To elucidate the metabolism of hispidulin in the large intestine, its biotransformation by the pig caecal microflora was studied. In addition, the efficiency of the pig caecal microflora to degrade galangin (3,5,7-trihydroxyflavone), kaempferol (3,5,7,4?-tetrahydroxyflavone), apigenin (5,7,4?-trihydroxyflavone), and luteolin (5,7,3?,4?- tetrahydroxyflavone) was investigated. Identification of the formed metabolites was performed by high-performance liquid chromatography (HPLC)-diode array detection, HPLC-electrospray ionization-tandem mass spectrometry, and high-resolution gas chromatography-mass spectrometry. The caecal microflora transformed ... kaempferol to 4-hydroxyphenylacetic acid, phloroglucinol, and 4-methylphenol; ... To elucidate to what extent different hydroxylation patterns on the B-ring influence the degradation degree of flavonoids, the conversions of galangin and kaempferol as well as that of apigenin and luteolin were compared with those of quercetin (3,5,7,3?, 4?-pentahydroxyflavone) and chrysin (5.7-dihydroxyflavone), respectively. Regardless of the flavonoid subclass, the presence of a hydroxy group at the 4?-position seems to be a prerequisite for fast breakdown. An additional hydroxy group at the B-ring did not affect the degradation degree.
The metabolism of the flavonoids quercetin and kaempferol by rat hepatocytes was investigated using liquid chromatography coupled with electrospray mass spectrometry (LC-ESI MS). Quercetin and kaempferol were extensively metabolized (98.8 +/- 0.1% and 81.0 +/- 5.1% respectively, n = 4), with four glucuronides of quercetin and two of kaempferol being detected after incubation. The glucuronides of quercetin and kaempferol formed upon incubation with rat hepatocytes were identified as the same ones formed after incubation with the UDP-glucuronosyltransferase isoform UGT1A9. In addition, plasma samples from human volunteers taken after consumption of capsules of Ginkgo biloba, a plant rich in flavonoid glycosides, were analysed by LC-MS for the presence of flavonoid glucuronides and flavonoid glycosides. Reported is evidence for the presence of flavonoid glycosides in samples of plasma. The results suggest that UGT1A9 is a key UDP-glucuronosyltransferase isoform for the metabolism of flavonoids, and that absorption of intact flavonoid glycosides is possible.
Kaempferol is a flavonoid widely distributed in edible plants and has been shown to be genotoxic to V79 cells in the absence of external metabolizing systems. The presence of an external metabolizing system, such as rat liver homogenates (S9 mix), leads to an increase in its genotoxicity, which is attributed to its biotransformation to the more genotoxic flavonoid quercetin, via the cytochrome P450 (CYP) mono-oxygenase system. ...
Kaempferol has known human metabolites that include (2S,3S,4S,5R)-6-[3,5-Dihydroxy-2-(4-hydroxyphenyl)-4-oxochromen-7-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid and Kaempferol-3-glucuronide.
来源:NORMAN Suspect List Exchange
毒理性
致癌物分类
国际癌症研究机构致癌物：山柰酚
IARC Carcinogenic Agent:Kaempferol
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构（IARC）致癌物分类：第3组：无法归类其对人类致癌性
IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity to humans
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构专著：第31卷：（1983年）某些食品添加剂、饲料添加剂和天然存在物质
IARC Monographs:Volume 31: (1983) Some Food Additives, Feed Additives and Naturally Occurring Substances
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
3, 其对人类致癌性无法分类。
3, not classifiable as to its carcinogenicity to humans. (L135)
It has been reported that tamoxifen is a substrate of P-glycoprotein (P-gp) and microsomal cytochrome P450 (CYP) 3A, and kaempferol is an inhibitor of P-gp and CYP3A. Hence, it could be expected that kaempferol would affect the pharmacokinetics of tamoxifen. Thus, tamoxifen was administered orally (10 mg/kg) without or with oral kaempferol (2.5 and 10 mg/kg). In the presence of kaempferol, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of tamoxifen was significantly greater, C(max) was significantly higher and F was considerably greater than those without kaempferol. The enhanced bioavailability of oral tamoxifen by oral kaempferol could have been due to an inhibition of CYP3A and P-gp by kaempferol. The presence of kaempferol did not alter the pharmacokinetic parameters of a metabolite of tamoxifen, 4-hydroxytamoxifen. This could have been because the contribution of CYP3A to the formation of 4-hydroxytamoxifen is not considerable in rats.
