喹诺酮药物对异育银鲫P450酶系的影响及3A亚型克隆
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摘要
本论文的研究内容分为两部分：第一部分为2种喹诺酮药物对异育银鲫细胞色素P450的影响。氟甲喹研究其对不同组织中P450各亚型的影响变化；恩诺沙星研究其对P450影响的时间与剂量关系。两种药物试验都从酶活、蛋白和mRNA三个水平结合体外试验进行研究；第二部分为异育银鲫细胞色素P450 3A亚型的克隆及组织表达分布。采用RACE技术获取了全长cDNA序列,运用RT-PCR方法研究了CYP3A mRNA在异育银鲫各组织中的分布。
1.氟甲喹与恩诺沙星对异育银鲫细胞色素P450的影响
异育银鲫以剂量35mg/kg腹腔注射氟甲喹24h后,肝微粒体的7-乙氧基异吩唑酮-O-脱乙基酶(EROD)活性为54.33±5.42 pmol/mg-min,显著高于对照组(34.00±5.87pmol/mg-min)(p<0.01),而红霉素-N-脱甲基酶(ERND)(177.98±32.94 pmol/mg-min)、氨基比林-N-脱甲基酶(APD) (934.40±173.29 pmol/mg-min)及7-乙氧基香豆素-O-脱乙基酶(ECOD) (9.84±3.29 pmol/mg-min)与对照组(分别为140.90±22.89pmol/mg-min、850.71±229.68 pmol/mg·min和8.93±2.77 pmol/mg-min)相比无显著性差异。Western blotting表明,试验组肝脏中CYP1A蛋白含量显著高于对照组(2倍),与酶活(EROD)相符合；肾、肠中没有检测到特异条带。半定量RT-PCR结果显示,CYP1A mRNA在肝、肾和肠均有表达,但试验组与对照组并无显著差异。体外试验中,EROD活性与氟甲喹浓度、时间无依赖关系。综上推测,氟甲喹对异育银鲫肝CYP1A的诱导发生在翻译后水平,是加强蛋白的稳定性。
恩诺沙星10mg/kg腹腔注射对鲫鱼CYP3A依赖的红霉素-N-脱甲基酶(ERND)有显著抑制作用(40%),48h达到最低值(306.93±19.30 pmol/mg-min),8d恢复到给药前水平(496.76±46.04 pmol/mg-min)。对于CYP1A,7-乙氧基异吩唑酮氧脱乙基酶(EROD)活性在24h即达到最大抑制(对照组85.79±6.86 pmol/mg-min/给药组71.50±7.38 pmol/mg-min),但抑制程度不及CYP3A。恩诺沙星使CYP1A蛋白含量随时间增加,而CYP3A蛋白受抑制趋势与其酶活变化相似；半定量RT-PCR显示CYP1A mRNA与CYP3A mRNA在肝脏中的表达与EROD, ERND抑制曲线相符合,分别在24h,48h达到最低值(60%,64%),但8d后均未恢复到对照水平。不同剂量的恩诺沙星3mg/kg、10mg/kg、30mg/kg、60mg/kg)腹腔给药24h后取样结果显示,EROD、ERND活性随给药剂量的增大而降低,最大抑制率分别为48%、52%。Western blotting结果表明,CYP1A蛋白含量在3mg/kg、10mg/kg恩诺沙星组中变化不大,但在30mg/kg、60mg/kg组中下降了约50%。CYP3A蛋白含量在不同剂量的恩诺沙星给药后相比对照组无明显变化。CYP1A mRNA在肝脏中的表达与EROD抑制曲线相符合,而CYP3A mRNA表达水平无明显变化。体外试验中,恩诺沙星显示出对CYP3A蛋白的机理性抑制,而对代表CYP1A的EROD活性则没有影响。综上结果说明恩诺沙星对CYP1A的抑制发生在体内水平,而对CYP3A的抑制是体内与体外水平综合的结果,在体外还存在对蛋白的机理性抑制。
2.异育银鲫细胞色素P450 3A亚型的克隆及组织表达分布
本试验根据4种鱼类CYP3A同源性序列设计兼并引物,采用RT-PCR和RACE的方法,得到了异育银鲫CYP3A全长cDNA序列。基因全长1770bp,5’端非编码区30bp,3’端非编码区195bp,开放阅读框1545bp,编码515个氨基酸。序列分析表明异育银鲫CYP3A氨基酸序列与人、小鼠、大鼠的相似性为73%-75%,与稀有鮈鲫的相似性为92%。进化树分析显示异育银鲫CYP3A氨基酸序列与鲤科鱼类同源性较高,而与其它物种遗传距离较远。利用半定量RT-PCR方法研究CYP3A在异育银鲫各组织中的表达分布,结果表明CYP3A在肝脏,肠中表达量最高,肾、鳃中次之,其余组织表达较低。
Effect of quinolones on cytochrome P450 in Crucian Carp (Carassius auratus gibelio) and cloning of CYP3A gene Hu Xiao (Aquaculture) Directed by Dr. Wen-hong Fang
