Bromobenzene causes hepatic and extrahepatic toxicity in rats. Toxicity is related to the presence of covalently bound material in these tissues. A major bromobenzene metabolite, p-bromophenol, has been shown to give rise to covalently bound material in liver, lung and kidney in vivo, but is not toxic. p-Bromophenol is formed from bromobenzene in liver, lung and kidney microsomes and is subsequently metabolized to 4-bromocatechol and covalently bound material. Bromobenzene-3,4-oxide generated in situ by liver microsomes, is detoxified by kidney, liver and lung cytosol. The results suggest that the kidney toxicity caused by bromobenzene is probably not mediated by either bromobenzene-3,4-oxide or the reactive metabolites of p-bromophenol. In contrast, bromobenzene-3, 4-oxide may play a role in the lung toxicity observed after bromobenzene administration. However, the covalently bound material found in extrahepatic tissues may be derived from both bromobenzene-3,4-oxide or the reactive metabolites of p-bromophenol, which may be formed directly by these tissues or transported there from the liver.
4-Bromophenol and 4-bromocatechol are formed as metabolites of bromobenzene in vivo and in isolated rat hepatocytes. Both of these metabolites may potentially contribute to the hepatotoxicity of bromobenzene. Bromobenzene metabolism in hepatocytes isolated from phenobarbital-treated rats forms 0.12 to 0.17 mM 4-bromophenol and 4-bromocatechol in 2 hr, with 1 to 3 mM bromobenzene.
A microsomal metabolite of p-bromophenol was isolated and identified as 6-(glutathion-S-yl)-4-bromocatechol. p-Bromophenol is metabolized in rat liver microsomes in part to 4-bromocatechol. The catechol undergoes autooxidation to the corresponding quinone or semiquinone, which can either covalently bind to microsomal protein or, in the presence of glutathione, form a glutathione conjugate. Superoxide dismutase inhibited these reactions by preventing the superoxide anion-mediated oxidation of 4-bromocatechol. Thus, in the presence of glutathione, superoxide dismutase caused a decrease in conjugate formation with a corresponding increase in 4-bromocatechol levels. Conditions which increased the in vitro covalent binding of p-bromophenol (namely, phenobarbital treatment and the absence of glutathione) did not cause toxicity in vivo. Thus, chemically reactive metabolite(s) of p-bromophenol do not play a role in bromobenzene-mediated hepatotoxicity.
来源:Hazardous Substances Data Bank (HSDB)
代谢
溴苯代谢在诱导了苯巴比妥的大鼠的孤立肝细胞和肝脏微粒体中以及在活体诱导了苯巴比妥的大鼠中进行了研究。在用溴苯孵育孤立的大鼠肝细胞时，产生的代谢物轮廓随着肝细胞浓度的不同而有所差异。在肝细胞浓度较低（0.5 x 10+6细胞/mL）时，4-溴苯酚是主要的代谢物，而在较高的肝细胞浓度（2.0和5.0 x 10+6细胞/mL）时，溴苯-3,4-二氢二醇是主要的代谢物。在大鼠肝脏微粒体的孵育中，4-溴苯酚是主要的代谢物。在活体中，3-和4-溴苯酚更为主要，形成的二氢二醇非常少。4-溴儿茶酚，作为一种潜在的溴苯有毒代谢物，在活体以及孤立肝细胞和微粒体中都有形成。然而，儿茶酚形成的机制不同，这是通过溴苯对位上氘标记的保留来确定的。在微粒体中，4-溴苯酚是4-溴儿茶酚的主要前体代谢物。在孤立肝细胞中，尽管4-溴苯酚作为溴儿茶酚前体的相对贡献随着肝细胞浓度的不同而有所差异，但在所有浓度下，溴苯-3,4-二氢二醇都是主要的前体。在活体中，与孤立肝细胞一样，4-溴儿茶酚主要是通过溴苯-3,4-二氢二醇形成的。
The metabolism of bromobenzene has been examined in isolated hepatocytes and liver microsomes from phenobarbital-induced rats and in phenobarbital-induced rats in vivo. The metabolite profile produced upon incubation of isolated rat hepatocytes with bromobenzene differed with the hepatocyte concentration. At a low hepatocyte concentration (0.5 x 10+6 cells/mL), 4-bromophenol was the major metabolite, while at higher hepatocyte concentrations (2.0 and 5.0 x 10+6 cells/mL) bromobenzene-3,4-dihydrodiol was the major metabolite. 4-Bromophenol was the primary metabolite in incubations with rat liver microsomes. In vivo, 3- and 4-bromophenol were more predominant, with very little dihydrodiol formed. 4-Bromocatechol, a potentially toxic metabolite of bromobenzene, was formed in vivo as well as in isolated hepatocytes and microsomes. However, the mechanism of catechol formation differed, as determined by the retention of a deuterium label at the para position of bromobenzene. In microsomes, 4-bromophenol was the predominant precursor metabolite of 4-bromocatechol. In isolated hepatocytes, although the relative contribution of 4-bromophenol as the bromocatechol precursor differed with hepatocyte concentration, bromobenzene-3,4-dihydrodiol was the predominant precursor at all concentrations. In vivo, as in isolated hepatocytes, 4-bromocatechol was formed primarily via bromobenzene-3,4-dihydrodiol.
