Deacetylclivorine: A Gender-Selective Metabolite of Clivorine Formed in Female Sprague-Dawley Rat Liver Microsomes

Lin, Ge; Tang, Jun; Liu, Xiao Quan; Jiang, Yan; Zheng, Jiang

doi:10.1124/dmd.106.014100

Cited by 83 publications

(82 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The species-, strain-or gender-depending variations in enzymatic activities or expressions, resulting in different overall balances of the detoxification and activation pathways, can influence the higher susceptibility of certain animals (e.g. male rat > guinea pig) to PA toxicity (Huan et al, 1998a;Lin et al, 2002Lin et al, , 2003Chung and Buhler, 2004;Lin et al, 2007).…”

Section: Metabolismmentioning

confidence: 99%

Scientific Opinion on Pyrrolizidine alkaloids in food and feed

2011

EFS2

226

130

View full text Add to dashboard Cite

The European Food Safety Authority (EFSA) was asked by the European Commission to deliver a scientific opinion on pyrrolizidine alkaloids (PA) in food and feed. PAs are toxins exclusively biosynthesised by plants. To date, approximately 600 different PAs are known. Results for 13,280 bulk honey and 1324 retail honey samples were provided to EFSA by one Member State and 351 feed samples were provided by a second Member State. The EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) performed estimates of both acute and chronic exposure to PAs through honey for three different age groups. Although there might be other sources of PA exposure, due to lack of data the CONTAM Panel was not able to quantify dietary exposure from food other than honey. A number of PAs were identified as being of particular importance for food and feed. Based on the present knowledge of metabolism, activation, DNA adduct-formation, genotoxicity and carcinogenicity, the CONTAM Panel concluded that 1,2-unsaturated PAs may act as genotoxic carcinogens in humans. Therefore, the CONTAM Panel decided to apply the Margin of Exposure (MOE) approach. A benchmark dose lower confidence limit for a 10 % excess cancer risk (BMDL 10 ) of 70 µg/kg b.w. per day for induction of liver haemangiosarcomas by lasiocarpine in male rats was calculated as the reference point for comparison with the estimated dietary exposure. The CONTAM Panel concluded that there is a possible health concern for those toddlers and children who are high consumers of honey. There is generally a low risk of PA poisoning in livestock and companion animals in the EU as most PA poisonings reported recently are due to accidental exposure. © European Pyrrolizidine alkaloids in food and feedEFSA Journal 2011;9(11):2406 2 SUMMARYFollowing a request from the European Commission, the Panel on Contaminants in the Food Chain (CONTAM Panel) was asked to deliver a scientific opinion on the risks to human and animal health related to the presence of pyrrolizidine alkaloids (PA) in food and feed. PAs are toxins exclusively biosynthesised by plants. They are typical plant secondary metabolites against herbivores. It has been estimated that approximately 6000 plant species world wide, representing 3 % of all flowering plants, may contain pyrrolizidine alkaloids. PAs are mainly found in the distantly related angiosperm families of the Boraginaceae (all genera), Asteraceae (tribes Senecioneae and Eupatorieae) and Fabaceae (genus Crotalaria). The PA-content of plant material depends on a large number of factors (species, plant organ, harvest, storage, extraction procedures). Reported contents vary from trace amounts up to 19 % based on dry weight. The name pyrrolizidine is the chemical description of two-fused 5-membered rings with a nitrogen atom at the bridgehead. This motif is the central structure of a variety of PAs. PAs generally consist of an amino alcohol which is referred to as necine or necine base and an acid part which is called a necic acid. Most of the known PAs are este...

show abstract

Section: Metabolismmentioning

confidence: 99%

Scientific Opinion on Pyrrolizidine alkaloids in food and feed

2011

EFS2

226

130

View full text Add to dashboard Cite

show abstract

“…This finding implies that the esterase(s) present in our microsomal incubation system might be different isoforms specially targeted for the acetyl substituent. Similarly, a recent study (Lin et al, 2007) showed that clivorine could undergo deacetylation by PMSF-sensitive microsomal hydrolase A, suggesting a possible detoxification pathway in female rats. In our study, M1 and M2 were deacetylated metabolites of isoline, with formation inhibited dose dependently in mice by either TOCP or PMSF.…”

Section: Discussionmentioning

confidence: 99%

“…It is well established that the liver microsomal fraction contains the highest activity of esterase(s), but there are large species differences, especially among small laboratory animals. Although the corresponding isoform in mouse (MH1) could be found with homology and characteristics similar to those of rat hydrolase A (Satoh and Hosokawa, 1998;Lin et al, 2007), further research to verify its identity and functions is needed.…”

Section: Discussionmentioning

confidence: 99%

“…The mixtures described above were incubated at 37°C for 60 min with one of the following inhibitors: TOCP (0.01, 0.1, 1, and 2.5 mM) and PMSF (0.1, 0.5, and 1 mM) for esterase(s) or SKF 525A (0.1 and 0.5 mM) and ANF (0.1 and 0.5 mM) for P450s, each with differential selectivity. The inhibitor concentrations were defined according to the preliminary TLC studies or published data to achieve significant inhibition effects by TOCP and PMSF (Dueker et al, 1992a,b;Lin et al, 2007) and SKF 525A and ANF (Hayes et al, 1984;Williams et al, 1989). Because these inhibitors were dissolved in dimethyl sulfoxide (Ͻ0.5% in the incubation mixture), the control incubation also contained this solvent.…”

