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121.
Jian Y.Chen L.Yuan M.Zhuang X.-M.Li H. 《中国药理学与毒理学杂志》2016,(8):848-854
OBJECTIVE: To investigate enzyme kinetic characteristics of imperatorin in rat liver microsomes (RLM) or human liver microsomes (HLM), and to identify the reaction phenotyping of human recombinant cytochrome P450 enzyme (CYP) mediated phase I metabolism. METHODS: Imperatorin was incubated at 37°C with HLM or RLM in the presence or absence of nicotinamide adenine dinucleotide phosphate (NADPH) or uridine 5'-diphosphoglucuronic acid (UDGPA). The concentrations of imperatorin in the incubation systems were determined with LC-MS/MS to evaluate its metabolic stability and enzymatic kinetics. The CYP phenotyping of imperatorin was identified using a panel of human recombinant CYP isoforms (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and also using a group of specific inhibitors in HLM. RESULTS: Imperatorin was metabolically eliminated in the presence of NADPH in HLM or RLM. The elimination rates for HLM and RLM in 30 min were 69.7% and 94.5%, respectively, and elimination half-life (t1/2) values were 18.9±0.6 and (2.8±0.4)min, respectively. The extrapolated hepatic clearance parameters (Clh) were 16.9±0.1 and (51.9±0.4)mL·min-1-kg-1. The Michaelism-Menten parameters (Km) were 13.60±0.16 and (14.00± 0.24)umol·L-1 and maximum velocity (Vmax) were (2928±96) and (8434±27)nmol·min-1·g-1, respectively. The metabolic elimination of imperatorin in RLM was quicker than in HLM. The results of CYP phenotyping indicated that CYP1A2, CYP2B6, CYP2C19 and CYP3A4 were the major CYP isoforms involved in the imperatorin metabolism. Their individual contributions assessed using the method of total normalized rate were 20.4%, 7.3%,10.5% and 61.8%, respectively. CONCLUSION: Imperatorin is mainly eliminated by CYP mediated metabolism in HLM and RLM. CYP1A2 and CYP3A4 are the major responsible enzymes with a contribution rate above 20%. 相似文献
122.
为评价氧氟沙星(OFLX)对映体葡醛酸化代谢的立体选择性,采用手性HPLC法测定大鼠肝微粒体孵育液中OFLX对映体. 结果显示:经苯巴比妥(PB)和β-萘黄酮(BNF)诱导的不同葡醛酸转移酶(UDPGT)亚族对OFLX对映体葡醛酸化代谢有不同的影响. 在所试验的对照,PB或BNF诱导的微粒体中S-(-)-和R-(+)-OFLX之间,Km和Vmax无显著性差异;但PB组中S- (-)-和R-(+)-OFLX的Km和Vmax与对照组或BNF组相应的对映体比较有显著性差异;OFLX对映体之间的Clint在对照组与BNF组没有显著性差异;而在PB组则有显著性差异. 另外BNF组的Clint较对照组和PB组分别有显著性差异. 因此,经PB诱导的UDPGT亚族对S-和R-OFLX的Ⅱ相代谢存在立体选择性,并主要是由于其催化部位的差异引起了内在清除率的变化. 相似文献
123.
Nakajima A Fukami T Kobayashi Y Watanabe A Nakajima M Yokoi T 《Biochemical pharmacology》2011,(11):1747-1756
Rifamycins such as rifampicin, rifabutin, and rifapentine are used for the treatment of tuberculosis and induce various drug-metabolizing enzymes. Rifamycins have been reported to be mainly deacetylated by esterase(s) expressed in human liver microsomes (HLM) to 25-deacetylrifamycins, but the responsible enzyme remained to be determined. In this study, we found that recombinant human arylacetamide deacetylase (AADAC) could efficiently deacetylate rifamycins, whereas human carboxylesterases, which are enzymes responsible for the hydrolysis of many prodrugs, showed no activity. The involvement of AADAC in the deacetylation of rifamycins in HLM was verified by the similarities of the Km and Ki values and the inhibitory characteristics between recombinant AADAC and HLM. Rifamycins exhibited potent cytotoxicity to HepG2 cells, but their 25-deacetylated metabolites did not. Luciferase assay using a reporter plasmid containing CYP3A4 direct repeat 3 and everted repeat 6 motifs revealed that 25-deacetylrifamycins have lesser potency to transactivate CYP3A4 compared with the parent drugs. Supporting these results, HepG2 cells infected with a recombinant adenovirus expressing human AADAC showed low cytotoxicity and induction potency of CYP3A4 by rifamycins. In addition, CYP3A4 induction in human hepatocytes by rifamycins was increased by transfecting siRNA for human AADAC. Thus, we found that human AADAC was the enzyme responsible for the deacetylation of rifamycins and would affect the induction rate of drug-metabolizing enzymes by rifamycins and their induced hepatotoxicity. 相似文献
124.
