酰胺类模药APAP在家蚕体内的代谢途径研究
|
摘要
对乙酰氨基酚（APAP）是一种广泛应用于临床的退烧镇痛类药物，利用APAP成分及其衍生物开发新型退烧镇痛类药物的研究还在广泛进行。APAP也是临床和基础研究中肝损伤建模和酰胺类药物毒理研究的模式药物。本实验旨在研究APAP在家蚕体内的代谢及损伤情况，探索利用无脊椎模式动物家蚕在药物开发和毒理学研究领域实验动物替代的可能性。研究结果报告如下：
1APAP在家蚕使用的剂量换算
医学实验动物替代的基本问题之一是剂量互换。目前家蚕与小鼠和人类的剂量尚无可靠的换算公式，根据体表面积经验计算公式得出的APAP对家蚕经口暴露的LD50为1664.7mg/kg，与实验测得的LD502450.3~3226.85mg/kg，相差50%以上。通过系统调查APAP对5龄2日家蚕皓月品种的时间-剂量影响的死亡效应，获得APAP经口暴露的安全剂量为600mg/kg，损伤剂量为3600mg/kg，损伤临界剂量为1800mg/kg。
2APAP在家蚕体内的组织代谢及产物
以APAP对家蚕的安全剂量、损伤剂量和损伤临界剂量经口暴露皓月品种5龄2日幼虫。HPLC分析显示，APAP在家蚕体内的主要代谢产物是糖基化产物，其次是硫酸化产物，与小鼠体内高度相似。糖基化主要发生在消化管，而硫酸化代谢产物主要在血淋巴中生成，脂肪体不是APAP累积和正常代谢的场所。
家蚕与小鼠对APAP代谢的不同点在于家蚕丝腺的作用。损伤剂量和损伤临界剂量经口暴露时，蚕体能够将APAP原药转运入丝腺储存，从而降低血淋巴和其它组织中的原药含量，并在血淋巴中APAP原药浓度低于0.2mg/L时向血淋巴开始释放。这在研究高浓度模药长时间作用，特别是研究模药对体内生殖腺等具有生理屏障组织的影响时具有特殊意义。
3APAP暴露后组织中UGTs酶基因表达特征及酶活变化
家蚕5龄2日幼虫的消化管和血淋巴中UGTs酶本底活性略高于脂肪体。安全剂量600mg/kgAPAP经口暴露家蚕皓月品种5龄2日幼虫，消化管和血淋巴中UGTs酶活性分别在给药后24min和16min有微弱上升，而脂肪体中的UGTs酶活性在给药后8min内上调了3倍，并在24min时超过对照6倍，暗示脂肪体的糖基化酶活性对APAP是敏感的。
给药后Ugt30，Ugt86和Ugt89这3个基因在消化管和脂肪体中的转录本水平都显著上升，其中Ugt30和Ugt89基因上调表达更快速，在消化管中30min就上升至峰值，脂肪体则没有消化管敏感。
4高浓度APAP对家蚕组织的损伤研究
经口给药3600mg/kg的APAP后，家蚕幼虫2h后表现出行动迟缓和取食减少，还伴有吐液和身体收缩等中毒症状，蚕体甚至出现黑化现象。组织形态和组织切片观察结果显示，18h内消化管组织出现局部溃烂，消化管内膜结构被严重破坏，细胞膜也出现破损，柱状细胞、微绒毛和杯状细胞等主要结构被破坏分辨不清。表明该剂量APAP能够导致家蚕幼虫消化管的吸收营养物质功能受到严重破坏。APAP暴露后12h，脂肪体细胞缩短成圆形，细胞膜增厚或破损，细胞内空泡增加、细胞核变小细胞排列变得杂乱松散；至给药后18h，组织中空泡增大，出现了细胞核完全破坏的无核细胞。表明脂肪体发生了严重损伤。
3600mg/kg的APAP经口暴露后，消化管中ROS含量在给药后8min时出现一时的增加，随后很快恢复至阳性对照水平，至消化管组织形态严重损坏的处理后12-18h，处理组中没有出现大量的ROS，表明APAP对消化管的损伤可能不是其它常见的药物组织氧化损伤。
高浓度APAP经口给药后12h，家蚕血淋巴中死亡细胞的比例没有增加，但APAP处理后32min内造血器官中的ROS不断增加，至12h以后才逐渐恢复至对照NS处理组水平。说明APAP对家蚕血淋巴中的血球细胞可能没有损伤，但在一定时间内会导致造血器官中发现ROS增加，可能会影响该组织的造血功能。
Acetaminophen (APAP) is an operative medicine widely used for the treatment offever and analgesia, and is a pattern drug of amide class widely used for liver injury model,too. Along with the conversion of medicine research pattern, the alternatives to animaltesting have become an important aspect of toxicology development. For drug toxicity test,the experimental animals used are mostly mammals such as mice. The drug administeredby orally exposure stays in the stomach for a relatively long period, and are easily digestedby gastric fluid, making the observation of the influence of drug on digestive tract difficult.In this study, Bombyx mori as an invertebrate, was used as the experimental animal.
1Appropriate dose of APAP in Bombyx larvae
One of the topic problems for alternatives to animal testing is the conversion of dose.Before, there is no reliable formula for the dose of clinical drugs from mice and human tosilkworm. According to the experiment the LD50of APAP in silkworm is2450.3~3226.85mg/kg, over50%more than1664.7mg/kg which got by the empiricalformula. Our results showed that a safe dose for day2of5th instar larvae of haoyue strainis600mg/kg, while the damage dose is3600mg/kg and the critical dose is1800mg/kg.
2The metabolites of APAP in multiple tissues of Bombyx larvae
The HPLC results showed that the products of glycosylation and sulfation are the twomain metabolites of APAP in multiple tissues of Bombyx larvae after orally explosion on2d of5thinstar. The metabolites are similar with the mice. There are tissue metabolismdifferences of APAP in Bombyx larvae, the glycosylation metabolic target organ might bedigestive tract while sulfation target organ might be haemolymph.