The whole dissertation was divided into two parts. Part one was to investigate the effects of two fluoroquinolones, flumequine and enrofloxacin on cytochrome P450 of Crucian Carp(Carassius auratus gibelio). In this part, fish administered with flumequine was used to study the enzymes, protein and mRNA of CYPs in different tissue; In the second group, time course and dose-response of inhibition by enrofloxacin was studied at enzymes, protein and mRNA level. In part two, cloning, sequencing and tissue expression of the cytochrome CYP3A gene in Crucian Carp (Carassius auratus gibelio) was present, using RACE and semiquantitative RT-PCR assay.
1. Effect of flumequine and enrofloxacin on cytochrome P450 in Crucian Carp
The effects of flumequine on microsomal cytochrome P450 monooxygenases in Crucian Carp(Carassius auratus gibelio) were examined during this study. After 24h treatment, flumequine, administered to fish with a single intraperitoneal injection at a dose of 35mg/kg, resulted in a significant induction in the liver of the P4501A-linked ethoxyresorufin-O-deethylase (EROD) activity (54.33±5.42 pmol/mg-min) compared to control values (34.00±5.87 pmol/mg-min) (p<0.01). Erythromycin N-demethylase (ERND), aminopyrine N-demethylase (APD) and ethoxycoumarin O-deethylase (ECOD) were not affected by flumequine. Liver has the highest P450 enzymes activities except for ERND in kidney. Western blotting indicated that CYP1A protein level was induced (about 2 fold), which is consistent with the EROD activity in the experimental group. Semiquantitative RT-PCR analysis showed CYP1A mRNA were all expressed in liver, kidney and intestine, however, there is no significant differences between control and experimental groups. In vitro assay, various concentrations of flumequine were incubated with microsomes, no dose-and time-dependent manner was observed. The lack of induction speculated that flumequine caused an activation of CYP1A, occured at post-translational level, probably by protein stabilisation.
