摘要：
Although sanguinarine ( SANG) can be transformed to dihydrosanguinarine (DHSA) in human and animals, the enzyme involved in the imine bond reduction of SANG is still unknown. In this study, we found that rat NAD(P)H:quinone oxidoreductase 1 expressed by prokaryotic system can transform SANG to DHSA in an NADPH dependent manner. We also found out that there was more DHSA in rAAV-NQO1 infected than rAAV-CYP1A1 and rAAV-control infected BRL cells. SANG decreased rat BRL cell proliferation and augmented cell apoptosis in a time and dose dependent manner. However, the influence of DHSA to BRL cells is not significant difference than SANG. SANG-induced apoptosis was correlated with the up-regulation of Bax/Bcl2 ratio and the down-regulation of Bcl2. SANG can also dose dependently down regulate NQO1 expression, but CYP1A1 expression was a little up regulated. Since CYP1A1 involving in SANG oxidative reactions and NQO1 involving in the transform of SANG to DHSA, we hypothesized that up regulation of NQO1 could reduce SANG cytotoxicity and up regulation of CYP1A1 could increase SANG cytotoxitity. Our further study showed that recombinant adeno-associated virus (rAAV) mediated overexpression of NQO1 significantly increased cell proliferation and decreased Bax/Bcl2 ratio, apoptosis, and cytotoxicity, whereas rAAV mediated CYP1A1 overexpression had opposite effects. These data illustrated that NQO1 involved in the imine bond reduction of sanguinarine and this was a less toxic metabolizing pathway than CYP1A1-metabolizing pathway. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
摘要：
The aim of this article is to get an overview of the metabolism of quinoxaline 1,4-di-N-oxides (QdNOs) used in food animals. The derivatives of QdNOs (carbadox, olaquindox, mequindox, quinocetone, and cyadox) are the potent synthetic antimicrobial agents that are used for improving the feed efficiency and controlling dysentery in food-producing animals. Studies have demonstrated that the toxicity of QdNOs is closely associated with the production of their metabolism, especially with the production of their reduced metabolites. To the best of our knowledge, no one has systematically compiled the metabolism data of QdNOs. Therefore, the metabolism of QdNOs in animals has been discussed in the review for the first time. These drugs undergo extensive metabolism prior to excretion. N-oxide group reduction is the major metabolic pathway of QdNOs. Moreover, the N1- and N4-oxide reductions of QdNOs by different reducing mechanisms are also described. Obvious differences in metabolic pathways for QdNOs were observed owing to the differences on the side chain of these drugs. Therefore, understanding the metabolic pathways of QdNOs in animals will provide the guides for further studies of metabolism and toxicology of these drugs, and will also provide abundant information for the food safety assessment.
摘要：
This study investigated the inhibitory effects of sanguinarine (SA) on PKC-CPI-17 pathway in rat intestinal smooth muscle cells (ISMC). Previous studies indicate that the inhibitory effects of SA on ISMC contraction are possibly mediated by the Ca2+ influx. ISMC was treated with 1 mu M SA for 24 h remarkably inhibited the mRNA expression of m(2) and m(3) receptors. ISMC treated with 1 or 3 mu M SA for 30 min significantly decreased the mRNA expression of PKC-delta, PKC-epsilon, PKC-eta, and CPI-17. 1 mu M SA could markedly inhibit carbachol (CCh)-mediated increase PKC-delta, PKC-eta, and CPI-17 mRNA but had no effect in PKC-epsilon.Treatment of ISMC with SA (1 mu M, 30 min) caused a decrease in protein expression of PKC-delta. However, the expression of CPI-17 was significantly inhibited in a time-dependent manner. These results demonstrate that the inhibitory effect of SA is coupled with alteration of PKC-mediated signal transduction and intracellular Ca2+ concentration. (C) 2013 Elsevier Ltd. All rights reserved.