The silkgland is a special organ in Bombyx larvae instead of in mice or human. Thesilkworm larvae are able to transfer the original medicine of APAP to the silkgland viahaemolymph from digestive tract, and the physiological effect might be store the redundantAPAP and the critical concentration could be0.2mg/ml at this stage. This phenomenon isuseful for the long-term toxicology studies.
3Changes of activities of UGTs and its gene expression levels
The activity of UGTs in digestive tract is higher than that in fat body on a2d of5thinstar larva of silkworm. However, this activity increased in digestive tract andhaemolymph start at24min and16min, respectively, after oral exposed to600mg/kg APAP.While the active is rapid rised in fat body, showed2times higher than its positive control at8min, and5times at24min, and suggested that the fat body is very sensitive to APAPbut might not been a main metabolic tissue.
The results of gene expression patterns showed that Ugt30, Ugt86and Ugt89are allupregulated expression level in digestive tract and fat body. A peek level of Ugt30andUgt89gene mRNA in digestive tract presents to30min later, while they slowly increasedin the fatbody, supported the above results and guess.
4The injury in silkmorm tissues caused by APAP
After oral injected APAP of3600mg/kg, the larvae showed behaviors of sluggish andfeeding disturbance, accompanied by vomiting and body poisoning symptoms such asshrinkage even melanism at2hours later. The results from morphology and sectionsshowed that there were local fester in digestive tract. The structure of tunica intima wasseverely damaged, and the microvilli distinguish and cytomembranes of mast and gobletcells were damaged gravely. Follow the cells of fat body shorten then become a circle at12hours later, while the intracellular cavitations increased and the cytomembrane thickenedor damaged, the even losed nuclei, indicated that the fat body was suffered serious damageby APAP.
ROS was temporary increased in digestive tract at8min after oral injected3600mg/kg of APAP, nevertheless the ROS was almost disappeared at the quite late of12h-18h,and even the tissue was serious injured, suggested that the damage of APAP may not been aoxidative damage pathway as a common drug in the digestive tract. The ROS inhematopoietic organs was been increasing in32min and was recovered gradually after12h,meanwhile, the hematocyte has not been cut significantly than control. These resultsindicated that the blood cell injury in vivo induced by APAP is different from that in mice.
1APAP在家蚕使用的剂量换算
医学实验动物替代的基本问题之一是剂量互换。目前家蚕与小鼠和人类的剂量尚无可靠的换算公式，根据体表面积经验计算公式得出的APAP对家蚕经口暴露的LD50为1664.7mg/kg，与实验测得的LD502450.3~3226.85mg/kg，相差50%以上。通过系统调查APAP对5龄2日家蚕皓月品种的时间-剂量影响的死亡效应，获得APAP经口暴露的安全剂量为600mg/kg，损伤剂量为3600mg/kg，损伤临界剂量为1800mg/kg。
2APAP在家蚕体内的组织代谢及产物
以APAP对家蚕的安全剂量、损伤剂量和损伤临界剂量经口暴露皓月品种5龄2日幼虫。HPLC分析显示，APAP在家蚕体内的主要代谢产物是糖基化产物，其次是硫酸化产物，与小鼠体内高度相似。糖基化主要发生在消化管，而硫酸化代谢产物主要在血淋巴中生成，脂肪体不是APAP累积和正常代谢的场所。
家蚕与小鼠对APAP代谢的不同点在于家蚕丝腺的作用。损伤剂量和损伤临界剂量经口暴露时，蚕体能够将APAP原药转运入丝腺储存，从而降低血淋巴和其它组织中的原药含量，并在血淋巴中APAP原药浓度低于0.2mg/L时向血淋巴开始释放。这在研究高浓度模药长时间作用，特别是研究模药对体内生殖腺等具有生理屏障组织的影响时具有特殊意义。
3APAP暴露后组织中UGTs酶基因表达特征及酶活变化
家蚕5龄2日幼虫的消化管和血淋巴中UGTs酶本底活性略高于脂肪体。安全剂量600mg/kgAPAP经口暴露家蚕皓月品种5龄2日幼虫，消化管和血淋巴中UGTs酶活性分别在给药后24min和16min有微弱上升，而脂肪体中的UGTs酶活性在给药后8min内上调了3倍，并在24min时超过对照6倍，暗示脂肪体的糖基化酶活性对APAP是敏感的。
给药后Ugt30，Ugt86和Ugt89这3个基因在消化管和脂肪体中的转录本水平都显著上升，其中Ugt30和Ugt89基因上调表达更快速，在消化管中30min就上升至峰值，脂肪体则没有消化管敏感。
4高浓度APAP对家蚕组织的损伤研究
经口给药3600mg/kg的APAP后，家蚕幼虫2h后表现出行动迟缓和取食减少，还伴有吐液和身体收缩等中毒症状，蚕体甚至出现黑化现象。组织形态和组织切片观察结果显示，18h内消化管组织出现局部溃烂，消化管内膜结构被严重破坏，细胞膜也出现破损，柱状细胞、微绒毛和杯状细胞等主要结构被破坏分辨不清。表明该剂量APAP能够导致家蚕幼虫消化管的吸收营养物质功能受到严重破坏。APAP暴露后12h，脂肪体细胞缩短成圆形，细胞膜增厚或破损，细胞内空泡增加、细胞核变小细胞排列变得杂乱松散；至给药后18h，组织中空泡增大，出现了细胞核完全破坏的无核细胞。表明脂肪体发生了严重损伤。
3600mg/kg的APAP经口暴露后，消化管中ROS含量在给药后8min时出现一时的增加，随后很快恢复至阳性对照水平，至消化管组织形态严重损坏的处理后12-18h，处理组中没有出现大量的ROS，表明APAP对消化管的损伤可能不是其它常见的药物组织氧化损伤。
高浓度APAP经口给药后12h，家蚕血淋巴中死亡细胞的比例没有增加，但APAP处理后32min内造血器官中的ROS不断增加，至12h以后才逐渐恢复至对照NS处理组水平。说明APAP对家蚕血淋巴中的血球细胞可能没有损伤，但在一定时间内会导致造血器官中发现ROS增加，可能会影响该组织的造血功能。
Acetaminophen (APAP) is an operative medicine widely used for the treatment offever and analgesia, and is a pattern drug of amide class widely used for liver injury model,too. Along with the conversion of medicine research pattern, the alternatives to animaltesting have become an important aspect of toxicology development. For drug toxicity test,the experimental animals used are mostly mammals such as mice. The drug administeredby orally exposure stays in the stomach for a relatively long period, and are easily digestedby gastric fluid, making the observation of the influence of drug on digestive tract difficult.In this study, Bombyx mori as an invertebrate, was used as the experimental animal.