Enrofloxacin exhibited a potent inhibition (40%) on CYP3A-linked erythromycin N-demethylase (ERND) after a single intraperitoneal injection at a dose of 10mg/kg. ERND activity was decreased within 48h (306.93±19.30 pmol/mg·min) and retrun to pre-treatment level at 8d (496.76±46.04 pmol/mg-min). As for CYP1A, ethoxyresorufin-O-deethylase (EROD) activity was maximal inhibited at 24h (85.79±6.86/71.50±7.38 pmol/mg·min, for control and experimental group, respectively), but not as much as that in CYP3A. Enrofloxacin caused a slight increase in CYP1A protein level, while CYP3A protein was markedly decreased in 4d. Semiquantitative RT-PCR analysis showed that CYP1A mRNA and CYP3A mRNA were all decreased at 24h and 48h respectively, but have not returned to control level after 8d. This suggest a long-term inhibition of CYP1A, CYP3A by enrofloxacin. In the dose-response study, different concentrations of enrofloxacin (0mg/kg,3mg/kg,10mg/kg,30mg/kg,60mg/kg) were administered. Fish were sampled 24h after treatment, the results showed a dose-response reduction of hepatic CYP1A and CYP3A activity. The maximal inhibition of EROD and ERND was 48%,52%, respectively. Western blotting indicated that CYP1A protein level was not affect at dose of 3mg/kg,10mg/kg, but was significantly decreased (about 50%) at a higher dose. CYP3A protein content was remain at pre-treatment level after various concentration of enrofloxacin injection. Semiquantitative RT-PCR assay suggested that the changes of CYP1A mRNA is correlated well with that in EROD activity. The content of CYP3A mRNA was still unchanged. In vitro experiment, enrofloxacin, when preincubated with Crucian Carp liver microsomes, inhibited ERND activity in a dose-and time-dependent manner, however, the CYP1A-linked EROD activity was not affected. Taken overall, the inhibition of enrofloxacin on CYP1A probably occured in vivo, while enrofloxacin has been also demonstrated to be a powerful mechanism-based inhibitor primarily of P450 3A isoform in Crucian Carp.
2. Cloning, sequencing and tissue expression of the cytochrome P450 3A gene in Crucian Carp
Degenerate primers derived from conserved CYP3A sequences of four kind of fish were used to clone Crucian Carp CYP3A. A cDNA sequence (GenBank accession number: GU998964) was isolated and identified from the total RNA using RT-PCR and RACE assay. The sequence of CYP3A is 1770bp which contains a 5'UTR of 30bp and 3'UTR of 195bp, and an open reading frame (ORF) with 1545 bp that encodes a protein of 515 amino acids. The amino acid sequence of Crucian Carp shared 73%-75% of residue identity with the CYP3A subfamily in human, mouse and rat, and shared 92% of residue identity with Gobiocypris rarus. Molecular phylogenetic analysis of Crucian Carp CYP3A with other CYP3A forms from mammals and teleosts indicated that Crucian Carp CYP3A amino acid sequence has the highest identity with cyprinid fishes (Cyprinidae). Semiquantitative RT-PCR analysis showed that mRNA expression of CYP3A can be detected in liver, kidney, intestine, gill, muscle and spleen. Liver was found to have the highest CYP3A mRNA expression, followed by intestine, kidney and gill.
