Alteration of phospholipid composition of mouse liver microsomes in vivo and the effect on membrane properties

1982 ◽  
Vol 688 (2) ◽  
pp. 667-670 ◽  
Author(s):  
Denis M. Boyle ◽  
William L. Dean
Keyword(s):  
Mouse Liver ◽  
Liver Microsomes ◽  
Phospholipid Composition ◽  
Membrane Properties

scholarly journals Metabolic Stability and Metabolite Characterization of Capilliposide B and Capilliposide C by LC–QTRAP–MS/MS

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 178 ◽  
Author(s):  
Zhongzhe Cheng ◽  
Xing Zhou ◽  
Zhifeng Du ◽  
Wenyi Li ◽  
Bingying Hu ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Species Difference ◽  
Liver Microsomes ◽  
Metabolic Stability ◽  
Rat Liver Microsomes ◽  
Triterpenoid Saponins ◽  
Additional Information

Capilliposide B (LC-B) and Capilliposide C (LC-C), two new triterpenoid saponins extracted from Lysimachia capillipes Hemsl, exhibit potential anticancer activity both in vitro and in vivo. However, their metabolic process remains unclear. In this study, the metabolic stability of LC-B, LC-C, and Capilliposide A (LC-A, a bioactive metabolite of LC-B and LC-C) was investigated in human, rat, and mouse liver microsomes, respectively. Thereafter, their metabolites were identified and characterized after oral administration in mice. As a result, species difference was found in the metabolic stability of LC-B and LC-C. All three compounds of interest were stable in human and rat liver microsomes, but LC-B and LC-C significantly degraded in mouse liver microsomes. The metabolic instability of LC-B and LC-C was mainly caused by esterolysis. Moreover, 19 metabolites were identified and characterized in mouse biological matrices. LC-B and LC-C mainly underwent deglycosylation and esterolysis, accompanied by dehydration, dehydrogenation, and hydroxylation as minor metabolic reactions. Finally, the metabolic pathway of LC-B and LC-C in mice was proposed. Our results updated the preclinical metabolism and disposition process of LC-B and LC-C, which provided additional information for better understanding efficacy and safety.

In vivo and in vitro effects of pentavalent antimony on mouse liver cytochrome P450s

2016 ◽  
Vol 36 (1) ◽  
pp. 33-41 ◽  
Author(s):  
DR Coelho ◽  
ACAX De-Oliveira ◽  
TEM Parente ◽  
BS Leal ◽  
LF das Chagas ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Mouse Liver ◽  
Liver Microsomes ◽  
Mrna Levels ◽  
Intact Cells ◽  
Cyp1a Activity ◽  
In Vitro Effects ◽  
Catalyzed Reactions

Pentavalent antimonial (Sb5+) drugs such as meglumine antimoniate (MA) are the mainstay treatment of leishmaniases in developing countries. The effects of these compounds on drug-metabolizing enzymes have not been characterized and their potential pharmacokinetic interactions with other drugs are therefore unknown. The present study investigated whether treatment with MA (300 mg Sb5+/kg body weight/day, subcutaneously) for 24 days affected the activities of cytochrome P450 (CYP)1A (ethoxyresorufin- O-deethylase), CYP2A5 (coumarin 7-hydroxylase), CYP2E1 ( p-nitrophenol-hydroxylase), CYP2B9/10 (benzyloxy-resorufin- O-debenzylase), or CYP3A11 (erythromycin- N-demethylase) in the livers of Swiss Webster (SW) and DBA-2 male and female mice. The results showed that CYP2A5-, CYP2E1-, and CYP3A11-catalyzed reactions were unaffected by MA treatment. A decrease in CYP2B9/10 activity was noted in DBA-2 females (but not males) and was not observed in SW males or females. However, repeated MA administration reduced mouse liver CYP1A activity. CYP1A2 messenger RNA (mRNA) levels were not affected by MA and in vitro exposure of mouse liver microsomes to Sb3+ and Sb5+ did not reduce CYP1A activity. These findings suggested that in vivo treatment with Sb5+ drugs depressed CYP1A activity, without downregulating CYP1A2 mRNA expression. Since in vitro treatment of liver microsomes failed to inhibit CYP1A activity, this effect may require intact cells.

Comprehensive Analysis of in Vivo Phosphoproteome of Mouse Liver Microsomes

2015 ◽  
Vol 14 (12) ◽  
pp. 5215-5224
Author(s):  
Oh Kwang Kwon ◽  
JuHee Sim ◽  
Sun Ju Kim ◽  
Eunji Sung ◽  
Jin Young Kim ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Liver Microsomes ◽  
Comprehensive Analysis

scholarly journals Metabolism of JQ1, an inhibitor of bromodomain and extra terminal bromodomain proteins, in human and mouse liver microsomes†

2020 ◽  
Vol 103 (2) ◽  
pp. 427-436 ◽  
Author(s):  
Feng Li ◽  
Kevin R MacKenzie ◽  
Prashi Jain ◽  
Conrad Santini ◽  
Damian W Young ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Half Life ◽  
Mouse Liver ◽  
Liver Microsomes ◽  
Drug Efficacy ◽  
Specific Protein ◽  
Contraceptive Effect ◽  
Human And Mouse

Abstract JQ1 is a small-molecule inhibitor of the bromodomain and extra terminal (BET) protein family that potently inhibits the bromodomain testis-specific protein (BRDT), which is essential for spermatogenesis. JQ1 treatment produces a reversible contraceptive effect by targeting the activity of BRDT in mouse male germ cells, validating BRDT as a male contraceptive target. Although JQ1 possesses favourable physical properties, it exhibits a short half-life. Because the details of xenobiotic metabolism play important roles in the optimization of drug candidates and in determining the role of metabolism in drug efficacy, we investigated the metabolism of JQ1 in human and mouse liver microsomes. We present the first comprehensive view of JQ1 metabolism in liver microsomes, distinguishing nine JQ1 metabolites, including three monohydroxylated, one de-tert-butylated, two dihydroxylated, one monohydroxylated/dehydrogenated, one monohydroxylated-de-tert-butylated and one dihydroxylated/dehydrogenated variant of JQ1. The dominant metabolite (M1) in both human and mouse liver microsomes is monohydroxylated on the fused three-ring core. Using recombinant cytochrome P450 (CYP) enzymes, chemical inhibitors and the liver S9 fraction of Cyp3a-null mice, we identify enzymes that contribute to the formation of these metabolites. Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) is the main contributor to the production of JQ1 metabolites in vitro, and the CYP3A4/5 inhibitor ketoconazole strongly inhibits JQ1 metabolism in both human and mouse liver microsomes. Our findings suggest that JQ1 half-life and efficacy might be improved in vivo by co-administration of a selective CYP inhibitor, thereby impacting the use of JQ1 as a probe for BRDT activity in spermatogenesis and as a probe or therapeutic in other systems.

Sign in / Sign up

Export Citation Format

Share Document