1Appropriate dose of APAP in Bombyx larvae
One of the topic problems for alternatives to animal testing is the conversion of dose.Before, there is no reliable formula for the dose of clinical drugs from mice and human tosilkworm. According to the experiment the LD50of APAP in silkworm is2450.3~3226.85mg/kg, over50%more than1664.7mg/kg which got by the empiricalformula. Our results showed that a safe dose for day2of5th instar larvae of haoyue strainis600mg/kg, while the damage dose is3600mg/kg and the critical dose is1800mg/kg.
2The metabolites of APAP in multiple tissues of Bombyx larvae
The HPLC results showed that the products of glycosylation and sulfation are the twomain metabolites of APAP in multiple tissues of Bombyx larvae after orally explosion on2d of5thinstar. The metabolites are similar with the mice. There are tissue metabolismdifferences of APAP in Bombyx larvae, the glycosylation metabolic target organ might bedigestive tract while sulfation target organ might be haemolymph.
The silkgland is a special organ in Bombyx larvae instead of in mice or human. Thesilkworm larvae are able to transfer the original medicine of APAP to the silkgland viahaemolymph from digestive tract, and the physiological effect might be store the redundantAPAP and the critical concentration could be0.2mg/ml at this stage. This phenomenon isuseful for the long-term toxicology studies.
3Changes of activities of UGTs and its gene expression levels
The activity of UGTs in digestive tract is higher than that in fat body on a2d of5thinstar larva of silkworm. However, this activity increased in digestive tract andhaemolymph start at24min and16min, respectively, after oral exposed to600mg/kg APAP.While the active is rapid rised in fat body, showed2times higher than its positive control at8min, and5times at24min, and suggested that the fat body is very sensitive to APAPbut might not been a main metabolic tissue.
The results of gene expression patterns showed that Ugt30, Ugt86and Ugt89are allupregulated expression level in digestive tract and fat body. A peek level of Ugt30andUgt89gene mRNA in digestive tract presents to30min later, while they slowly increasedin the fatbody, supported the above results and guess.
4The injury in silkmorm tissues caused by APAP
After oral injected APAP of3600mg/kg, the larvae showed behaviors of sluggish andfeeding disturbance, accompanied by vomiting and body poisoning symptoms such asshrinkage even melanism at2hours later. The results from morphology and sectionsshowed that there were local fester in digestive tract. The structure of tunica intima wasseverely damaged, and the microvilli distinguish and cytomembranes of mast and gobletcells were damaged gravely. Follow the cells of fat body shorten then become a circle at12hours later, while the intracellular cavitations increased and the cytomembrane thickenedor damaged, the even losed nuclei, indicated that the fat body was suffered serious damageby APAP.
ROS was temporary increased in digestive tract at8min after oral injected3600mg/kg of APAP, nevertheless the ROS was almost disappeared at the quite late of12h-18h,and even the tissue was serious injured, suggested that the damage of APAP may not been aoxidative damage pathway as a common drug in the digestive tract. The ROS inhematopoietic organs was been increasing in32min and was recovered gradually after12h,meanwhile, the hematocyte has not been cut significantly than control. These resultsindicated that the blood cell injury in vivo induced by APAP is different from that in mice.
引文
1. Aggarwal K, Silverman NS. Positive and negative regμlation of the Drosophilaimmune response [J]. BMB Rep2008,41:267–277.
2. Ahmad SA&Hopkins TL. B-glucosylation of plant phenolics by phenolb-glucosyltransferase in larval tissues of the tobacco hornworm, Manduca sexta (L.).Insect Biochem. Mol. Biol.1993,23,581–589.
3. Alencon Ed, Sezutsu H, Legeai F, Permal E, Bernard SS, Gagneur C, Cousserans F,Shimomura M, Brun-Barale A, Flutre T, Coμloux A, East P, Gordon K, Mita K,Quesneville H, Fournier P, Feyereisen R. Extensive synteny conservation ofholocentric chromosomes in Lepidoptera despite high rates of local genomerearrangements [J]. Proceedings of the National Academy of Sciences,2010,107(17):7680-7685.
4. Asami Y, Horie R, Hamamoto H, Sekimizu K. Use of silkworms for identification ofdrug candidates having appropriate pharmacokinetics from plant sources [J]. BMCpharmacology,2010,10(1):7.
5. Beament JWL, Treherne JOE, Wigglesworth VB. Advances in insect physiology [J].Academic Press, London,1963,163–165.
6. Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury [C],Seminars in liver disease,2009,29(4):337.
7. Berger J. Preclinical testing on insects predicts human haematotoxic potentials [J].Laboratory animals,2009,43(4):328-332.
8. Bμll DL, Whitten CJ. Factors influencing organophosphorus insecticide resistance intobacco budworms.[J] Agric Food Chem.1972,20(3):561-564.