The extreme sensitivity of turkeys to aflatoxin B1 (AFB1) is associated with efficient epoxidation by hepatic cytochromes P450 (P450) 1A5 and 3A37 to exo-aflatoxin B1-8,9-epoxide (exo-AFBO). The combined presence of 1A5 and 3A37, which obey different kinetic models, both of which metabolize AFB1 to the exo-AFBO and to detoxification products aflatoxin M1 (AFM1) and aflatoxin Q1 (AFQ1), respectively, complicates the kinetic analysis of AFB1 in turkey liver microsomes (TLMs). Antisera directed against 1A5 and 3A37, thereby individually removing the catalytic contribution of these enzymes, were used to identify the P450 responsible for epoxidating AFB1 in TLMs. In control TLMs, AFB1 was converted to exo-AFBO in addition to AFM1 and AFQ1 confirming the presence of functional 1A5 and 3A37. Pretreatment with anti-1A5 inhibited exo-AFBO formation, especially at low, submicromolar (~ 0.1 μM), while anti-3A37, resulted in inhibition of exo-AFBO formation, but at higher (> 50 μM) AFB1 concentrations. Metabolism in immunoinhibited TLMs resembled that of individual enzymes: 1A5 produced exo-AFBO and AFM1, conforming to Michaelis-Menten, while 3A37 produced exo-AFBO and AFQ1 following the kinetic Hill equation. At 0.1 μM AFB1, close to concentrations in livers of exposed animals, 1A5 contributed to 98% of the total exo-AFBO formation. At this concentration, 1A5 accounted for a higher activation:detoxification (50:1, exo-AFBO: AFM1) compared to 3A37 (0.15: 1, exo-AFBO: AFQ1), suggesting that 1A5 is high, while 3A4 is the low affinity enzyme in turkey liver. The data support the conclusion that P450 1A5 is the dominant enzyme responsible for AFB1 bioactivation and metabolism at environmentally-relevant AFB1 concentrations in turkey liver. 相似文献
125.
Kaoru Kobayashi Eri Kajiwara Masayuki Ishikawa Hidenobu Oka Kan Chiba 《Biopharmaceutics & drug disposition》2012,33(8):466-473
Benzbromarone (BBR) is metabolized to 1′‐hydroxy BBR and 6‐hydroxy BBR in the liver. 6‐Hydroxy BBR is further metabolized to 5,6‐dihydroxy BBR. The aim of this study was to identify the CYP isozymes involved in the metabolism of BBR to 1′‐hydroxy BBR and 6‐hydroxy BBR and in the metabolism of 6‐hydroxy BBR to 5,6‐dihydroxy BBR in human liver microsomes. Among 11 recombinant P450 isozymes examined, CYP3A4 showed the highest formation rate of 1′‐hydroxy BBR. The formation rate of 1′‐hydroxy BBR significantly correlated with testosterone 6β‐hydroxylation activity in a panel of 12 human liver microsomes. The formation of 1′‐hydroxy BBR was completely inhibited by ketoconazole in pooled human liver microsomes. On the other hand, the highest formation rate of 6‐hydroxy BBR was found in recombinant CYP2C9. The highest correlation was observed between the formation rate of 6‐hydroxy BBR and diclofenac 4′‐hydroxylation activity in 12 human liver microsomes. The formation of 6‐hydroxy BBR was inhibited by tienilic acid in pooled human liver microsomes. The formation of 5,6‐dihydroxy BBR from 6‐hydroxy BBR was catalysed by recombinant CYP2C9 and CYP1A2. The formation rate of 5,6‐dihydroxy BBR was significantly correlated with diclofenac 4′‐hydroxylation activity and phenacetin O‐deethylation activity in 12 human liver microsomes. The formation of 5,6‐dihydroxy BBR was inhibited with either tienilic acid or α‐naphthoflavone in human liver microsomes. These results suggest that (i) the formation of 1′‐hydroxy BBR and 6‐hydroxy BBR is mainly catalysed by CYP3A4 and CYP2C9, respectively, and (ii) the formation of 5,6‐dihydroxy BBR is catalysed by CYP2C9 and CYP1A2 in human liver microsomes. Copyright © 2012 John Wiley & Sons, Ltd. 相似文献
126.
