scholarly journals Further Evidence on the Intramolecular Lactonization in Rat Liver Microsomal Metabolism of 12-O-acetylated Retronecine-type Pyrrolizidine Alkaloids

2013 ◽  
Vol 8 (11) ◽  
pp. 1934578X1300801 ◽  
Author(s):  
Jun Tang ◽  
Zhengtao Wang ◽  
Teruaki Akao ◽  
Masao Hattori
Keyword(s):  
Physical Properties ◽  
Spectral Data ◽  
Rat Liver ◽  
Pyrrolizidine Alkaloids ◽  
Pyrrolizidine Alkaloid ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
Microsomal Metabolism ◽  
Chromatographic Methods ◽  
Transformation Pathway

We have previously found evidence of intramolecular lactonization in rat liver microsomal metabolism of isoline, a 12- O-acetylated pyrrolizidine alkaloid. In this study, the metabolism of another 12- O-acetylated pyrrolizidine alkaloid, acetylduciformine, by the proposed transformation pathway was investigated under the same incubation conditions. Two deacetylated metabolites from acetylduciformine were isolated and purified by chromatographic methods, and further characterized based on their physical properties and spectral data. One metabolite (lankongensisine A) was the lactone of another one (duciformine). Both compounds were first obtained as hydrolyzed metabolites from acetylduciformine by rat liver microsomes. More importantly, the present study provided further evidence for the intramolecular lactonization in the microsomal metabolism of 12- O-acetylated retronecine-type PAs.

scholarly journals The effects of unsaturated fatty acids on hepatic microsomal drug metabolism and cytochrome P-450

1969 ◽  
Vol 115 (3) ◽  
pp. 547-554 ◽  
Author(s):  
Richard P. Di Augustine ◽  
James R. Fouts
Keyword(s):  
Fatty Acids ◽  
Linoleic Acid ◽  
Rat Liver ◽  
Unsaturated Fatty Acids ◽  
Liver Microsomes ◽  
Type I ◽  
Rat Liver Microsomes ◽  
Microsomal Metabolism ◽  
Nitrobenzoic Acid

1. The effects of unsaturated fatty acids on drug-metabolizing enzymes in vitro were measured by using rat and rabbit hepatic 9000g supernatant fractions. 2. Unsaturated fatty acids inhibited the hepatic microsomal metabolism of ‘type I’ drugs with inhibition increasing with unsaturation: arachidonic acid>linolenic acid>linoleic acid>oleic acid. Inhibition was independent of lipid peroxidation. Linoleic acid competitively inhibited the microsomal O-demethylation of p-nitroanisole and the N-demethylation of (+)-benzphetamine. 3. The hepatic microsomal metabolism of ‘type II’ substrates, aniline and (−)-amphetamine, was not affected by unsaturated fatty acids. 4. The rate of reduction of p-nitrobenzoic acid and Neoprontosil was accelerated by unsaturated fatty acids. 5. Linoleic acid up to 3·5mm did not decelerate the generation of NADPH by rat liver soluble fraction, nor the activity of NADPH–cytochrome c reductase of rat liver microsomes. Hepatic microsomal NADPH oxidase activity was slightly enhanced by added linoleic acid. 6. No measurable disappearance of exogenously added linoleic acid occurred when this fatty acid was incubated with rat liver microsomes and an NADPH source. 7. The unsaturated fatty acids used in this study produced type I spectra when added to rat liver microsomes, and affected several microsomal enzyme activities in a manner characteristic of type I ligands.

