Most MX-derived radioactivity was excreted within the first 24 hr postdosing. ... Oral administration produced highest tissue/blood ratios in the following order: forestomach (>100), glandular stomach, intestine, and kidney. Intravenous administration resulted in high, prolonged levels of radioactivity in blood compared to oral dosing. Therefore, MX disposition appears to be dominated by its chemical reactivity with highest concentrations of radioactivity being found at the site of administration.
The pharmacokinetics of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was evaluated after a single oral or intravenous administration in the rats using 14C-labelled compound. Twenty to 35% of the dose was absorbed into circulation from the gastrointestinal tract as assessed from the excretion in urine. The mean elimination half-life of the radioactivity in blood (T1/2 k10) was 3.8 hr. Traces of radioactivity remained in the blood for several days. The tissues lining the gastrointestinal and urinary tract, kidneys, stomach, small intestines and urinary bladder contained the highest radioactivity. The activity declined slowest in the kidneys. Urine was the main excretion route. Seventy-seven % of the total amount excreted appeared in urine in 12 hr and 90% in 24 hr. No radioactivity was exhaled in air suggesting that elimination through respiration did not occur. After an intravenous administration of 14C-MX, the T1/2 k10, was much longer, 22.9 hr, and the total elimination half-life (T1/2 beta), 42.1 hr. The results indicate that MX is absorbed from the gastrointestinal tract to a considerable degree and it is excreted in urine very rapidly. A fraction of MX or its metabolites is retained in blood for a longer period of time. The pharmacokinetics of MX does not suggest extensive cumulation of MX in tissues after continuous exposure.
In another experiment, a dose of 2 mg/kg (14C)MX was administered to Wistar rats and radioactivity was determined in tissues after 2 and 6 hr. After 2 hr, the highest amount of radioactivity was detected in kidneys, followed by the stomach, ileum, urinary bladder and liver. At 6 hr, the concentration of radioactivity was markedly decreased in kidneys and urinary bladder and to a lesser extent in the gastrointestinal tract.
... Excretion in urine of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) ... was evaluated in male Wistar rats ... dosed by gavage in deionized water at doses between 200 mg/kg and 600 mg/kg, for one animal at a time ... Urine was collected in metabolism cages up to 72 hr after dosing for chemical analysis of MX in urine. ... Only 0.03-0.07% of the dose (200 mg/kg or 300 mg/kg) was excreted in urine as intact MX...
Identification of an Ethenoformyl Adduct Formed in the Reaction of the Potent Bacterial Mutagen 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5<i>H</i>)-furanone with Guanosine
作者：Tony Munter、Frank Le Curieux、Rainer Sjöholm、Leif Kronberg
DOI：10.1021/tx9801514
日期：1999.1.1
water. In this study, we have reacted MX with guanosine, cytidine, thymidine, and calf thymus DNA in aqueous solutions. HPLC analyses of the reaction mixture of MX with guanosine showed that one main product peak was formed. In the reactions of MX with cytidine or thymidine, no product peaks representing base-modified nucleosides could be observed. The product from the MX guanosinereaction mixture was
5-dimethoxybenzaldehyde) was chlorinated in the laboratory at different reaction time, temperature, pH and chlorine dose, and MX was determined and quantified by GC/MS. The finding suggests that the optimal chlorination conditions are as follows: temperature=298 K, pH=5, Cl:syrin. (mol:mol)=9:1. We also found that the formation of MX increased with the syringaldehyde concentration in a linear relationship
Reaction of the Potent Bacterial Mutagen 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5<i>H</i>)-furanone (MX) with 2‘-Deoxyadenosine and Calf Thymus DNA: Identification of Fluorescent Propenoformyl Derivatives
作者：Tony Munter、Frank Le Curieux、Rainer Sjöholm、Leif Kronberg
DOI：10.1021/tx970195x
日期：1998.3.1
water disinfection byproduct 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was reacted with 2'-deoxyadenosine and calfthymusDNA in aqueous solutions at neutral conditions. HPLC analyses of the 2'-deoxyadenosinereaction mixtures showed that two previously unidentified products were formed. The products were isolated by preparative C18 chromatography, and their structures were characterized
在中性条件下，将有效的细菌诱变剂和饮用水消毒副产物3-chloro-4-（dichloromethyl）-5-hydroxy-2（5H）-呋喃酮（MX）与2'-脱氧腺苷和小牛胸腺DNA反应。2'-脱氧腺苷反应混合物的HPLC分析表明，形成了两个先前未鉴定的产物。通过制备型C18色谱法分离产物，并通过UV吸收，荧光发射，1 H和13 C NMR光谱以及质谱对它们的结构进行表征。可以得出结论，在两种产品中，腺嘌呤单元的N-1和N6之间都形成了一个丙炔桥。在其中一种产品中，丙炔桥带有甲酰基[3-（2'-脱氧-β-D-呋喃呋喃糖基）-7H-8-甲酰基[2,1-i]嘧啶嘌呤++ +（pfA-dR）]，另一个取代基由甲酰基和氯原子[3-（2'-脱氧-β-D-呋喃呋喃糖基）-7H-8-甲酰基-9-氯[2,1-i]嘧啶嘌呤（ Cl-pfA-dR）]。这些新型加合物在可见光区域显示荧光，最大发射波长在460
Anti-inflammatory botanical products for the treatment of metabolic syndrome and diabetes
申请人：Metaproteomics, LLC
公开号：EP2737897A2
公开（公告）日：2014-06-04
The present invention relates to compositions consisting essentially of a therapeutically effective amount of a compound selected from the group consisting of tetrahydro-isohumulone, tetrahydro-isocohumulone, and tetrahydro-isoadhumulone; and metformin, to be used in the treatment of an insulin related disorder, diabetes, obesity, or a cardiovascular disease.
Negative selection and stringency modulation in continuous evolution systems
申请人：President and Fellows of Harvard College
公开号：US10179911B2
公开（公告）日：2019-01-15
Strategies, systems, methods, reagents, and kits for phage-assisted continuous evolution are provided herein. These include strategies, systems, methods, reagents, and kits allowing for stringency modulation to evolve weakly active or inactive biomolecule variants, negative selection of undesired properties, and/or positive selection of desired properties.