9. Cavar I, Kelava T, Pravdic D, Cμlo F. Anti-thromboxane B2antibodies protectagainst acetaminophen-induced liver injury in mice [J]. Journal of Xenobiotics.2011,Vol1, No1:38-44.
10. Chen TS, Richie JP, Lang CA. Life span profiles of glutathione and acetaminophendetoxification [J]. Drug Metabolism and Disposition,1990,18(6):882-887.
11. Cheng PY, Morgan ET. Hepatic cytochrome P450regμlation in disease states [J].Current drug Metabolism,2001,2(2):165-183.
12. Claudianos C, Ranson H, Johnson RM, Biswas S, Schμler MA, Berenbaum MR,Feyereisen R, Oakeshott JG. A deficit of detoxification enzymes: pesticide sensitivityand environmental response in the honeybee [J]. Insect Molecular Biology,2006,15(5):615-636.
13. Daimon T, Hirayama C, Kanai M, Ruike Y, Meng Y, Kosegawa E, Nakamura M,Tsujimoto G, Katsuma S, Shimada T. The silkworm Green b locus encodes aquercetin5-O-glucosyltransferase that produces green cocoons with UV-shieldingproperties [J]. Proceedings of the National Academy of Sciences,2010,107(25):11471-11476.
14. Fay KK, Marissa RK,Diana J. Auyeung, Joseph K.R， Glucuronidation ofacetaminophen catalyzed by mμltiple rat phenol UDP-Glucuronosyltransferases [J]，Drug Metabolism and Disposition,2002,30:324-330.
15. Hamamoto H, Sekimizu K, Miranda T. Evaluation of the therapeutic effects ofantibiotics using silkworm as an animal model [J]. Res Adv Antimicrob AgentsChemother,2005,5:1-23.
16.1. Hamamoto H,Kurokawa K, Kaito C, Kamura K, Manitra RI, Kusuhara H, SantaT, Sekimizu K. Quantitative evaluation of the therapeutic effects of antibiotics usingsilkworms infected with human pathogenic microorganisms [J]. Antimicrob AgentsChemother.2004,48(3):774-779.
17. Hamamoto H., Kurokawa K., Kaito C., Kamura K., Razanajatovo IM, Kusuhara H,Santa T, Sekimizu K. Quantitative evaluation of the therapeutic effects of antibioticsusing silkworms infected with human pathogenic microorganisms.Antimicrob [J].Agents Chemother.2004.48:774-779.
18. Hamamoto H., Sekimizu K., Evaluation of the therapeutic effects of antibiotics usingsilkworm as an animal model [J]. Res. Adv. Antimicrob Agents Chemother.2005,5:1-23.
19. Hemingway J, Karunaratne SH. Mosquito carboxylesterases: a review of themolecμlar biology and biochemistry of a major insecticide resistance mechanism [J].Medical and Veterinary Entomology,1998,12(1):1-12.
20. Huang FF, Chai CL, Zhang Z, Lu C. The UDP-glucosyltransferase multigene familyin Bombyx mori.[J] Bmc Genomics.2008,9:563-570
21. Inagaki Y, Matsumoto Y, Kataoka K, Matsuhashi N, Sekimizu K. Evaluation ofdrug-induced tissue injury by measuring alanine aminotransferase (ALT) activity insilkworm hemolymph [J]. BMC Pharmacology and Toxicology,2012,13(1):1-7.
22. Inagaki Y, Matsumoto Y, Kataoka K, Matsuhashi N, Sekimizu K. Evaluation ofdrug-induced tissue injury by measuring alanine aminotransferase (ALT) activity insilkworm hemolymph [J]. BMC Pharmacol Toxicol.2012,13:13.
23. Jedlitschky G,Cassidy AJ, Sales M, Pratt N, Burchell B. Cloning and characterizationof a novel human olfactory UDP-glucuronosyltransferase [J]. Biochemical journal,1999,340(Pt3):837.
24. Kienhuis AS, Bessems JG, Pennings JL, Driessen M, Luijten M, van Delft JH,Peijnenburg AA, van der Ven LT. Application of toxicogenomics in hepatic systemstoxicology for risk assessment: acetaminophen as a case study [J]. Toxicol ApplPharmacol,2011,250(2):96-107.
25. Lai TY, Weng YJ, Chen WK, Yueh-Min Lin, Tsai FJ, Cheng YC, Chen LM, Eric YC.,Huang CY, Hwang J The Anti-Hepatitis Effect by Tao-He-Cheng-Qi-Tang onAcetaminophen (APAP) Induced Rats [J]. Adaptive Medicine,2011,3(1):16-20.
26. Landino J, Buckley J, Roy JM, David VBA, Krystyna GBS, Mohan KMS, AndreasW, Gualberto RMD. Guidance of pharmacotherapy in a complex psychiatric case byCYP450DNA typing [J]. Journal of the American Academy of Nurse Practitioners,2011,23(9):459-463.
27. Lazard D, Zupko K, Poria Y, Nef P, Lazarovits J, Horn S, Khen M, Lancet D.Odorant signal termination by olfactory UDP glucuronosyl transferase.[J] Nature.1991,349(6312):790-793.
28. Lewen A， Matz P， Chan PH． Free radical pathways in CNS injury[J]． Neurotrauma，2000，17:871－90．
29. Li X, Schuler MA, Berenbaum MR. Molecular mechanisms of metabolic resistanceto synthetic and natural xenobiotics [J]. Annu. Rev. Entomol.,2007,52:231-253.
30. Lindroth RL, Weisbrod AV. Genetic variation in response of the gypsy moth to aspenphenolic glycosides [J]. Biochemical systematics and ecology,1991,19(2):97-103.
31. Lindroth RL. Host plant alteration of detoxication activity in Papilio glaucus glaucus[J]. Entomologia experimentalis et applicata,1989,50(1):29-35.