摘要：
Background: Sanguinarine (SA) is a quaternary benzo[c]phenanthridine alkaloid that is mainly present in the Papaveraceae family. SA has been extensively studied because of its antimicrobial, anti-inflammatory, antitumor, antihypertensive, antiproliferative and antiplatelet activities. Metabolic studies demonstrated that SA bioavailability is apparently low, and the main pathway of SA metabolism is iminium bond reduction resulting in dihydrosanguinarine (DHSA) formation. Nevertheless, the metabolic enzymes involved in SA reduction are still not known in detail. Thus, the aim of this study was to investigate the rat liver microsomes and cytosol-induced SA iminium bond reduction, and to examine the effects of cytosol reductase inhibitors on the reductive activity. Methods: DHSA formation was quantified by HPLC. The possible enzymes responsible for DHSA formation were examined using selective individual metabolic enzyme inhibitors. Results: When SA was incubated with liver microsomes and cytosol in the absence of NAD(P)H, DHSA, the iminium bond reductive metabolite was formed. The reductase activity of the liver microsomes and cytosol was also enhanced significantly in the presence of NADH. The amount of DHSA formed in the liver cytosol was 4.6-fold higher than in the liver microsomes in the presence of NADH. The reductase activity in the liver cytosol was inhibited by the addition of flavin mononucleotide and/or riboflavin. Inhibition studies indicated that menadione, dicoumarol, quercetin and 7-hydroxycoumarin inhibited rat liver cytosol-mediated DHSA formation in the absence of NADH. However, only menadione and quercetin inhibited rat liver cytosol-mediated DHSA formation in the presence of NADH. Conclusions: These results suggest that the SA iminium bond reduction proceeds via two routes in the liver cytosol. One route is direct non-enzymatic reduction by NAD(P)H, and the other is enzymatic reduction by possible carbonyl and/or quinone reductases in the liver cytosol.
作者：
Xiao, Hong-Bo*;Lu, Xiang-Yang;Zhang, Heng-Bo;Sun, Zhi-Liang;Fang, Jun
期刊：
Journal of Physiology and Biochemistry,2013年69(4):719-725 ISSN：1138-7548
通讯作者：
Xiao, Hong-Bo
作者机构：
[Xiao, Hong-Bo; Sun, Zhi-Liang] Hunan Agr Univ, Coll Vet Med, Changsha 410128, Hunan, Peoples R China.;[Lu, Xiang-Yang] Hunan Agr Bioengn Res Inst, Changsha 410128, Hunan, Peoples R China.;[Zhang, Heng-Bo] Furong Dist Red Cross Hosp, Changsha 410126, Hunan, Peoples R China.;[Sun, Zhi-Liang] Hunan Agr Univ, Natl Res Ctr Engn & Technol Utilizat Bot Funct In, Biol Vet Drugs Branch, Changsha 410128, Hunan, Peoples R China.;[Fang, Jun] Hunan Agr Univ, Coll Biosci & Biotechnol, Changsha 410128, Hunan, Peoples R China.
通讯机构：
[Xiao, Hong-Bo] H;Hunan Agr Univ, Coll Vet Med, Changsha 410128, Hunan, Peoples R China.
关键词：
Undaria pinnatifida;Soluble fiber;Angiopoietin-like protein 3;Hyperlipidemia;Mice
摘要：
Angiopoietin-like protein 3 (Angptl3)-lipoprotein lipase (LPL) pathway may be a useful pharmacologic target for hyperlipidemia. The present study was conducted to test the effect of soluble fiber extracted from Undaria pinnatifida (UP), on hyperlipidemia in apolipoprotein E-deficient (ApoE(-/-)) mice. Forty mice were divided into four groups (n = 10): control group (C57BL/6J mice), ApoE(-/-) mice group, and two groups of ApoE(-/-) mice treated with UP fiber (5 or 10 % per day). UP soluble fiber treatment significantly decreased plasma and hepatic total cholesterol, triglycerides levels, plasma low-density lipoprotein cholesterol, and malondialdehyde concentrations and increased plasma high-density lipoprotein cholesterol level and downregulated protein expression of Angptl3 concomitantly with upregulated protein expression of LPL. In addition, T0901317 caused elevated expression of hepatic Angptl3 protein, and the effect of T0901317 was also abrogated by UP soluble fiber in C57BL/6J mice. The present results suggest that the UP soluble fiber regulates Angptl3-LPL pathway to lessen hyperlipidemia in mice.
