The sex-based differences between the effects of two novel sugar-based drug candidates,a sulfated polymannuroguluronate(SPMG-911)and an acidic oligosaccharide sugar chain compound(AOSC-971),on the enzymes CYP 1A2,CYP2...The sex-based differences between the effects of two novel sugar-based drug candidates,a sulfated polymannuroguluronate(SPMG-911)and an acidic oligosaccharide sugar chain compound(AOSC-971),on the enzymes CYP 1A2,CYP2E1 and CYP3A4 of Chinese human liver microsome were investigated.The results showed that neither SPMG-911 nor AOSC-971 have any effect on CYP3A4,AOSC-971 induced the CYP 2E1 in men but have no effect on CYP1A2,SPMG-911 inhibit the CYP1A2 also in men but have no effect on CYP2E1.The results are useful for their safety evaluation,as well as for the prediction of inter-drug interactions associated with the two drugs.展开更多
Objective To determine whether the cytochrome P4502B6(CYP2B6)is involved in the oxidation of propofol by human liver microsomes.Methods The change of propofol concentration in an incubation mixture with human liver mi...Objective To determine whether the cytochrome P4502B6(CYP2B6)is involved in the oxidation of propofol by human liver microsomes.Methods The change of propofol concentration in an incubation mixture with human liver microsomes was monitored by the high performance liquid chromatography(HPLC),in order to calculate the rate constants of metabolism of propofol.The correlation between the rate constants and the rate of metabolism of CYP2B6 selective substrate bupropion,and the effect of two different CYP2B6 specific inhibitors on the propofol metabolism were examined.Results The mean rate constant of propofol metabolism by liver microsomes obtained from twelve individuals was 3.9(95% confidence intervals 3.3,4.5)nmol·min-1·mg-1 protein.The rate constants of propofol metabolism by liver microsomes were significantly correlated with bupropion hydroxylation(r=0.888,P<0.001).Both selective chemical inhibitors of CYP2B6,orphenadrine and N,N',N″-triethylenethiophosphoramide(thioTEPA),reduced the rate constants of propofol metabolism by 37.5%(P<0.001)and 42.7%(P<0.001)in liver microsomes,respectively.Conclusions CYP2B6 is predominantly involved in the oxidation of propofol by human liver microsomes.展开更多
Background: T-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 to...Background: T-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 toxin, we investigated the role of two principal phase Ⅰ drug-metabolizing enzymes(cytochrome P450 [CYP450] enzymes) on the metabolism of T-2 toxin, which are crucial to the metabolism of endogenous substances and xenobiotics. We also investigated carboxylesterase, which also plays an important role in the metabolism of toxic substances.Methods: A chemical inhibition method and a recombinant method were employed to investigate the metabolism of the T-2 toxin by the CYP450 enzymes, and a chemical inhibition method was used to study carboxylesterase metabolism. Samples incubated with human liver microsomes were analyzed by high performance liquid chromatography-triple quadrupole mass spectrometry(HPLC- Qq Q MS) after a simple pretreatment.Results: In the presence of a carboxylesterase inhibitor, only 20% T-2 toxin was metabolized. When CYP enzyme inhibitors and a carboxylesterase inhibitor were both present, only 3% of the T-2 toxin was metabolized. The contributions of the CYP450 enzyme family to T-2 toxin metabolism followed the descending order CYP3A4, CYP2E1, CYP1A2, CYP2B6 or CYP2D6 or CYP2C19.Conclusions: Carboxylesterase and CYP450 enzymes are of great importance in T-2 toxin metabolism, in which carboxylesterase is predominant and CYP450 has a subordinate role. CYP3A4 is the principal member of the CYP450 enzyme family responsible for T-2 toxin metabolism. The metabolite produced by carboxylesterase is HT-2, and the metabolite produced by CYP 3A4 is 3'-OH T-2. The different metabolites show different toxicities. Our results will provide useful data concerning the toxic mechanism, the safety evaluation, and the health risk assessment of T-2 toxin.展开更多
The dynamic changes of liver microsomal drug-metabolizing system (MDMS) andlipoperoxidation were studied in scalded rats. The effects of treatment with vitamin E and silybinwere also evaluated. The results showeed tha...The dynamic changes of liver microsomal drug-metabolizing system (MDMS) andlipoperoxidation were studied in scalded rats. The effects of treatment with vitamin E and silybinwere also evaluated. The results showeed that liver microsomal cytochrome P-450 content, and p-nitroanisole demethylase (P-NOD) and aniline hydroxylase (AH) activity decreased markedlypostburn. On the contrary, liver lipoperoxide and mierosomal lipoperoxidation increased significantlyafter scalding. Both the increase of liver lipoperoxide and mierosomal lipoperoxidation and the de-crease of MDMS activity were prevented by vitamin E and silybin treatments.展开更多
文摘The sex-based differences between the effects of two novel sugar-based drug candidates,a sulfated polymannuroguluronate(SPMG-911)and an acidic oligosaccharide sugar chain compound(AOSC-971),on the enzymes CYP 1A2,CYP2E1 and CYP3A4 of Chinese human liver microsome were investigated.The results showed that neither SPMG-911 nor AOSC-971 have any effect on CYP3A4,AOSC-971 induced the CYP 2E1 in men but have no effect on CYP1A2,SPMG-911 inhibit the CYP1A2 also in men but have no effect on CYP2E1.The results are useful for their safety evaluation,as well as for the prediction of inter-drug interactions associated with the two drugs.