The aim of this study was to assess kaempferol bioavailability in healthy humans, after bean (Phaseolus vulgaris L.) consumption through the monitoring of the excretion in relation to intake. In seven healthy subjects receiving kaempferol from cooked bean, maximum excretion of hydrolyzed flavonol was obtained after 2-8 hr. Intersexual variations in urinary excretion were found to be 6.10+/-5.50% and 5.40+/-5.40% of the kaempferol dose for male and female subjects, respectively. Although a 6.72-fold inter-individual variation between the highest and lowest excretion concentrations was found, all individuals exhibited similar excretion profiles. Moreover, a direct correlation between the percentage of kaempferol excreted and the body mass index of volunteers was observed with a correlation index equal to 0.80. All except two individuals exhibited a first peak of kaempferol excretion 2 hr after ingestion. The study reveals information about inter-individual excretion capacity after kaempferol intake and that kaempferol can be used as a biomarker for flavonol consumption.
... A pharmacokinetic study of kaempferol from endive ... /was studied in / four healthy males and four healthy females. Kaempferol, from a relatively low dose (9 mg), was absorbed from endive with a mean maximum plasma concentration of 0.1 uM, at a time of 5.8 hr, indicating absorption from the distal section of the small intestine and/or the colon. Although a 7.5-fold interindividual variation between the highest and lowest maximum plasma concentration was observed, most individuals showed remarkably consistent pharmacokinetic profiles. This contrasts with profiles for other flavonoids that are absorbed predominantly from the large intestine (eg rutin). An average of 1.9% of the kaempferol dose was excreted in 24 hr. Most subjects also showed an early absorption peak, probably corresponding to kaempferol-3-glucoside, present at a level of 14% in the endive. Kaempferol-3-glucuronide was the major compound detected in plasma and urine. Quercetin was not detected in plasma or urine indicating a lack of phase I hydroxylation of kaempferol. Kaempferol is absorbed more efficiently than quercetin in humans even at low oral doses. The predominant form in plasma is a 3-glucuronide conjugate, and interindividual variation in absorption and excretion is low, suggesting that urinary kaempferol could be used as a biomarker for exposure.
Ten adult volunteers with an average age 28 years were given a single oral dose of six tablets of Ginkgo biloba extract. Quercetin and kaempferol in different period of human urine were determined by using RP-HPLC. The results showed the elimination rate constant k and the absorption rate constant ka of quercetin were slightly more than that of kaempferol; and the absorption half-life (t(1/2a)), the elimination half-life (t(1/2)) and t(max) of quercetin were less than that of kaempferol, the differences were, however, not statistically significant. The mean values of ka were 0.61 hr(-1) and 0.55 hr(-1), t(1/2a) 1.51 hr and 1.56 hr, k 0.37 hr(-1) and 0.30 hr(-1), t(1/2) 2.17 hr and 2.76 hr, T(max) 2.30 hr and 2.68 hr for quercetin and kaempferol, respectively, which mean absorption and elimination of quercetin and kaempferol are 0.17% and 0.22%, respectively. Quercetin and kaempferol are excreted in the human urine mainly as glucuronides.
