Alkyl-substituted polycyclic aromatic hydrocarbons may be metabolized to highly reactive benzylic sulfuric acid esters via benzylic hydroxylation and subsequent sulfonation. We have studied the benzylic hydroxylation of 1-methylpyrene (MP), a hepatocarcinogen in rodents, and 1-ethylpyrene (EP), whose benzylic hydroxylation would produce a secondary alcohol (alpha-HEP), in contrast to the primary alcohol (alpha-HMP) formed from MP. The hydrocarbons were incubated with hepatic microsomal preparations from humans and rats, as well as with V79-derived cell lines engineered for the expression of individual cytochrome P450 (CYP) forms from human (1A1, 1A2, 1B1, 2A6, 2E1, 3A4) and rat (1A1, 1A2, 2B1). All microsomal systems and CYP-expressing cell lines used, but not CYP-deficient V79 cells, showed biotransformation of both hydrocarbons. Formation of the benzylic alcohol was detected in each case. alpha-HMP and its oxidation product, 1-pyrenylcarboxylic acid (COOH-P), accounted for a major part of the total amount of the metabolites formed from MP in the presence of human liver microsomes (38-64%) and cells expressing human 3A4, 2E1 or 1B1 (80-85%). Likewise, cells expressing human 1A1 showed a higher contribution of alpha-HMP and COOH-P to the total metabolites (45%) than cells expressing the orthologous enzyme of the rat (3%). EP was metabolized at a higher rate and with modified regioselectivity compared with MP, although omega-hydroxylation of the side chain was not detected with the cell lines and only accounted for a small percent of the biotransformation by the microsomal preparations. The highest contributions of alpha-HEP to the total metabolites from EP were detected with the cells expressing human 1A1, 1B1 and 3A4 (38-51%). alpha-HEP accounted for 16% of the metabolites formed in the presence of human hepatic microsomes. Thus, benzylic hydroxylation is a major initial step in the metabolism of MP and EP. This pathway appears to be even more important in humans than in rats. Previously, we had shown that the second step of the activation, the sulfonation of alpha-HMP and alpha-HEP, is also efficiently catalysed by various forms of human sulfotransferases.
1-Methylpyrene, an alkylated polycyclic aromatic hydrocarbon and environmental carcinogen, is activated by side-chain hydroxylation to 1-hydroxymethylpyrene (1-HMP) and subsequent sulfo conjugation to the DNA-reactive 1-sulfooxymethylpyrene. In addition to the bioactivation, processes of metabolic detoxification and transport greatly influence the genotoxicity of 1-methylpyrene. For a better understanding of 1-HMP detoxification in vivo we studied urinary and fecal metabolites in rats following intraperitoneal doses of 19.3 mg 1-HMP/kg body weight (5 rats) or the same dose containing 200?Ci [(14)C]1-HMP/kg body weight (2 rats). After 48h, 48.0% (rat 1) and 29.1% (rat 2) of the radioactivity was recovered as 1-HMP in the feces. Six major metabolites were observed by UV and on-line radioactivity detection in urine samples and feces after HPLC separation. The compounds were characterized by mass spectrometry, (1)H NMR and (1)H-(1)H COSY NMR spectroscopy, which allowed assigning tentative molecular structures. Two prominent metabolites, 1-pyrene carboxylic acid (M-6) and the acyl glucuronide of 1-pyrene carboxylic acid (M-5) accounted for 17.7% (rat 1) and 25.2% (rat 2) of the overall radioactive dose. Further, we detected the acyl glucuronide of 6-hydroxy-1-pyrene carboxylic acid (M-1) and 8-sulfooxy-1-pyrene carboxylic acid (M-3) together with two regioisomers of M-3 (M-2 and M-4) differing in position of the sulfate group at the pyrene ring. In urine samples, the radioactivity of 1-pyrene carboxylic acid and its five derivatives amounted to 32.4% (rat 1) or 45.5% (rat 2) of the total [(14)C]1-HMP dose.
Transformation of nonsubstituted and alkyl-substituted polycyclic aromatic hydrocarbons (PAHs) by the benthic invertebrate Nereis diversicolor was compared in this study. Pyrene and 1-methylpyrene were used as model compounds for nonsubstituted and alkyl-substituted PAHs, respectively. Qualitative and quantitative analyses of metabolites and parent compounds in worm tissue, water, and sediment were performed. Transformation of 1-methylpyrene generated the benzylic hydroxylated phase I product, 1-pyrenecarboxylic acid that comprised 90% of the total metabolites of 1-methylpyrene, and was mainly found in water extracts. We tentatively identified 1-methylpyrene glucuronides and 1-carbonylpyrene glycine as phase II metabolites not previously reported in literature. Pyrene was biotransformed to 1-hydroxypyrene, pyrene-1-sulfate, pyrene-1-glucuronide, and pyrene glucoside sulfate, with pyrene-1-glucuronide as the most prominent metabolite. Transformation of 1-methylpyrene (21% transformed) was more than 3 times as efficient as pyrene transformation (5.6% transformed). Because crude oils contain larger amounts of C?-C?-substituted PAHs than nonsubstituted PAHs, the rapid and efficient transformation of sediment-associated 1-methylpyrene may result in a high exposure of water-living organisms to metabolites of alkyl-substituted PAHs, whose toxicities are unknown. ...