文摘Objective To determine whether the cytochrome P4502B6(CYP2B6)is involved in the oxidation of propofol by human liver microsomes.Methods The change of propofol concentration in an incubation mixture with human liver microsomes was monitored by the high performance liquid chromatography(HPLC),in order to calculate the rate constants of metabolism of propofol.The correlation between the rate constants and the rate of metabolism of CYP2B6 selective substrate bupropion,and the effect of two different CYP2B6 specific inhibitors on the propofol metabolism were examined.Results The mean rate constant of propofol metabolism by liver microsomes obtained from twelve individuals was 3.9(95% confidence intervals 3.3,4.5)nmol·min-1·mg-1 protein.The rate constants of propofol metabolism by liver microsomes were significantly correlated with bupropion hydroxylation(r=0.888,P<0.001).Both selective chemical inhibitors of CYP2B6,orphenadrine and N,N',N″-triethylenethiophosphoramide(thioTEPA),reduced the rate constants of propofol metabolism by 37.5%(P<0.001)and 42.7%(P<0.001)in liver microsomes,respectively.Conclusions CYP2B6 is predominantly involved in the oxidation of propofol by human liver microsomes.
基金supported by the Key Projects in the National Science & Technology Pillar Program of China (2011BAK10B07)the National Major Special Projects in the Ministry of Science and Technology of China (2012 2X09301003-001-010)
文摘Background: T-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 toxin, we investigated the role of two principal phase Ⅰ drug-metabolizing enzymes(cytochrome P450 [CYP450] enzymes) on the metabolism of T-2 toxin, which are crucial to the metabolism of endogenous substances and xenobiotics. We also investigated carboxylesterase, which also plays an important role in the metabolism of toxic substances.Methods: A chemical inhibition method and a recombinant method were employed to investigate the metabolism of the T-2 toxin by the CYP450 enzymes, and a chemical inhibition method was used to study carboxylesterase metabolism. Samples incubated with human liver microsomes were analyzed by high performance liquid chromatography-triple quadrupole mass spectrometry(HPLC- Qq Q MS) after a simple pretreatment.Results: In the presence of a carboxylesterase inhibitor, only 20% T-2 toxin was metabolized. When CYP enzyme inhibitors and a carboxylesterase inhibitor were both present, only 3% of the T-2 toxin was metabolized. The contributions of the CYP450 enzyme family to T-2 toxin metabolism followed the descending order CYP3A4, CYP2E1, CYP1A2, CYP2B6 or CYP2D6 or CYP2C19.Conclusions: Carboxylesterase and CYP450 enzymes are of great importance in T-2 toxin metabolism, in which carboxylesterase is predominant and CYP450 has a subordinate role. CYP3A4 is the principal member of the CYP450 enzyme family responsible for T-2 toxin metabolism. The metabolite produced by carboxylesterase is HT-2, and the metabolite produced by CYP 3A4 is 3'-OH T-2. The different metabolites show different toxicities. Our results will provide useful data concerning the toxic mechanism, the safety evaluation, and the health risk assessment of T-2 toxin.
文摘The dynamic changes of liver microsomal drug-metabolizing system (MDMS) andlipoperoxidation were studied in scalded rats. The effects of treatment with vitamin E and silybinwere also evaluated. The results showeed that liver microsomal cytochrome P-450 content, and p-nitroanisole demethylase (P-NOD) and aniline hydroxylase (AH) activity decreased markedlypostburn. On the contrary, liver lipoperoxide and mierosomal lipoperoxidation increased significantlyafter scalding. Both the increase of liver lipoperoxide and mierosomal lipoperoxidation and the de-crease of MDMS activity were prevented by vitamin E and silybin treatments.