Section: Methodsmentioning

confidence: 99%

“…On the other hand, alternative metabolic routes, including ester hydrolysis to the subgroup retronecine by guinea pig liver carboxylesterase GPH1 (Dueker et al, 1992a(Dueker et al, , 1995Chung and Buhler, 1995) and N-oxidation by monooxygenase-containing flavine or P450s (Williams et al, 1989;Miranda et al, 1991;Huan et al, 1998), appear to constitute a detoxification mechanism. More recently, clivorine, a representative otonecine-type PA, was found to be hydrolyzed by microsomal esterase to generate a female Sprague-Dawley rat-specific metabolite deacetylclivorine (Lin et al, 2007). Nevertheless, unlike metabolic activation by P450s, the ester hydrolysis of PAs by hepatic esterase and its physiological role in hepatotoxicity are still largely unknown.…”

mentioning

confidence: 99%

See 2 more Smart Citations

In Vitro Metabolism of Isoline, a Pyrrolizidine Alkaloid fromLigularia duciformis, by Rodent Liver Microsomal Esterase and Enhanced Hepatotoxicity by Esterase Inhibitors

Tang¹,

Akao²,

Nakamura³

et al. 2007

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

ABSTRACT:Isoline, a major retronecine-type pyrrolizidine alkaloid (PA) from the Chinese medicinal herb Ligularia duciformis, was suggested to be the most toxic known PA. Its in vitro metabolism was thus examined in rat and mouse liver microsomes, and its toxicity was compared with that of clivorine and monocrotaline after i.p. injection in mice. Isoline was more rapidly metabolized by both microsomes than clivorine and monocrotaline and converted to two polar metabolites M1 and M2, which were spectroscopically determined to be bisline (a deacetylated metabolite of isoline) and bisline lactone, respectively. Both metabolites were formed in the presence or absence of an NADPH-generating system with liver microsomes but not cytosol. Their formation was completely inhibited by the esterase inhibitors, triorthocresyl phosphate (TOCP) and phenylmethylsulfonyl fluoride, but not at all or partially by cytochrome P450 (P450) inhibitors, ␣-naphthoflavone and proadifen (SKF 525A), respectively. These results demonstrated that both metabolites were produced by microsomal esterase(s) but not P450 isozymes. The esterase(s) involved showed not only quite different activities but also responses to different inhibitors in rat and mouse liver microsomes, suggesting that different key isozyme(s) or combinations might be responsible for the deacetylation of isoline. Isoline injected i.p. into mice induced liver-specific toxicity that was much greater than that with either clivorine or monocrotaline, as judged by histopathology as well as serum alanine aminotransferase and aspartate aminotransferase levels. Isoline-induced hepatotoxicity was remarkably enhanced by the esterase inhibitor TOCP but was reduced by the P450 inhibitor SKF 525A, indicating that rodent hepatic esterase(s) played a principal role in the detoxification of isoline via rapid deacetylation in vivo.

show abstract

pH‐Controlled Reversible Formation of a Supramolecular Hyperbranched Polymer Showing Fluorescence Switching

Wang

Guo

et al. 2013

Chemistry A European J

View full text Add to dashboard Cite

A π-conjugated AB2 monomer 1 with a dibenzo[24]crown-8 (DB24C8) ring and two secondary amine centres has been synthesised. Treatment of a solution of 1 in dichloromethane with trifluoroacetic acid (TFA) leads to protonation of the amine groups, and then the DB24C8 rings are threaded by the dialkylammonium ion centres of other monomer molecules, leading to the formation of a supramolecular hyperbranched polymer, TFA-1. Rather strong π-π stacking interactions between the conjugated cores are evident in this polymer. The supramolecular hyperbranched polymer (SHP) can be completely depolymerised by adding a slight excess of N-tert-butyl-N',N',N'',N'',N''',N'''-hexamethylphosphorimidic triamide, tetrabutylammonium fluoride, or tetrabutylammonium acetate. The acid-base-controlled process induces a reversible change in the fluorescence intensities of the solutions due to the controllable presence of the π-π stacking interactions between the conjugated cores. This dynamic behaviour is significant with respect to "smart" supramolecular polymer materials.

show abstract

Deacetylclivorine: A Gender-Selective Metabolite of Clivorine Formed in Female Sprague-Dawley Rat Liver Microsomes

Cited by 83 publications

References 30 publications

Scientific Opinion on Pyrrolizidine alkaloids in food and feed

Scientific Opinion on Pyrrolizidine alkaloids in food and feed

In Vitro Metabolism of Isoline, a Pyrrolizidine Alkaloid fromLigularia duciformis, by Rodent Liver Microsomal Esterase and Enhanced Hepatotoxicity by Esterase Inhibitors

pH‐Controlled Reversible Formation of a Supramolecular Hyperbranched Polymer Showing Fluorescence Switching

Contact Info

Product

Resources

About