The common polycyclic aromatic hydrocarbon 1-methylpyrene is hepatocarcinogenic in the newborn mouse assay. In vitro studies showed that it is metabolically activated via benzylic hydroxylation and sulphation to a reactive ester, which forms benzylic DNA adducts, N(2)-(1-methylpyrenyl)-2'-deoxyguanosine (MPdG) and N(6)-(1-methylpyrenyl)-2'-deoxyadenosine (MPdA). Formation of these adducts was also observed in animals treated with the metabolites, 1-hydroxymethylpyrene and 1-sulphooxymethylpyrene (1-SMP), whereas corresponding data are missing for 1-methylpyrene. In the present study, we treated mice with 1-methylpyrene and subsequently analyzed blood serum for the presence of the reactive metabolite 1-SMP and tissue DNA for the presence of MPdG and MPdA adducts. We used wild-type mice and a mouse line transgenic for human sulphotransferases (SULT) 1A1 and 1A2, males and females. All analyses were conducted using ultra-performance liquid chromatography coupled with tandem mass spectrometry, for the adducts with isotope-labelled internal standards. 1-SMP was detected in all treated animals. Its serum level was higher in transgenic mice than in the wild-type (p < 0.001). Likewise, both adducts were detected in liver, kidney and lung DNA of all exposed animals. The transgene significantly enhanced the level of each adduct in each tissue of both sexes (p < 0.01-0.001). Adduct levels were highest in the liver, the target tissue of carcinogenesis, in each animal model used. MPdG and MPdA adducts were also observed in rats treated with 1-methylpyrene. Our findings corroborate the hypothesis that 1-SMP is indeed the ultimate carcinogen of 1-methylpyrene and that human SULT are able to mediate the terminal activation in vivo.
IDENTIFICATION AND USE: 1-Methylpyrene (1-MP) is a polynuclear aromatic hydrocarbon. HUMAN EXPOSURE AND TOXICITY: A Chinese hamster V79-derived cell line expressing both human CYP2E1 and human SULT1A1 was used to investigate the ability of 1-MP to induce cytotoxicity, micronuclei and Hprt gene mutations. 1-MP induced micronuclei in V79-hCYP2E1-hSULT1A1 cells in a concentration-dependent manner; however, it was inactive in V79 cells. It caused an increase in Hprt mutant frequency in V79-hCYP2E1-hSULT1A1 cells, bur not in V79 cells. The results suggest that human CYP2E1 and SULT1A1 cooperate to activate 1-MP and cause genotoxicity in mammalian cells. 1-methylpyrene or perylene, individually or when combined, significantly upregulated IL-1alpha and IL-6 secretion from human skin keratinocytes. 1-methylpyrene also exerted a cytotoxic effect on human keratinocytes. ANIMAL STUDIES: 1-MP was inactive in Chinese hamster V79-derived cell line without metabolic activation. Modification of adenine residues by 1-MP caused termination of DNA replication by E. coli DNA polymerase I (Klenow fragment) in vitro at the position opposite the MP adduct and at the preceding base.
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 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. /Aromatic hydrocarbons and related compounds/
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 necessary. 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 L of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aromatic hydrocarbons and related compounds/
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 if necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) 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 (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aromatics hydrocarbons and related compounds/
/GENOTOXICITY-DNA ADDUCTS/ The procarcinogen 1-methylpyrene is activated by hepatic enzymes via 1-hydroxymethylpyrene to 1-sulfooxymethylpyrene (1-SMP), a highly reactive and mutagenic metabolite. Previously, high levels of 1-SMP DNA adducts were observed in rat kidneys after intraperitoneal administration of 1-hydroxymethylpyrene or 1-SMP. This study examined whether organic anion transporters (OAT) that are expressed at the basolateral membrane of proximal tubule cells are involved in uptake of SMP. Human epithelial kidney (HEK293) cells that stably express human OAT1 (hOAT1) and hOAT3 were used. Stable isomers of 1-SMP, (2-SMP and 4-SMP) competitively inhibited the uptake of characteristic substrates p-aminohippurate for hOAT1 and estrone sulfate for hOAT3. Both inhibitors exhibited high affinity for hOAT1 (K(i) = 4.4 uM for 2-SMP; K(i) = 5.1 uM for 4-SMP) as well as hOAT3 (K(i) = 1.9 uM for 2-SMP; K(i) = 2.1 uM for 4-SMP). The uptake rate of 4-SMP (at a concentration of 10 uM) by hOAT1- and hOAT3-expressing cells was 3.0 and 1.6 times higher, respectively, than in control cells. Uptake of the reactive isomer 1-SMP was investigated using as the end point the level of DNA adducts that were formed in the cells. After exposure to 1-SMP (10 uM), the DNA adduct level was 4.6 and 3.0 times higher in hOAT1- and hOAT3-expressing cells, respectively, than in control cells. The enhanced DNA adduct formation in hOAT-expressing cells was abolished in the presence of the OAT inhibitor probenecid. This study indicates that OAT can mediate the basolateral uptake of reactive sulfuric acid esters into proximal tubule cells and thereby participate in kidney cell damage by these compounds.
