Highly active and recoverable nanobioreactors prepared by immobilizing rat liver microsomes on magnetic nanoparticles (LMMNPs) were utilized in metabolic study of Angelica dahurica extracts. Five metabolites were detected in the incubation solution of the extracts and LMMNPs, which were identified by means of HPLC-MS as trans-imperatorin hydroxylate (M1), cis-imperatorin hydroxylate (M2), imperatorin epoxide (M3), trans-isoimperatorin hydroxylate (M1') and cis-isoimperatorin hydroxylate (speculated M2'). Compared with the metabolisms of imperatorin and isoimperatorin, it was found that the five metabolites were all transformed from these two major compounds present in the plant. Since no study on isoimperatorin metabolism by liver microsomal enzyme system has been reported so far, its metabolites (M1' and M3') were isolated by preparative HPLC for structure elucidation by (1) H-NMR and MS(2) analysis. M3' was identified as isoimperatorin epoxide, which is a new compound as far as its chemical structure is concerned. However, interestingly, M3' was not detected in the metabolism of the whole plant extract. In addition, a study with known chemical inhibitors on individual isozymes of the microsomal enzyme family revealed that CYP1A2 is involved in metabolisms of both isoimperatorin and imperatorin, and CYP3A4 only in that of isoimperatorin.
Biotransformation studies conducted on the furanocoumarins isoimperatorin (1) and imperatorin (3) have revealed that 1 was metabolized by Glomerella cingulata to give the corresponding reduced acid, 6,7-furano-5-prenyloxy hydrocoumaric acid (2), and 3 was transformed by G. cingulata to give the dealkylated metabolite, xanthotoxol (4) in high yields (83% and 81%), respectively. The structures of the new compound 2 have been established on the basis of spectral data. The metabolites 2 and 4 were tested for the beta-secretase (BACE1) inhibitory activity in vitro, and metabolite 2 slightly inhibited the beta-secretase activity with an IC(50) value of 185.6+/-6.8 uM. The metabolite 4 was less potent activity than compounds 1-3. In addition, methyl ester (2Me), methyl ether (2a) and methyl ester and ether (2aMe) of 2 were synthesized, and investigated for the ability to inhibit beta-secretase. Compound 2aMe exhibited the best beta-secretase inhibitory activity at the IC(50) value 16.2+/-1.2 uM and found to be the 2aMe showed competitive mode of inhibition against beta-secretase with K(i) value 11.3+/-2.8 uM.
Paraoxonase (PON1) is a key enzyme in the metabolism of organophosphates. PON1 can inactivate some organophosphates through hydrolysis. PON1 hydrolyzes the active metabolites in several organophosphates insecticides as well as, nerve agents such as soman, sarin, and VX. The presence of PON1 polymorphisms causes there to be different enzyme levels and catalytic efficiency of this esterase, which in turn suggests that different individuals may be more susceptible to the toxic effect of OP exposure.
IDENTIFICATION AND USE: Isoimperatorin is a solid. Isoimperatorin was found in Chinese medicine tablets. It is used as laboratory chemical, manufacture of substances. HUMAN STUDIES: Coumarins from A. dahurica, including isoimperatorin markedly inhibited melatonin metabolism in vivo and in vitro. Isoimperatorin inactivated cytochromes P450 A2 and 2B6. ANIMAL STUDIES: Isoimperatorin was photoirritant when tested in mice. Isoimperatorin given to mice orally at 40 mg/kg altered serum activities of alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and/or levels of albumin, showing hepatotoxicity. Isoimperatorin inhibited proliferation of bovine cerebral microvascular endothelial cell stimulated by platelet-derived growth factor. Isoimperatoin was capable of inhibiting carcinogen activation by cytochrome P450 1B1. ECOTOXICITY STUDIES: Furocoumarins such as imperatorin and isoimperatorin accumulating in the older shoots of Pituranthos triradiatus acted as natural protectants against grazing. Only hyrax (Procavia capensis syriaca) that had eaten old branches and had been left in the sunlight developed photosensitization symptoms.
Isoimperatorin 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. The mechanism of action many furocoumarins is based on their ability to form photoadducts with DNA and other cellular components such as RNA, proteins, and several proteins found in the membrane such as phospholipases A2 and C, Ca-dependent and cAMPdependent protein-kinase and epidermal growth factor. Furocoumarins intercalate between base pairs of DNA and after ultraviolet-A irradiation, giving cycloadducts. (L579).