1.氟甲喹与恩诺沙星对异育银鲫细胞色素P450的影响
异育银鲫以剂量35mg/kg腹腔注射氟甲喹24h后,肝微粒体的7-乙氧基异吩唑酮-O-脱乙基酶(EROD)活性为54.33±5.42 pmol/mg-min,显著高于对照组(34.00±5.87pmol/mg-min)(p<0.01),而红霉素-N-脱甲基酶(ERND)(177.98±32.94 pmol/mg-min)、氨基比林-N-脱甲基酶(APD) (934.40±173.29 pmol/mg-min)及7-乙氧基香豆素-O-脱乙基酶(ECOD) (9.84±3.29 pmol/mg-min)与对照组(分别为140.90±22.89pmol/mg-min、850.71±229.68 pmol/mg·min和8.93±2.77 pmol/mg-min)相比无显著性差异。Western blotting表明,试验组肝脏中CYP1A蛋白含量显著高于对照组(2倍),与酶活(EROD)相符合；肾、肠中没有检测到特异条带。半定量RT-PCR结果显示,CYP1A mRNA在肝、肾和肠均有表达,但试验组与对照组并无显著差异。体外试验中,EROD活性与氟甲喹浓度、时间无依赖关系。综上推测,氟甲喹对异育银鲫肝CYP1A的诱导发生在翻译后水平,是加强蛋白的稳定性。
恩诺沙星10mg/kg腹腔注射对鲫鱼CYP3A依赖的红霉素-N-脱甲基酶(ERND)有显著抑制作用(40%),48h达到最低值(306.93±19.30 pmol/mg-min),8d恢复到给药前水平(496.76±46.04 pmol/mg-min)。对于CYP1A,7-乙氧基异吩唑酮氧脱乙基酶(EROD)活性在24h即达到最大抑制(对照组85.79±6.86 pmol/mg-min/给药组71.50±7.38 pmol/mg-min),但抑制程度不及CYP3A。恩诺沙星使CYP1A蛋白含量随时间增加,而CYP3A蛋白受抑制趋势与其酶活变化相似；半定量RT-PCR显示CYP1A mRNA与CYP3A mRNA在肝脏中的表达与EROD, ERND抑制曲线相符合,分别在24h,48h达到最低值(60%,64%),但8d后均未恢复到对照水平。不同剂量的恩诺沙星3mg/kg、10mg/kg、30mg/kg、60mg/kg)腹腔给药24h后取样结果显示,EROD、ERND活性随给药剂量的增大而降低,最大抑制率分别为48%、52%。Western blotting结果表明,CYP1A蛋白含量在3mg/kg、10mg/kg恩诺沙星组中变化不大,但在30mg/kg、60mg/kg组中下降了约50%。CYP3A蛋白含量在不同剂量的恩诺沙星给药后相比对照组无明显变化。CYP1A mRNA在肝脏中的表达与EROD抑制曲线相符合,而CYP3A mRNA表达水平无明显变化。体外试验中,恩诺沙星显示出对CYP3A蛋白的机理性抑制,而对代表CYP1A的EROD活性则没有影响。综上结果说明恩诺沙星对CYP1A的抑制发生在体内水平,而对CYP3A的抑制是体内与体外水平综合的结果,在体外还存在对蛋白的机理性抑制。
2.异育银鲫细胞色素P450 3A亚型的克隆及组织表达分布
本试验根据4种鱼类CYP3A同源性序列设计兼并引物,采用RT-PCR和RACE的方法,得到了异育银鲫CYP3A全长cDNA序列。基因全长1770bp,5’端非编码区30bp,3’端非编码区195bp,开放阅读框1545bp,编码515个氨基酸。序列分析表明异育银鲫CYP3A氨基酸序列与人、小鼠、大鼠的相似性为73%-75%,与稀有鮈鲫的相似性为92%。进化树分析显示异育银鲫CYP3A氨基酸序列与鲤科鱼类同源性较高,而与其它物种遗传距离较远。利用半定量RT-PCR方法研究CYP3A在异育银鲫各组织中的表达分布,结果表明CYP3A在肝脏,肠中表达量最高,肾、鳃中次之,其余组织表达较低。
Effect of quinolones on cytochrome P450 in Crucian Carp (Carassius auratus gibelio) and cloning of CYP3A gene Hu Xiao (Aquaculture) Directed by Dr. Wen-hong Fang
The whole dissertation was divided into two parts. Part one was to investigate the effects of two fluoroquinolones, flumequine and enrofloxacin on cytochrome P450 of Crucian Carp(Carassius auratus gibelio). In this part, fish administered with flumequine was used to study the enzymes, protein and mRNA of CYPs in different tissue; In the second group, time course and dose-response of inhibition by enrofloxacin was studied at enzymes, protein and mRNA level. In part two, cloning, sequencing and tissue expression of the cytochrome CYP3A gene in Crucian Carp (Carassius auratus gibelio) was present, using RACE and semiquantitative RT-PCR assay.