The objective of this study was to investigate whether kaempferol and quercetin could be transported into primary cultured cerebral neurons, to establish a practical HPLC method with UV detection for the two flavonols in the neurons, and to study the uptake and transport behaviors of them through the neurons. The present results showed that the level of kaempferol in the neurons increased linearly and then reached a plateau with incubation time at the high concentration of 10 ?g/mL, but not at the other two concentrations of 1 and 0.1 ug/mL. However, the levels of quercetin in the neurons were not detected at the three incubating concentrations, and there was a new peak detected in the cell whose retention time was shorter (3.42 min) than that of quercetin (4.65 min). This phenomenon suggested that quercetin might be transported into the neurons and then metabolized quickly to some derivative. Kaempferol could be transported into the neurons in a concentration- and time-dependent manner when the neurons were incubated with the culture medium containing kaempferol at the high dose. There was an apparent correlation between the concentrations of kaempferol in the medium and in the cell, indicating that the uptake of kaempferol in the cell increased along with its dose (10 ug/mL). However, there was a negative correlation between the concentrations of quercetin in the medium and in the cell. The results suggested that kaempferol and quercetin were disposed by the neurons at different way, and this might be an important factor for their different effects on primary cultured cortical cells.
Primary aminomethyl derivatives of kaempferol: hydrogen bond-assisted synthesis, anticancer activity and spectral properties
作者：Shuanglian Cai、Yangyang Kong、Dan Xiao、Yun Chen、Qiuan Wang
DOI：10.1039/c7ob02927f
日期：——
products of kaempferol. The formation of appropriate hydrogen bonds between strong nucleophilic amino acids and phenol is essential for the smooth reaction of the SN2 nucleophilicsubstitution. The SN2 mechanism hypothesis involving a hydrogen bond-assisted process was also supported by the density functional theory (DFT) analysis. An antiproliferative test of synthetic compounds shows the moderate to potent
通过涉及曼尼希反应和S N 2亲核取代两个步骤的组合策略合成了山emp酚的一系列伯氨甲基伯衍生物。产物的结构表明，优先的氨基甲基化在山emp酚的A环的C-6或C-8位置，尤其是后者。有趣的是，实验数据表明分子间氢键在山ka酚的主要氨基甲基产物的形成中起关键作用。在强亲核氨基酸和苯酚之间形成适当的氢键对于S N 2亲核取代的平稳反应是必不可少的。在S Ñ密度泛函理论（DFT）分析也支持涉及氢键辅助过程的2种机理假说。合成化合物的抗增殖测试显示，通过CCK-8分析，它对三种人类癌细胞系（HeLa，HCC1954和SK-OV-3）具有中等至有效的细胞毒活性。化合物4e对HeLa细胞显示出选择性的抗增殖活性，且IC50值较低（4.27μm），值得进一步开发。另一个有趣的结果是，大多数金属络合物的最大发射带位于约480 nm处，而Tm和Yb络合物的最大发射带出现在约533 nm处。
Accurate Prediction of Glucuronidation of Structurally Diverse Phenolics by Human UGT1A9 Using Combined Experimental and In Silico Approaches
作者：Baojian Wu、Xiaoqiang Wang、Shuxing Zhang、Ming Hu
DOI：10.1007/s11095-012-0666-z
日期：2012.6
Catalytic selectivity of human UGT1A9, an important membrane-bound enzyme catalyzing glucuronidation of xenobiotics, was determined experimentally using 145 phenolics and analyzed by 3D-QSAR methods. Catalytic efficiency of UGT1A9 was determined by kinetic profiling. Quantitative structure activity relationships were analyzed using CoMFA and CoMSIA techniques. Molecular alignment of substrate structures was made by superimposing the glucuronidation site and its adjacent aromatic ring to achieve maximal steric overlap. For a substrate with multiple active glucuronidation sites, each site was considered a separate substrate. 3D-QSAR analyses produced statistically reliable models with good predictive power (CoMFA: q2 = 0.548, r2 = 0.949, r pred 2 = 0.775; CoMSIA: q2 = 0.579, r2 = 0.876, r pred 2 = 0.700). Contour coefficient maps were applied to elucidate structural features among substrates that are responsible for selectivity differences. Contour coefficient maps were overlaid in the catalytic pocket of a homology model of UGT1A9, enabling identification of the UGT1A9 catalytic pocket with a high degree of confidence. CoMFA/CoMSIA models can predict substrate selectivity and in vitro clearance of UGT1A9. Our findings also provide a possible molecular basis for understanding UGT1A9 functions and substrate selectivity.