Metal-Free Direct Deoxygenative Borylation of Aldehydes and Ketones
作者：Jianbin Li、Haining Wang、Zihang Qiu、Chia-Yu Huang、Chao-Jun Li
DOI：10.1021/jacs.0c03813
日期：2020.7.29
Direct conversion of aldehydes and ketones into alkylboronic esters via deoxygenative borylation represents an unknown yet highly desirable transformation. Herein, we present a one-step and metal-free method for carbonyl deoxy-borylation under mild conditions. A wide range of aromatic aldehydes and ketones are tolerated and successfully converted into the corresponding benzylboronates. By the same
Un grand nombre d'hydrocarbures insatures ont ete reduits par les metaux alcalins dans NH 3 liquide et les intermediaires carbanioniques ont ete detectes in situ par RMN et RPE. Les substrats sont partages en 3 groupes differents: a) ceux qui persistent comme dianions; b) ceux qui sont protones par NH 3 pour donner des anions monohydro; c) ceux qui subissent d'autres etapes de protonation/transfert
Un Grand nombre d'hydrocarbures insatures ont ete reduits par les metaux alcalins dans NH 3liquide et les intermediaires carbanioniques ont ete 在原位检测到 RMN 和 RPE。Les substrats sont partages en 3 groupes differents: a) ceux qui persistent comme dianions; b) ceux qui sont protones par NH 3 pour donner des anions monohydro；c) ceux qui subissent d'autres etapes de protonation/transfert d'electrons pour
A methylation platform of unconventional inert aryl electrophiles: trimethylboroxine as a universal methylating reagent
作者：Boya Feng、Yudong Yang、Jingsong You
DOI：10.1039/d0sc01641a
日期：——
electrophiles is a highly important yet challenging task in catalytic methylation. Disclosed herein is a series of transition metal-catalyzed methylations of unconventional inert aryl electrophiles using trimethylboroxine (TMB) as the methylating reagent. This transformation features a broad substrate type, including nitroarenes, benzoic amides, benzoic esters, aryl cyanides, phenol ethers, aryl pivalates and aryl
Ni-Catalyzed cross-coupling of aryl thioethers with alkyl Grignard reagents <i>via</i> C–S bond cleavage
作者：Dan Zhu、Lei Shi
DOI：10.1039/c8cc03665a
日期：——
A Ni-catalyzed cross-coupling of aryl thioethers with alkyl Grignardreagents, accompanied by the cleavage of the C(aryl)–SMe bond, has been presented. This method is distinguished by its mild conditions and moderate functional group tolerance, such as hydroxyl, halogen, and heterocycles, which should provide a straightforward access to the modification of sulfur-containing molecules.
Light-emitting device material and light-emitting device
申请人：Murase Seiichiro
公开号：US20090096356A1
公开（公告）日：2009-04-16
A light emitting device material containing a pyrene compound of formula (1) and a light emitting device. In formula (1), R
1
to R
18
are the same or different and are selected from hydrogen, alkyl, cycloalkyl, heterocyclic, alkenyl, cycloalkenyl, alkynyl, alkoxy, alkylthio, arylether, arylthioether, aryl, heteroaryl, halogen, carbonyl, carboxyl, oxycarbonyl, carbamoyl, amino, phosphine oxide and silyl; adjacent substituents among R
1
to R
18
may be combined with each other to form a ring; n represents an integer of 1 to 3; X is —O—, —S— or —NR
19
—; R
19
is selected from hydrogen, alkyl, cycloalkyl, heterocyclic, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl or amino; R
19
may be combined with R
11
or R
18
to form a ring; Y is a single bond, arylene or heteroarylene; and n substituents among R
1
to R
10
and any one of R
11
to R
19
are used for linkage with Y