1. Effect of flumequine and enrofloxacin on cytochrome P450 in Crucian Carp
The effects of flumequine on microsomal cytochrome P450 monooxygenases in Crucian Carp(Carassius auratus gibelio) were examined during this study. After 24h treatment, flumequine, administered to fish with a single intraperitoneal injection at a dose of 35mg/kg, resulted in a significant induction in the liver of the P4501A-linked ethoxyresorufin-O-deethylase (EROD) activity (54.33±5.42 pmol/mg-min) compared to control values (34.00±5.87 pmol/mg-min) (p<0.01). Erythromycin N-demethylase (ERND), aminopyrine N-demethylase (APD) and ethoxycoumarin O-deethylase (ECOD) were not affected by flumequine. Liver has the highest P450 enzymes activities except for ERND in kidney. Western blotting indicated that CYP1A protein level was induced (about 2 fold), which is consistent with the EROD activity in the experimental group. Semiquantitative RT-PCR analysis showed CYP1A mRNA were all expressed in liver, kidney and intestine, however, there is no significant differences between control and experimental groups. In vitro assay, various concentrations of flumequine were incubated with microsomes, no dose-and time-dependent manner was observed. The lack of induction speculated that flumequine caused an activation of CYP1A, occured at post-translational level, probably by protein stabilisation.
Enrofloxacin exhibited a potent inhibition (40%) on CYP3A-linked erythromycin N-demethylase (ERND) after a single intraperitoneal injection at a dose of 10mg/kg. ERND activity was decreased within 48h (306.93±19.30 pmol/mg·min) and retrun to pre-treatment level at 8d (496.76±46.04 pmol/mg-min). As for CYP1A, ethoxyresorufin-O-deethylase (EROD) activity was maximal inhibited at 24h (85.79±6.86/71.50±7.38 pmol/mg·min, for control and experimental group, respectively), but not as much as that in CYP3A. Enrofloxacin caused a slight increase in CYP1A protein level, while CYP3A protein was markedly decreased in 4d. Semiquantitative RT-PCR analysis showed that CYP1A mRNA and CYP3A mRNA were all decreased at 24h and 48h respectively, but have not returned to control level after 8d. This suggest a long-term inhibition of CYP1A, CYP3A by enrofloxacin. In the dose-response study, different concentrations of enrofloxacin (0mg/kg,3mg/kg,10mg/kg,30mg/kg,60mg/kg) were administered. Fish were sampled 24h after treatment, the results showed a dose-response reduction of hepatic CYP1A and CYP3A activity. The maximal inhibition of EROD and ERND was 48%,52%, respectively. Western blotting indicated that CYP1A protein level was not affect at dose of 3mg/kg,10mg/kg, but was significantly decreased (about 50%) at a higher dose. CYP3A protein content was remain at pre-treatment level after various concentration of enrofloxacin injection. Semiquantitative RT-PCR assay suggested that the changes of CYP1A mRNA is correlated well with that in EROD activity. The content of CYP3A mRNA was still unchanged. In vitro experiment, enrofloxacin, when preincubated with Crucian Carp liver microsomes, inhibited ERND activity in a dose-and time-dependent manner, however, the CYP1A-linked EROD activity was not affected. Taken overall, the inhibition of enrofloxacin on CYP1A probably occured in vivo, while enrofloxacin has been also demonstrated to be a powerful mechanism-based inhibitor primarily of P450 3A isoform in Crucian Carp.
2. Cloning, sequencing and tissue expression of the cytochrome P450 3A gene in Crucian Carp
Degenerate primers derived from conserved CYP3A sequences of four kind of fish were used to clone Crucian Carp CYP3A. A cDNA sequence (GenBank accession number: GU998964) was isolated and identified from the total RNA using RT-PCR and RACE assay. The sequence of CYP3A is 1770bp which contains a 5'UTR of 30bp and 3'UTR of 195bp, and an open reading frame (ORF) with 1545 bp that encodes a protein of 515 amino acids. The amino acid sequence of Crucian Carp shared 73%-75% of residue identity with the CYP3A subfamily in human, mouse and rat, and shared 92% of residue identity with Gobiocypris rarus. Molecular phylogenetic analysis of Crucian Carp CYP3A with other CYP3A forms from mammals and teleosts indicated that Crucian Carp CYP3A amino acid sequence has the highest identity with cyprinid fishes (Cyprinidae). Semiquantitative RT-PCR analysis showed that mRNA expression of CYP3A can be detected in liver, kidney, intestine, gill, muscle and spleen. Liver was found to have the highest CYP3A mRNA expression, followed by intestine, kidney and gill.
引文
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