Background: Numerous studies have explored the etiologic or permissive role of 11β‐hydroxysteroid dehydrogenase (11β‐HSD1) in obesity and Type 2 diabetes, biochemical conditions often with concurrent hyperinsulinism. In contrast, there are limited data on the effect of insulin deficiency (i.e. Type 1 diabetes) on 11β‐HSD1 or endoplasmic reticulum enzymes that generate the reduced pyridine cofactor NADPH. Thus, the aim of the present study was to examine the effect of insulin‐deficient, streptozotozin diabetes on key microsomal enzymes involved in rat hepatic corticosterone production. Methods: After rats had been rendered diabetic with streptozotocin and some had been treated with insulin (2–6 units, s.c., long‐acting insulin once daily) for 7 days, hepatic microsomes were isolated. Serum corticosterone and fructosamine were obtained premortem. Intact microsomes were incubated in vitro and 11β‐HSD1, hexose‐6‐phosphate dehydrogenase (H6PDH), and isocitrate dehydrogenase (IDH) measured. Results: Although diabetes markedly altered body weight gain and serum protein glycosylation (assessed by fructosamine), there was no significant change in hepatic 11β‐HSD1 reductase activity, with or without insulin treatment. However, serum corticosterone levels were significantly correlated with 11β‐HSD1 reductase activity when all groups were analyzed together (P < 0.05). Untreated diabetes modified (P < 0.01) two hepatic microsomal NADPH‐generating enzymes, namely H6PDH and IDH, resulting in a 37% decrease and 14% increase in enzyme levels, respectively. Conclusions: Consistent with most in vivo studies, chronic insulin deficiency with attendant hyperglycemia does not significantly modify hepatic 11β‐HSD1 reductase activity, but does alter the activity of two microsomal enzymes coupled with pyridine cofactors. 相似文献
127.
The specific CYP enzymes involved in kavalactone (KLT) metabolism and their kinetics have not been fully examined. This study used rat liver microsomes (RLM) to determine kavain (KA), methysticin (MTS) and desmethoxyyangonin (DMY) enzyme kinetic parameters, to elucidate the major CYP450 isoforms involved in KLT metabolism and to examine gender differences in KLT metabolism. Formation of the major KLT metabolites was first‐order, consistent with classic enzyme kinetics. In both male and female RLM, clotrimazole (CLO) was the most potent inhibitor of KA and MTS metabolism. This suggests CYP3A1/3A23 (females) and CYP3A2 (males) are the main isoenzymes involved in the metabolism of these KLTs in rats, while the roles of CYP1A2, ‐2 C6, ‐2 C9, ‐2E1 and ‐3A4 are limited. Desmethoxyyangonin metabolism was equally inhibited by cimetidine (CIM) and CLO in females, and CIM and nortriptyline in males. This implies that DMY metabolism involves CYP2C6 and CYP2C11 in males, and CPY2C12 in females. CYP3A1/3A23 may also be involved in females. Copyright © 2011 John Wiley & Sons, Ltd. 相似文献
128.