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。 /Poisons A and B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
/ENDOCRINE MODULATION/ ... The estrogen-like activity of phenol, 4-bromophenol (4-BP), 2,4-dibromophenol (2,4-DBP), 2,4,6-tribromophenol (2,4,6-TBP) and 4-tert-butylphenol (tert-BP) /was characterized/ using the estrogen-dependent human breast cancer cell line MCF-7. 4-BP, 2,4-DBP and 4-tert-BP all bind to the estrogen receptor (ER) with approximately 10,000-fold less affinity than 17 beta-estradiol (17 beta-E). 2,4,6-TBP was only able to displace 43% of radiolabelled estrogen when tested at concentrations up to 1 uM, whereas phenol had no affinity for the ER. 4-tert-BP stimulated cell growth and induced estrogen-regulated proteins such as the progesterone receptor (PgR) and pS2. The brominated phenols, however, although binding to the ER, did not stimulate cell growth or increase the levels of the PgR or pS2, or reduce the level of 17 beta-E induced pS2. On the contrary, 4-BP, 2,4-DBP and partly 4-tert-BP reduced 17 beta-E-stimulated cell growth apparently by an ER independent mechanism.
/ALTERNATIVE and IN VITRO TESTS/ /The/ study assessed the potential effects of nineteen polybrominated diphenyl ethers (BDEs), five hydroxylated BDEs (OH-BDEs), one methoxylated BDE (CH(3)O-BDE), tetrabromobisphenol-A (TBBPA), its dibromopropane ether derivative (TBBPA-DBPE), and the brominated phenols/anisols 2,4,6-tribromophenol (TBP), 4-bromophenol (4BP) and 2,4,6-tribromoanisole (TBA) on the catalytic activity of the steroidogenic enzyme aromatase (CYP19) in H295R human adrenocortical carcinoma cells. Effects were studied in the concentration range from 0.5 to 7.5 uM; exposures were for 24 hr. Both 6-OH-BDE47 and 6-OH-BDE99 showed an inhibitory effect on aromatase activity at concentrations >2.5 uM and >5 uM, respectively. However, 6-OH-BDE47 also caused a statistically significant increase in cytotoxicity (based on mitochondrial MTT reduction and lactate dehydrogenase-leakage [LDH]) at concentrations >2.5 uM that could explain in part the apparent inhibitory effect on aromatase activity. Compared to 6-OH-BDE47, the methoxy analog (6-CH(3)O-BDE47) did not elicit a cytotoxic effect, whereas significant inhibition of aromatase remained. TBP caused a concentration-dependent induction of aromatase activity between 0.5 and 7.5 uM (with a maximum of 3.8-fold induction at 7.5 uM). This induction was not observed when a OH- group replaced the CH(3)O- group or when bromine atoms adjacent to this OH- group were absent...
A series of new hypervalentiodinereagents based on the 1,3‐dihydro‐3,3‐dimethyl‐1,2‐benziodoxole and 1,2‐benziodoxol‐3‐(1H)‐one scaffolds, which contain a functionalized tetrafluoroethyl group, have been prepared, characterized, and used in synthetic applications. Their corresponding electrophilic fluoroalkylation reactions with various sulfur, oxygen, phosphorus, and carbon‐centered nucleophiles
[EN] HYPERVALENT IODINE CF2CF2X REAGENTS AND THEIR USE<br/>[FR] RÉACTIFS CF2CF2X À BASE D'IODE HYPERVALENT ET LEUR UTILISATION
申请人：ETH ZUERICH
公开号：WO2016019475A1
公开（公告）日：2016-02-11
A hypervalent iodine of formula (I) or formula (II) wherein R is a nucleophile and a method for their production is described. Such compounds can be used for fluoroethylation of compounds carrying a reactive group. A preferred compound carrying a reactive group is cystein in any environment such as peptide targets.
Certain carbocyclic aryl- and heterocyclic aryl-substituted cyclopropyl N-hydroxyureas, N-hydoroxycarboxamides, and N-acyl-N-hydroxyamides inhibit 5- and/or 12-lipoxygenase and are useful in the treatment of inflammatory disease states.
The present invention relates to compounds and methods which may be useful as inhibitors of Rho kinase for the treatment or prevention of disease.
本发明涉及化合物和方法，这些化合物和方法可能作为Rho激酶的抑制剂在治疗或预防疾病方面有用。
NEW STRIGOLACTONE ANALOGUES AND THE USE THEREOF FOR THE TREATMENT OF PLANTS
申请人：INSTITUT NATIONAL DE LA RECHERCHE AGRONOMIQUE
公开号：US20150141255A1
公开（公告）日：2015-05-21
A compound of general formula (I):
in which X represents O, S, NH or an N-alkyl radical, R
1
and R
2
, identical or different, each represent H or a C
1
-C
10
hydrocarbon radical, R
1
and R
2
not both representing H, R
3
represents a C
1
-C
10
hydrocarbon radical, and R represents a phenyl radical monosubstituted or disubstituted by a substituent Y and, if applicable, a substituent Z, chosen from Cl, Br, I and CF
3
, or R represents a C═R
4
(R
5
) radical in which R
4
represents an hydrocarbon radical and R
5
represents a linear or branched, saturated or unsaturated, hydrocarbon radical, optionally substituted, a COR
6
group or a CO
2
R
6
group, where R
6
represents a hydrogen atom or a linear or branched, saturated or unsaturated, hydrocarbon radical. This compound can be used for the treatment of higher plants for controlling their growth and architecture.