32. Luque T, Okano K, O'Reilly DR. Characterization of a novel silkworm (Bombyx mori)phenol UDP‐glucosyltransferase [J]. European Journal of Biochemistry,2002,269(3):819-825.
33. Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L, Polyphenols: food sourcesand bioavailability [J]. The American Journal of Clinical Nutrition,2004,79(5):727-747.
34. Namiki T, Niwa R, Sakudoh T, Shirai K, Takeuchi H, Kataoka H. Cytochrome P450CYP307A1/Spook: a regμlator for ecdysone synthesis in insects [J]. Biochemical andBiophysical Research Communications,2005,337(1):367-374.
35. Petersen RA, Niamsup H, Berenbaum MR, Schμler MA. Transcriptional responseelements in the promoter of CYP6B1, an insect P450gene regμlated by plantchemicals [J]. Biochimica et Biophysica Acta,2003,1619(3)：269-282.
36. Powell GF, Ward DA, Prescott MC, Spiller DG, White MR, Turner PC, Earley FG,Phillips J, Rees HH. The molecμlar action of the novel insecticide, Pyridalyl [J].Insect Biochemistry and Molecμlar Biology,2011,41(7):459-469.
37. Rausell C, Llorca J, Real MD. Separation by FPLC chromatofocusing ofUDP‐g lucosyltransferases from three developmental stages ofDrosophilamelanogaster [J]. Archives of Insect Biochemistry and Physiology,1997,34(3):347-358.
38. Real MD, Ferre J, Chapa FJ. UDP-glucosyltransferase activity toward exogenoussubstrates in Drosophila melanogaster [J]. Analytical Biochemistry,1991,194(2):349-352.
39. Rewitz KF, O’Connor MB, Gilbert LI. Molecμlar evolution of the insect Halloweenfamily of cytochrome P450s: phylogeny, gene organization and functionalconservation [J]. Insect biochemistry and molecμlar biology,2007,37(8):741-753.
40. Richards S, Gibbs RA, Weinstock GM, The genome of the model beetle and pestTribolium castaneum [J]. Nature,2008,452(7190):949-955.
41. Robertson HM, Martos R, Sears CR, Todres EZ, Walden KK, Nardi JB. Diversity ofodourant binding proteins revealed by an expressed sequence tag project on maleManduca sexta moth antennae [J]. Insect Molecμlar Biology,1999,8(4):501-518..
42. Robertson HM, Wanner KW. The chemoreceptor superfamily in the honey bee, Apismellifera: expansion of the odorant, but not gustatory, receptor family [J]. GenomeResearch,2006,16(11):1395-1403.
43. Saskia N, Gregory L.K, Steven L, John N. A Glucuronidation in humans [J]. Clinicalpharmacokinetics,1999,36(6):439-452.
44. Smitha S, Rao AVB. Effects of Selenium on the Physiology of Heart Beat, OxygenConsumption and Growth in Silkworm Bombyx mori L [J]. American-EurasianJournal of Toxicological Sciences,2010,2(4):215-219.
45. Stadtman ER，Protein Oxidation and aging． Science,1992,2S7：1220-1224.
46. Talalay P, Fahey JW, Holtzclaw WD, Tory P, Zhang YS. Chemoprotection againstcancer by phase2enzyme induction [J]. Toxicology Letters,1995,82:173-179.
47. Talalay P. Chemoprotection against cancer by induction of phase2enzymes [J].Biofactors,2000,12(1):5-11.
48. Tephly TR, Burchell B. UDP-glucuronosyltransferase: a family of detoxifyingenzymes [J]. Trends Pharmacol Sciences,1990,11:276-279
49. Tucker FB, Wang KX, Fang J, Lü SL. Effect of Chromium on Hemolymph CatalaseActivity and Cocoon Quality of Two Mμlberry Silkworm (Bombyx mori) Races [J].Bulletin of environmental contamination and toxicology,2004,73(3):443-447.
50. Klotz U. Paracetamol (Acetaminophen)-a popμlar and widely used nonopioidanalgesic [J]. Arzneimittelforschung2012;62:355–359.
51. Vidyunmala S, Begum AF, Nagalakshmamma K, Rao AVB. Toxicity evaluation offluoride in silkworm Bombyx mori [J]. American-Eurasian Journal of ToxicologicalSciences,2010,2(2):96-99.
52. Vidyunmala S, Farhana AB, Nagalakshmamma K, Vijaya ABR. Toxicity Evaluationof Fluoride in Silkworm Bombyx mori L [J]. American-Eurasian Journal ofToxicological Sciences,2010,2(2):96-99.
53. Wang Q, Hasan G, Pikielny CW. Preferential expression of biotransformationenzymes in the olfactory organs of Drosophila melanogaster, the antennae [J].Journal of Biological Chemistry,1999,274(15):10309-10315.
54. Warren JT, Petryk A, Marqués G, Parvy JP, Shinoda T, Itoyama K, Kobayashi J,Jarcho M, Li Y, O’Connor MB, Dauphin-Villemant C, Gilbert L. Phantom encodesthe25-hydroxylase of Drosophila melanogaster and Bombyx mori: a P450enzymecritical in ecdysone biosynthesis [J]. Insect Biochemistry and Molecμlar Biology,2004,34(9):991-1010.
55. Wrighton S A, VandenBranden M, Ring B J. The human drug metabolizingcytochromes P450[J]. Journal of Pharmacokinetics and Biopharmaceutics,1996,24(5):461-473.
56. Matsumoto Y, Sumiya E, Sugita T, Sekimizu K. An invertebrate hyperglycemicmodel for the identification of anti-diabetic drugs. PLoS One.2011,6(3):e18292.
57. Yang H, Zhou Z, Zhang H, Chen M, Li J, Ma Y, Zhong B. Shotgun proteomicanalysis of the fat body during metamorphosis of domesticated silkworm (Bombyxmori)[J]. Amino Acids,2010,38(5):1333-1342.