Not listed by IARC. IARC has assessed other furocoumarins, classifying 8-methoxypsoralen as carcinogenic to humans (Group 1), 5-methoxypsoralen as possibly carcinogenic to humans (Group 2A), and certain other furocoumarins as not being classifiable as to their carcinogenicity to humans (Group 3). (L135)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
健康影响
急性暴露于胆碱酯酶抑制剂可能会导致胆碱能危象，表现为严重的恶心/呕吐、流涎、出汗、心动过缓、低血压、晕厥和抽搐。肌肉无力可能会逐渐加重，如果呼吸肌受累，可能会导致死亡。在运动神经处乙酰胆碱的积累会导致神经肌肉接头处烟碱受体的过度刺激。当这种情况发生时，可能会出现肌肉无力、疲劳、肌肉痉挛、肌束震颤和麻痹等症状。当自主神经节处乙酰胆碱积累时，会导致交感系统中烟碱受体的过度刺激。与此相关的症状包括高血压和低血糖。由于乙酰胆碱的积累，在中枢神经系统中烟碱乙酰胆碱受体的过度刺激会导致焦虑、头痛、抽搐、共济失调、呼吸和循环抑制、震颤、全身无力，甚至可能昏迷。当乙酰胆碱在毒蕈碱乙酰胆碱受体处过量时，表现出毒蕈碱过度刺激的症状，如视觉障碍、胸部紧绷、由于支气管收缩引起的喘息、支气管分泌物增多、唾液分泌增多、流泪、出汗、蠕动和排尿。某些关于生育、生长和发育的生殖效应，对于男性和女性，已被特别与有机磷农药暴露联系起来。大多数关于生殖效应的研究都是在农村地区使用杀虫剂和农药的农民身上进行的。在女性中，月经周期紊乱、孕期延长、自然流产、死产以及后代的一些发育效应已被与有机磷农药暴露联系起来。产前暴露与胎儿生长和发育受损有关。神经毒性效应也已被与有机磷农药中毒联系起来，导致人类四种神经毒性效应：胆碱能综合征、中间综合征、有机磷诱导的迟发性多发性神经病（OPIDP）和慢性有机磷诱导的神经精神障碍（COPIND）。这些综合征是在急性 and 慢性暴露于有机磷农药后出现的。呋喃香豆素8-甲氧基补骨脂素对人体具有致癌性，5-甲氧基补骨脂素也可能如此（L135）。一些来自小鼠研究的证据表明，当其他呋喃香豆素与UVA辐射暴露结合时，也具有致癌性（A15105）。SKLM认为，食用含有典型量呋喃香豆素的食物，其浓度显著低于光毒性剂量范围，引起的额外皮肤癌风险是不显著的。然而，对于某些食物，尤其是芹菜和欧防风，由于储存、加工和生产条件的影响，可能会导致呋喃香豆素浓度显著增加，因此不能排除食用光毒性剂量的可能性（L2157）。已知呋喃香豆素光化学疗法会诱导多种副作用，包括红斑、水肿、色素沉着过度和皮肤过早老化。所有呋喃香豆素的光生物效应都源于它们的 photochemical 反应。因为许多饮食或水溶性呋喃香豆素是细胞色素P450s的强抑制剂，所以当与其他药物一起服用时，它们也会引起不良药物反应。致癌效应的证据有限（L579）。
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. The furocoumarin 8-methoxypsoralen is carcinogenic to humans, and possibly 5-methoxypsoralen as well (L135). There is some evidence from mouse studies that other furocoumarins are carcinogenic when combined with exposure to UVA radiation (A15105). The SKLM regards the additional risk of skin cancer arising from the consumption of typical quantities of furocoumarin-containing foods, which remain significantly below the range of phototoxic doses, as insignificant. However, the consumption of phototoxic quantities cannot be ruled out for certain foods, particularly celery and parsnips, that may lead to significant increases in furocoumarin concentrations, depending on the storage, processing and production conditions. (L2157) Furocoumarin photochemotherapy is known to induce a number of side-effects including erythema, edema, hyperpigmentation, and premature aging of skin. All photobiological effects of furocoumarins result from their photochemical reactions. Because many dietary or water soluble furocoumarins are strong inhibitors of cytochrome P450s, they will also cause adverse drug reactions when taken with other drugs. Limited evidence of carcinogenic effect. (L579)
Symptoms of low dose exposure include excessive salivation and eye-watering. Acute dose symptoms include 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. Hypertension, hypoglycemia, anxiety, headache, tremor and ataxia may also result.