Metabolic Analysis of Triptolide Microspheres in Human, Dog, Rabbit and Rat Liver Microsomes with UPLC-MS/MS Method

2020 ◽  
Vol 17 ◽  
Author(s):  
LiJuan Wang ◽  
Yan Liu ◽  
Rui Li ◽  
DongXian He
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Internal Standard ◽  
Gradient Elution ◽  
Rat Liver Microsomes ◽  
Good Precision ◽  
Kinetics Parameters ◽  
Measure Concentration ◽  
Standard Curve ◽  
Variation Of Parameters

Objectives: Triptolide (TPL) has been shown to have a good clinical effect on rheumatoid arthritis (RA). We designed TPL microspheres (TPL-MS) and investigated its metabolic behavior in human, dog, rabbit and rat liver microsomes (HLM, DLM, RLM and SDRLM) with UPLC-MS/MS method. Methods: First, a UPLC-MS/MS method was established to measure concentration of TPL in samples. The sample was separated on a C18 column (2.1×100 mm, 1.8μm) and eluted with a gradient elution. The precursor ion/product ion were m/z 378.1/361.0 for TPL and 260.0/116.2 for the internal standard. Then T1/2, Vmax and CLint were calculated from the above data. Finally, the metabolites of TPL-MS were identified by high-resolution UPLC-MS/MS. The sample was separated on a C18 column (2.1×100 mm, 2.2 μm) and eluted with isocratic elution. Mass spectrometric detection was carried out on a thermo Q-exactive mass spectrometer with HESI. The scanning range of precursor ions was from m/z 50 to m/z 750. Result and Discussion: Through several indicators including standard curve, precision, accuracy, stability, matrix effect and recovery rate, the enzymatic kinetics parameters including T1/2, Vmax and CLint were completed. Several metabolites of TPL-MS were identified. Conclusion: UPLC-MS/MS method is an accurate and sensitive method for determination of TPL in liver microsome samples with good precision, accuracy and stability. The variation of parameters indicated that the microspheres can delay the elimination of TPL in liver microsomes. The metabolism of TPL-MS varied among species, but no new metabolites appeared.

scholarly journals The metabolism of gelsevirine in human, pig, goat and rat liver microsomes

2021 ◽  
Author(s):  
Hua‐Hai Zhang ◽  
Wen‐Jia Yang ◽  
Ya‐Jun Huang ◽  
Wen‐Jing Li ◽  
Shuo‐Xin Zhang ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes

scholarly journals Detoxification of the tricyclic antidepressant opipramol and its analog – IS-noh by UGT enzymes before and after activation by phase I enzymes in rat liver microsomes

2021 ◽  
Author(s):  
Anna Mieszkowska ◽  
Koleta Hemine ◽  
Anna Skwierawska ◽  
Ewa Augustin ◽  
Zofia Mazerska
Keyword(s):  
Phase I ◽  
Rat Liver ◽  
Phase Ii ◽  
Oxidation Product ◽  
Liver Microsomes ◽  
Correct Selection ◽  
Rat Liver Microsomes ◽  
Recombinant Enzymes ◽  
Data Set ◽  
Phase I Enzymes

AbstractThe present studies were carried out to evaluate the simultaneous one-pot metabolism of opipramol (IS-opi) and analog (IS-noh) by phase I and phase II enzymes present in rat liver microsomes (RLM) as an alternative to separate testing with recombinant enzymes. This approach allows for more time-saving and cost-effective screening of the metabolism of newly discovered drugs. We also considered that the lack of results for phase II, including UGT, often creates problems in correct selection of valuable compounds. Moreover, microsomes data set is richer in the contest and provides medical scientist to determine also the susceptibility of drugs to undergo phase I and then phase II. In the present work, we have shown that IS-noh was metabolized in vitro by phase I enzymes to the oxidation product, which was next transformed with UGTs to glucuronide. The results showed also that the previously known oxidation product of opipramol was changed to previously no reported glucuronidation product by UDP-glucuronosyltransferases. In addition, unlike IS-noh, opipramol did not prove to be the substrate for UGTs. Therefore, tricyclic antidepressants depending on the structure can trigger a different response after contact with UGT enzymes. Some will metabolize directly with UGTs, others only after activation by phase I enzymes.

scholarly journals Oxidation of docosahexaenoic acid by rat liver microsomes.

1984 ◽  
Vol 259 (9) ◽  
pp. 5776-5783 ◽  
Author(s):  
M VanRollins ◽  
R C Baker ◽  
H W Sprecher ◽  
R C Murphy
Keyword(s):  
Docosahexaenoic Acid ◽  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes
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