58. Yu QY, Lu C, Li WL, Xiang ZH, Zhang Z. Annotation and expression ofcarboxylesterases in the silkworm, Bombyx mori [J]. Bmc Genomics,2009,10(1):553.
59. Yutaka Orihara, Hiroshi Hamamoto,Hiroshi Kasuga,Toru Shimada,YasushiKawaguchi5，Kazuhisa Sekimizu2,‘A silkworm–baculovirus model for assessing thetherapeutic effects of antiviral compounds:characterization and application to theisolation of antivirals from traditional medicines[J]，Journal of General Virology2008,89:188–194
60. Zhou SF. Polymorphism of human cytochrome P4502D6and its clinical significance[J]. Clinical Pharmacokinetics,2009,48(12):761-804.
61.艾均文,薛宏,何行健,孟繁利,朱勇,向仲怀.家蚕细胞色素P450基因的研究进展[J].昆虫学报,2011,54(8):918-926.
62.艾均文.家蚕全基因组细胞色素P450基因结构与进化分析及CYP18A1克隆与功能研究[D].重庆:西南大学,2008.
63.成碟，徐为人，刘昌孝．细胞色素P450(CYP450)遗传多态性研究进展[J]．中国药理学通报，2006,22(12):1409—1414．
64.丁媛媛,曾明,邱麟,许景峰.影响尿苷二磷酸葡醛酸转移酶活性的研究进展[J].解放军药学学报,2012,28(6):541-544.
65.董久鸣.家蚕(Bombyx mori)5龄幼虫脂肪体蛋白质组及其相关功能基因的研究[D]，杭州：浙江大学，2008
66.傅吉涛,刘朝良,凌尔军,查新民,李东升.家蚕血细胞分类和造血功能研究[J].安徽农业科学,2005,33(5):803-804.
67.高绘菊，苏振霞，窦学娥，王彦文，牟志美.盐酸诺氟沙星在健康及细菌感染家蚕中的药代动力学研究[J].蚕业科学,2008,34(2):280-283.
68.葛君,李兵,沈卫德.昆虫脂肪体与抗药性的关系研究现状与分析[J].江苏农业科学,2010,6:183-185.
69.郭栋,庞良芳,周宏灏.尿苷二磷酸葡萄糖醛酸基转移酶基因多态性的研究进展[J]，生理科学进展,2010,42(2):107-111.
70.郭晶,高菊芳,唐振华.羧酸酯酶及其在含酯类化合物代谢中的作用[J].农药,2007,46(6):365-368.
71.胡蒙蒙,王青,杨益众.重金属在昆虫体内的累积、分布与排泄[J].中国农学通报,2012,28(18):213-217.
72.李芬,刘小宁.棉铃虫细胞色素P450CYP6B6基因启动子活性检测条件的优化[J].生物技术通报,2012,5:031.
73.李秋菊,蕾义雄,何建平,王映芬. Ebselen对扑热息痛的毒性代谢产物NAPQI的体外清除作用[J].中国药学(英文版).1996,5(1):13-19.
74.李晓宇,刘皋林. CYP450酶特性及其应用研究进展[J].中国临床药理学与治疗学,2008,13(8):942-946.
75.李新,余应年.药物的II相代谢与酶系及其进展[J].中国临床药理学杂志,2000,16(6):458-465.
76.林国杂,陈芳艳,黄志君,李文楚.败血病菌感染家蚕马氏管组织碱性磷酸酶的病理学研究[J].广东蚕业,39(4):28-31.
77.林金明,屈峰.活性氧测定的基本原理与方法[J].分析化学评述与进展,2002，30(12):1507-1514.
78.彭然.家蚕常用内参基因的稳定性分析及两种实时荧光定量PCR方法比较[D].苏州大学,2012.
79.齐艳萍,许宇霞,王端.药物性肝损伤小鼠血清指标及肝脏组织学变化[J].黑龙江兽医科技,2010,(13):128-129.
80.钱惠田,周仙美.中国三蚕解剖图谱[M].广西科学技术出版社,南宁（第一版）,1989
81.王静. Columbin对实验性2型糖尿病大鼠肝脏药物代谢酶CYP450的影响[D].华中科技大学,2011.
82.王猛.家蚕几种尿苷二磷酸-葡萄糖基转移酶的基因表达与功能研究[D]，苏州：苏州大学,2011.
83.王猛,牛艳山,司马杨虎,徐世清.家蚕不同茧色品种中尿苷二磷酸-葡萄糖基转移酶(UGT)基因的表达差异[J].蚕业科学,2010,36(1):0033-0039.
84.滕霞,孙曼霁.羧酸酯酶研究进展[J].生命科学,2003,(1):31-35.
85.夏木斯亚.对乙酰氨基酚的药代动力学及其肝毒性的生理节律调控[D].南京：南京理工大学，2010.
86.向仲怀主编.蚕丝生物学[M].中国林业出版社,北京(第一版):2005.
87.肖龙云,程嘉翎,王俊,王春华.家蚕氟化物中毒后血淋巴中脂质过氧化物和抗氧化物含量及抗氧化酶活性的变化[J].蚕业科学,2010,36(006):1047-1051.
88.杨帅,王玲,赵奎军,韩岚岚.大豆蚜羧酸酯酶基因AgCarE的克隆、表达及活性分析[J],中国农业科学2012,45(18):3755-3763
89.杨亦桦.棉铃虫对拟除虫菊酯氧化代谢抗性的生化与分子机理[D]，南京：南京农业大学,2005.
90.姚慧鹏,郭爱芹,何芳青,鲁兴萌;吴小锋.家蚕幼虫5龄期消化管蛋白质组学[J].生物工程学报,2008,24(1):89-94.
91.袁红霞,裔洪根,徐世清.壬基酚对家蚕生长发育的影响[J].农业环境科学学报,2009,28(4):777-782.
92.张瑶华、李端.中国常用药品集[M].上海交通大学出版社，上海(第一版)：2006.