being beneficial or detrimental to human health. Although their O-prenyl moieties often play crucial roles in the biological activities of these compounds, no plant gene encoding an aromatic O-prenyltransferase (O-PT) has been isolated to date. This study describes the isolation of an aromatic O-PT gene, CpPT1, belonging to the UbiA superfamily, from grapefruit (Citrus × paradisi, Rutaceae). This gene
Natural oxyprenylated coumarins are modulators of melanogenesis
作者：Serena Fiorito、Francesco Epifano、Francesca Preziuso、Ivana Cacciatore、Antonio di Stefano、Vito Alessandro Taddeo、Philippe de Medina、Salvatore Genovese
DOI：10.1016/j.ejmech.2018.04.051
日期：2018.5
Naturally occurring coumarins 7-isopentenyloxycoumarin, auraptene, and umbelliprenin are able to modulate the biosynthesis of melanin in murine Melan-a cells probably through the interaction with selected biological targets like estrogen receptor 13 and aryl hydrocarbon receptor. Such a modulation strictly depends on the individual structure of the coumarin: the presence of a 3,3-dimethylallyloxy side chain is a structural determinant for tanning activation whereas a farnesyl one leads to the opposite effect. The parent compound with a free OH group, umbelliferone, did not provide any interaction. Other coumarins assayed, having shorter chains and/or being substituted in other positions, and prenyloxypsoralens, were not active or not further investigated in this context being cytotoxic at low doses. (C) 2018 Elsevier Masson SAS. All rights reserved.
Resolution of prenyl bromohydrin esters and derivatives: synthesis of the quinoline alkaloid (+)-(R)- and (−)-(S)- lunacridine
作者：Stephen A. Barr、Derek R. Boyd、Narain D. Sharma、Timothy A. Evans、John F. Malone、Vimal D. Mehta
DOI：10.1016/s0040-4020(01)89424-2
日期：1994.1
Chromatographic separation of the bromohydrin MTPA diastereoisomers formed at the prenyl group attached to quinoline and coumarin rings is reported; base catalysed cyclization of the bromo MTPA esters in the quinoline series yielded the corresponding prenyl epoxide enantiomers. This provides a synthetic route to the enantiopure quinoline alkaloid lunacridine 11 and to the dihydrofuroquinoline 8-methoxy-platydesmine 8.
Biotransformation of isoimperatorin and imperatorin by Glomerella cingulata and β-secretase inhibitory activity
作者：Shinsuke Marumoto、Mitsuo Miyazawa
DOI：10.1016/j.bmc.2009.10.004
日期：2010.1
Biotransformation studies conducted on the furanocoumarins isoimperatorin (1) and imperatorin (3) have revealed that 1 was metabolized by Glomerella cingulata to give the corresponding reduced acid, 6,7-furano-5-prenyloxy hydrocoumaric acid (2), and 3 was transformed by G. cingulata to give the dealkylated metabolite, xanthotoxol (4) in high yields (83% and 81%), respectively. The structures of the new compound 2 have been established on the basis of spectral data. The metabolites 2 and 4 were tested for the beta-secretase (BACE1) inhibitory activity in vitro, and metabolite 2 slightly inhibited the beta-secretase activity with an IC50 value of 185.6 +/- 6.8 mu M. The metabolite 4 was less potent activity than compounds 1-3. In addition, methyl ester (2Me), methyl ether (2a) and methyl ester and ether (2aMe) of 2 were synthesized, and investigated for the ability to inhibit beta-secretase. Compound 2aMe exhibited the best beta-secretase inhibitory activity at the IC50 value 16.2 +/- 1.2 mu M and found to be the 2aMe showed competitive mode of inhibition against beta-secretase with K-i value 11.3 +/- 2.8 mu M. (C) 2009 Elsevier Ltd. All rights reserved.
Chakraborti; Bose, Transactions of the Bose Research Institute (Calcutta), 23 <1959/60) 55
