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：
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.
作者机构：
[Bai Xia; Xiao Hong-bo; Mai Pei; Sun Zhi-liang; Wang Shui-lian; Liu Zhao-ying; Dong Wei; Chen Xiao-jun; Wang Hui; Cai Jie] Hunan Agr Univ, Coll Vet Med, Changsha 410128, Hunan, Peoples R China.;[Bai Xia; Xiao Hong-bo; Mai Pei; Sun Zhi-liang; Liu Zhao-ying; Dong Wei; Chen Xiao-jun; Wang Hui; Cai Jie] Engn Res Ctr Vet Drugs Hunan Prov, Changsha 410311, Hunan, Peoples R China.
通讯机构：
[Sun Zhi-liang] H;Hunan Agr Univ, Coll Vet Med, Changsha 410128, Hunan, Peoples R China.
关键词：
angiopoietin-like protein 3;clone;pregnancy toxemia;goat
摘要：
Pregnancy toxemia is a metabolic disorder of lipid and glucose. Recent investigations have found that angiopoietin-like protein 3 (ANGPTL3) can contribute to disorder of carbohydrate and lipid metabolism. The present study was conducted to investigate the change of ANGPTL3 expression during pregnancy toxemia. We firstly cloned the full-length cDNA of ANGPTL3 in Liuyang Black goats, revealing that goat ANGPTL3 had the typical structure of the angiopoietin-like family, and its mRNA was exclusively expressed in liver. Pregnancy toxemia of pregnant goat does with twins during late gestation was induced by being fasted for 72 h, and then they were recovered after 5 d of refeeding. Hepatic ANGPTL3 gene expression was significantly down-regulated concomitantly with decreased serum glucose concentration, elevated serum β-hydroxybutyrate and free fatty acid levels in pregnant toxemic goats, and these changes were reversed after refeeding. These results suggest ANGPTL3 may play a certain role in the development of pregnancy toxemia in goats.
作者：
Zhang, D. S.;Liu, Z. Y.;Chen, X. J.;Kuang, G. W.;Pan, R. T.;...
期刊：
AFRICAN HEALTH SCIENCES,2012年12(4):522-529 ISSN：1680-6905
通讯作者：
Sun, Z. L.
作者机构：
[Chen, X. J.; Sun, Z. L.; Zhang, D. S.; Pan, R. T.; Liu, Z. Y.] Hunan Agr Univ, Coll Vet Med, Changsha 410128, Hunan, Peoples R China.;[Kuang, G. W.] Inst Hunan Prov Vet Drugs & Feed Supervis, Changsha 410006, Hunan, Peoples R China.;[Sun, Z. L.] Hunan Agr Univ, Changsha 410128, Hunan, Peoples R China.
通讯机构：
[Sun, Z. L.] H;Hunan Agr Univ, Changsha 410128, Hunan, Peoples R China.
关键词：
Angiopoietin-like protein 3 (ANGPTL3);DNA methylation;Pigs
摘要：
Background: Angiopoietin-like protein 3 (ANGPTL3), a member of angiopoietin-like proteins, has been demonstrated to affect lipid metabolism by inhibiting the activity of lipoprotein lipase (LPL). Objective: To compare the ANGPTL3 mRNA and protein expression, exon mutation and promoter district CpG island methylation state between Ningxiang Pigs and Changbai Pigs. Methods: Pigs were slaughtered and about 100 mg of tissue samples and subcutaneous adipose tissue were collected and stored for analysis. Quantitative Real-Time PCR, Western blotting, exons sequencing, and HRM analysis were carried out. Results: ANGPTL3 was expressed in liver but not in fat and lean meat. Compared with Changbai pigs, ANGPTL3 mRNA level in Ningxiang pigs was lower. However, the protein expression showed no difference between these two groups of pigs. Sequences analysis showed that four variations existed between Changbai Pigs and Ningxiang Pigs, among which three variations caused no change of amino acids, and the other one caused amino acid mutation from Val (Changbai) to Met (Ningxiang). The ANGPTL3 promoter district CpG island bisulfite-PCR and sequencing results showed that the mean methylation rate ranged from 70.952% to 95.238% between Changbai pig and Ningxiang pig (p<0.05). Conclusion: These results support the significant difference (p<0.05) between Changbai pig and Ningxiang pig in high-resolution melting (HRM) analysis. All these results may be helpful for a better understanding of the role of ANGPTL3 in lipid metabolism.
作者机构：
[Wu, Yong; Sun, Zhi-Liang; Liu, Zhao-Ying] Hunan Agr Univ, Coll Vet Med, Hunan Engn Res Ctr Vet Drug, Changsha 410128, Hunan, Peoples R China.;[Wan, Leren] Shimadzu Int Trading Shanghai Co Ltd, Shanghai 200052, Peoples R China.
通讯机构：
[Liu, Zhao-Ying] H;Hunan Agr Univ, Coll Vet Med, Hunan Engn Res Ctr Vet Drug, Changsha 410128, Hunan, Peoples R China.
关键词：
Diaveridine;Hybrid ion trap/time-of-flight mass spectrometry;Metabolism;Pig liver microsomes;Trimethoprim
摘要：
Trimethoprim (TMP) and diaveridine (DVD) are used in combination with sulfonamides and sulfaquinoxlaine as an effective antibacterial agent and antiprotozoal agent, respectively, in humans and animals. To gain a better understanding of the metabolism of TMP and DVD in the food-producing animals, the metabolites incubated with liver microsomes of pigs were analyzed for the first time with high-performance liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry. Seven TMP-related and six DVD-related metabolites were characterized based on the accurate MS2 spectra and known structure of the parent drug, respectively. The metabolites of TMP were identified as two O-demethylation metabolites, a di-O-demethylation metabolite, two N-oxides metabolites, a hydroxylated metabolite on the methylene carbon and a hydroxylated metabolite on the methyl group. DVD was also biotransformed to two O-demethylation metabolites, a di-O-demethylation metabolite, an N-oxide metabolite, a hydroxylation metabolite on the methylene carbon and a hydroxylation metabolite followed by O-demethylation. The results indicate that the two compounds have similar biotransformation pathways in pigs. O-Demethylation was the major metabolic route of TMP and DVD in the pig liver microsomes. The proposed metabolic pathways of TMP and DVD in liver microsomes will provide a basis for further studies of the in vivo metabolism of the two drugs in food-producing animals. Copyright (c) 2011 John Wiley & Sons, Ltd.