93.周庆祥,张志芳.家蚕血球的生成机理[J].中国蚕业,2004,25(2):82-84.
94.朱晓苏,宋艳,徐世清.家蚕作为模式生物在现代生物学中的应用[J].实验动物与比较医学,2009,29(1):61-65.
2. Ahmad SA&Hopkins TL. B-glucosylation of plant phenolics by phenolb-glucosyltransferase in larval tissues of the tobacco hornworm, Manduca sexta (L.).Insect Biochem. Mol. Biol.1993,23,581–589.
3. Alencon Ed, Sezutsu H, Legeai F, Permal E, Bernard SS, Gagneur C, Cousserans F,Shimomura M, Brun-Barale A, Flutre T, Coμloux A, East P, Gordon K, Mita K,Quesneville H, Fournier P, Feyereisen R. Extensive synteny conservation ofholocentric chromosomes in Lepidoptera despite high rates of local genomerearrangements [J]. Proceedings of the National Academy of Sciences,2010,107(17):7680-7685.
4. Asami Y, Horie R, Hamamoto H, Sekimizu K. Use of silkworms for identification ofdrug candidates having appropriate pharmacokinetics from plant sources [J]. BMCpharmacology,2010,10(1):7.
5. Beament JWL, Treherne JOE, Wigglesworth VB. Advances in insect physiology [J].Academic Press, London,1963,163–165.
6. Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury [C],Seminars in liver disease,2009,29(4):337.
7. Berger J. Preclinical testing on insects predicts human haematotoxic potentials [J].Laboratory animals,2009,43(4):328-332.
8. Bμll DL, Whitten CJ. Factors influencing organophosphorus insecticide resistance intobacco budworms.[J] Agric Food Chem.1972,20(3):561-564.
9. Cavar I, Kelava T, Pravdic D, Cμlo F. Anti-thromboxane B2antibodies protectagainst acetaminophen-induced liver injury in mice [J]. Journal of Xenobiotics.2011,Vol1, No1:38-44.
10. Chen TS, Richie JP, Lang CA. Life span profiles of glutathione and acetaminophendetoxification [J]. Drug Metabolism and Disposition,1990,18(6):882-887.
11. Cheng PY, Morgan ET. Hepatic cytochrome P450regμlation in disease states [J].Current drug Metabolism,2001,2(2):165-183.
12. Claudianos C, Ranson H, Johnson RM, Biswas S, Schμler MA, Berenbaum MR,Feyereisen R, Oakeshott JG. A deficit of detoxification enzymes: pesticide sensitivityand environmental response in the honeybee [J]. Insect Molecular Biology,2006,15(5):615-636.
13. Daimon T, Hirayama C, Kanai M, Ruike Y, Meng Y, Kosegawa E, Nakamura M,Tsujimoto G, Katsuma S, Shimada T. The silkworm Green b locus encodes aquercetin5-O-glucosyltransferase that produces green cocoons with UV-shieldingproperties [J]. Proceedings of the National Academy of Sciences,2010,107(25):11471-11476.
14. Fay KK, Marissa RK,Diana J. Auyeung, Joseph K.R， Glucuronidation ofacetaminophen catalyzed by mμltiple rat phenol UDP-Glucuronosyltransferases [J]，Drug Metabolism and Disposition,2002,30:324-330.
15. Hamamoto H, Sekimizu K, Miranda T. Evaluation of the therapeutic effects ofantibiotics using silkworm as an animal model [J]. Res Adv Antimicrob AgentsChemother,2005,5:1-23.
16.1. Hamamoto H,Kurokawa K, Kaito C, Kamura K, Manitra RI, Kusuhara H, SantaT, Sekimizu K. Quantitative evaluation of the therapeutic effects of antibiotics usingsilkworms infected with human pathogenic microorganisms [J]. Antimicrob AgentsChemother.2004,48(3):774-779.
17. Hamamoto H., Kurokawa K., Kaito C., Kamura K., Razanajatovo IM, Kusuhara H,Santa T, Sekimizu K. Quantitative evaluation of the therapeutic effects of antibioticsusing silkworms infected with human pathogenic microorganisms.Antimicrob [J].Agents Chemother.2004.48:774-779.
18. Hamamoto H., Sekimizu K., Evaluation of the therapeutic effects of antibiotics usingsilkworm as an animal model [J]. Res. Adv. Antimicrob Agents Chemother.2005,5:1-23.
19. Hemingway J, Karunaratne SH. Mosquito carboxylesterases: a review of themolecμlar biology and biochemistry of a major insecticide resistance mechanism [J].Medical and Veterinary Entomology,1998,12(1):1-12.
20. Huang FF, Chai CL, Zhang Z, Lu C. The UDP-glucosyltransferase multigene familyin Bombyx mori.[J] Bmc Genomics.2008,9:563-570
21. Inagaki Y, Matsumoto Y, Kataoka K, Matsuhashi N, Sekimizu K. Evaluation ofdrug-induced tissue injury by measuring alanine aminotransferase (ALT) activity insilkworm hemolymph [J]. BMC Pharmacology and Toxicology,2012,13(1):1-7.
22. Inagaki Y, Matsumoto Y, Kataoka K, Matsuhashi N, Sekimizu K. Evaluation ofdrug-induced tissue injury by measuring alanine aminotransferase (ALT) activity insilkworm hemolymph [J]. BMC Pharmacol Toxicol.2012,13:13.
23. Jedlitschky G,Cassidy AJ, Sales M, Pratt N, Burchell B. Cloning and characterizationof a novel human olfactory UDP-glucuronosyltransferase [J]. Biochemical journal,1999,340(Pt3):837.
24. Kienhuis AS, Bessems JG, Pennings JL, Driessen M, Luijten M, van Delft JH,Peijnenburg AA, van der Ven LT. Application of toxicogenomics in hepatic systemstoxicology for risk assessment: acetaminophen as a case study [J]. Toxicol ApplPharmacol,2011,250(2):96-107.