通过实验使用145种酚类化合物，并通过3D-QSAR方法分析，确定了人UGT1A9的催化选择性。UGT1A9是一种重要的膜结合酶，催化外源性物质的葡糖醛酸化反应。通过动力学分析确定了UGT1A9的催化效率。使用CoMFA和CoMSIA技术分析了定量结构活性关系。通过将葡糖醛酸化位点及其相邻的芳香环重叠，实现了底物结构的最大立体重叠。对于具有多个活性葡糖醛酸化位点的底物，每个位点被视为单独的底物。3D-QSAR分析产生了统计上可靠的模型，具有良好的预测能力（CoMFA：q2=0.548，r2=0.949，r pred 2=0.775；CoMSIA：q2=0.579，r2=0.876，r pred 2=0.700）。通过轮廓系数图阐明了底物中负责选择性差异的结构特征。将轮廓系数图叠加在UGT1A9的同源模型的催化口袋中，能够高度自信地识别UGT1A9的催化口袋。CoMFA/CoMSIA模型可以预测底物的选择性和UGT1A9的体外清除率。我们的发现还提供了理解UGT1A9功能和底物选择性的可能分子基础。
[EN] ALKYNE-, AZIDE- AND TRIAZOLE-CONTAINING FLAVONOIDS AS MODULATORS FOR MULTIDRUG RESISTANCE IN CANCERS<br/>[FR] FLAVONOÏDES CONTENANT DE L'ALCYNE, DE L'AZIDE ET DU TRIAZOLE UTILISÉS COMME MODULATEURS DE RÉSISTANCE MULTIPLE AUX MÉDICAMENTS DANS LES CANCERS
申请人：UNIV HONG KONG POLYTECHNIC
公开号：WO2013127361A1
公开（公告）日：2013-09-06
A triazole bridged flavonoid dimer compound library was efficiently constructed via the cycloaddition reaction of a series of flavonoid-containing azides (Az 1-15) and alkynes (Ac 1-17). These triazole bridged flavonoid dimers and their precursor alkyne- and azide-continaing flavonoids were screened for their ability to modulate multidrug resistance (MDR) in P-gp-overexpressed cell line (LCC6MDR), MRPl-overexpressed cell line (2008/MRPl) and BCRP-overexpressed cell line (HEK293/R2 and MCF7-MX100). Generally, they displayed very promising MDR reversal activity against P-gp-, MRPl- and BCRP-mediated drug resistance. Moreover, they showed different levels of selectivity for various transporters. Overall, they can be divided into mono-selective, dual-selective and multi-selective modulators for the P-gp, MRPl and BCRP transporters. The EC50 values for reversing paclitaxel resistance (141 - 340 nM) of LCC6MDR cells, DOX (78 - 590 nM) and vincristine (82 - 550 nM) resistance of 2008/MRPl cells and topotecan resistance (0.9 - 135 nM) of HEK293/R2 and MCF7-MX100 cells were at nanomolar range. Importantly, a number of compounds displayed EC50 at or below 10 nM in BCRP-overexpressed cell lines, indicating that these bivalent triazoles more selectively inhibit BCRP transporter than the P-gp and MRPl transporters. Most of the dimers are notably safe MDR chemosensitizers as indicated by their high therapeutic index values.
A process is provided for producing anthocyanidins of formula III
wherein m represents an integer from 1 to 3, and X⁻ represents an anion, which involves reducing a protected flavonol of formula
where each R⁴ represents a C₁#SB-#₁₀
hydrocarbyl group and m is 1 to 3 and converting OR⁴ groups to hydroxy groups.