Evodiamine is the main active alkaloid of Evodia rutaecarpa (E. rutaecarpa) and has been demonstrated to exhibit many pharmacological activities including vasorelaxation, uterotonic action, anoxia and control of body temperature. The present study focused on the metabolism of evodiamine. Human and phenobarbital‐induced rat liver microsomal incubation of evodiamine in the presence of NADPH resulted in the formation of five major metabolites (M‐1, M‐2, M‐3, M‐4, M‐5). Four metabolites (M‐1, M‐2, M‐3 and M‐5) were identified to mono‐hydroxylated evodiamine and one metabolite (M‐4) was identified to be N‐demethylated evodiamine. CYP3A4, CYP2C9 and CYP1A2 were identified to be the main CYP isoforms involved in the metabolism of evodiamine in human liver microsomes. Finding new metabolites can help us decipher novel substance basis of efficiency and toxicity. Elucidation of drug metabolizing enzymes will facilitate explaining the individual difference for response to the same drugs or herbs and the potential drug–drug interaction or herb–drug interaction. Taken together, these results are of significance for better understanding the pharmacokinetic behaviour of evodiamine and helpful for clinical application of evodiamine and E. rutaecarpa. Copyright © 2012 John Wiley & Sons, Ltd. 相似文献
129.
羟基芫花素对UGTs及UGT1A1活性抑制作用种属差异的体外研究 总被引:1,自引:0,他引:1
考察羟基芫花素对尿苷二磷酸葡萄糖醛酸转移酶(UGTs)及UGT1A1活性的影响,为预测其与其他药物的代谢性相互作用提供理论借鉴。该实验采用体外肝微粒体孵育模型,以4-硝基酚(4-NP)为底物检测UGTs活性;β-雌二醇为底物检测UGT1A1活性,利用UV和HPLC测定底物或代谢物含量。结果表明,在大鼠、小鼠和人肝微粒体(HLM)孵育体系,羟基芫花素能显著抑制UGTs活性;对UGT1A1,在小鼠肝微粒体(MLM)孵育体系中,羟基芫花素几乎无抑制作用(IC50=190μmol·L-1);在大鼠肝微粒体(RLM)和重组酶(r UGT1A1)孵育体系中,羟基芫花素表现为中等强度的抑制作用(IC50=10.93,20.07μmol·L-1),抑制类型分别为竞争性抑制和线性混合型抑制;在HLM孵育体系中,羟基芫花素表现为弱抑制作用(IC50=76.31μmol·L-1),抑制类型为竞争性抑制;其抑制强弱顺序为RLMr UGT1A1HLMMLM。综上,羟基芫花素对不同肝微粒体孵育体系中UGTs及UGT1A1活性均可产生抑制作用且存在种属差异性,提示羟基芫花素可能存在基于UGT1A1酶的药物相互作用。该研究可为合理开发利用羟基芫花素提供实验依据,并为研究药物在临床上的联合用药提供理论借鉴。 相似文献
130.
为探讨黄连与其他药物代谢性相互作用的机制,对6种黄连生物碱与尿苷二磷酸葡萄糖醛酸转移酶(UGTs)及UGT1A1的相互作用进行了考察。采用大小鼠肝微粒体,以及生物碱小鼠体内诱导后的肝微粒体,构建微粒体体外孵育模型,以4-硝基酚(4-NP)为底物检测UGTs活性,β-雌二醇为底物检测UGT1A1活性,利用UV和HPLC测定底物或代谢物含量。结果,在大鼠体外实验中,小檗碱、表小檗碱、黄连碱及药根碱均能显著抑制UGTs活性,其中表小檗碱抑制作用最强;对UGT1A1,药根碱表现为弱的抑制作用(IC50≈227μmol·L-1),而黄连碱和巴马汀则呈显著的激活作用。小鼠体外实验中,小檗碱、黄连碱、药根碱和巴马汀对UGTs均呈显著的抑制作用;而6种生物碱对UGT1A1均表现为显著的激活作用。小鼠体内诱导实验中,只有小檗碱对UGTs,药根碱对UGT1A1活性呈现显著升高作用,其他生物碱的作用不明显。综上,黄连生物碱在对UGT的作用上显示出明显的种属和体内外的差异,同时生物碱结构的变化对UGT活性也会产生较大的影响,这种影响可能是黄连与其他药物发生代谢性相互作用的原因之一。 相似文献