25. Lai TY, Weng YJ, Chen WK, Yueh-Min Lin, Tsai FJ, Cheng YC, Chen LM, Eric YC.,Huang CY, Hwang J The Anti-Hepatitis Effect by Tao-He-Cheng-Qi-Tang onAcetaminophen (APAP) Induced Rats [J]. Adaptive Medicine,2011,3(1):16-20.
26. Landino J, Buckley J, Roy JM, David VBA, Krystyna GBS, Mohan KMS, AndreasW, Gualberto RMD. Guidance of pharmacotherapy in a complex psychiatric case byCYP450DNA typing [J]. Journal of the American Academy of Nurse Practitioners,2011,23(9):459-463.
27. Lazard D, Zupko K, Poria Y, Nef P, Lazarovits J, Horn S, Khen M, Lancet D.Odorant signal termination by olfactory UDP glucuronosyl transferase.[J] Nature.1991,349(6312):790-793.
28. Lewen A， Matz P， Chan PH． Free radical pathways in CNS injury[J]． Neurotrauma，2000，17:871－90．
29. Li X, Schuler MA, Berenbaum MR. Molecular mechanisms of metabolic resistanceto synthetic and natural xenobiotics [J]. Annu. Rev. Entomol.,2007,52:231-253.
30. Lindroth RL, Weisbrod AV. Genetic variation in response of the gypsy moth to aspenphenolic glycosides [J]. Biochemical systematics and ecology,1991,19(2):97-103.
31. Lindroth RL. Host plant alteration of detoxication activity in Papilio glaucus glaucus[J]. Entomologia experimentalis et applicata,1989,50(1):29-35.
32. Luque T, Okano K, O'Reilly DR. Characterization of a novel silkworm (Bombyx mori)phenol UDP‐glucosyltransferase [J]. European Journal of Biochemistry,2002,269(3):819-825.
33. Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L, Polyphenols: food sourcesand bioavailability [J]. The American Journal of Clinical Nutrition,2004,79(5):727-747.
34. Namiki T, Niwa R, Sakudoh T, Shirai K, Takeuchi H, Kataoka H. Cytochrome P450CYP307A1/Spook: a regμlator for ecdysone synthesis in insects [J]. Biochemical andBiophysical Research Communications,2005,337(1):367-374.
35. Petersen RA, Niamsup H, Berenbaum MR, Schμler MA. Transcriptional responseelements in the promoter of CYP6B1, an insect P450gene regμlated by plantchemicals [J]. Biochimica et Biophysica Acta,2003,1619(3)：269-282.
36. Powell GF, Ward DA, Prescott MC, Spiller DG, White MR, Turner PC, Earley FG,Phillips J, Rees HH. The molecμlar action of the novel insecticide, Pyridalyl [J].Insect Biochemistry and Molecμlar Biology,2011,41(7):459-469.
37. Rausell C, Llorca J, Real MD. Separation by FPLC chromatofocusing ofUDP‐g lucosyltransferases from three developmental stages ofDrosophilamelanogaster [J]. Archives of Insect Biochemistry and Physiology,1997,34(3):347-358.
38. Real MD, Ferre J, Chapa FJ. UDP-glucosyltransferase activity toward exogenoussubstrates in Drosophila melanogaster [J]. Analytical Biochemistry,1991,194(2):349-352.
39. Rewitz KF, O’Connor MB, Gilbert LI. Molecμlar evolution of the insect Halloweenfamily of cytochrome P450s: phylogeny, gene organization and functionalconservation [J]. Insect biochemistry and molecμlar biology,2007,37(8):741-753.
40. Richards S, Gibbs RA, Weinstock GM, The genome of the model beetle and pestTribolium castaneum [J]. Nature,2008,452(7190):949-955.
41. Robertson HM, Martos R, Sears CR, Todres EZ, Walden KK, Nardi JB. Diversity ofodourant binding proteins revealed by an expressed sequence tag project on maleManduca sexta moth antennae [J]. Insect Molecμlar Biology,1999,8(4):501-518..
42. Robertson HM, Wanner KW. The chemoreceptor superfamily in the honey bee, Apismellifera: expansion of the odorant, but not gustatory, receptor family [J]. GenomeResearch,2006,16(11):1395-1403.
43. Saskia N, Gregory L.K, Steven L, John N. A Glucuronidation in humans [J]. Clinicalpharmacokinetics,1999,36(6):439-452.
44. Smitha S, Rao AVB. Effects of Selenium on the Physiology of Heart Beat, OxygenConsumption and Growth in Silkworm Bombyx mori L [J]. American-EurasianJournal of Toxicological Sciences,2010,2(4):215-219.
45. Stadtman ER，Protein Oxidation and aging． Science,1992,2S7：1220-1224.
46. Talalay P, Fahey JW, Holtzclaw WD, Tory P, Zhang YS. Chemoprotection againstcancer by phase2enzyme induction [J]. Toxicology Letters,1995,82:173-179.
47. Talalay P. Chemoprotection against cancer by induction of phase2enzymes [J].Biofactors,2000,12(1):5-11.
48. Tephly TR, Burchell B. UDP-glucuronosyltransferase: a family of detoxifyingenzymes [J]. Trends Pharmacol Sciences,1990,11:276-279
49. Tucker FB, Wang KX, Fang J, Lü SL. Effect of Chromium on Hemolymph CatalaseActivity and Cocoon Quality of Two Mμlberry Silkworm (Bombyx mori) Races [J].Bulletin of environmental contamination and toxicology,2004,73(3):443-447.
50. Klotz U. Paracetamol (Acetaminophen)-a popμlar and widely used nonopioidanalgesic [J]. Arzneimittelforschung2012;62:355–359.
51. Vidyunmala S, Begum AF, Nagalakshmamma K, Rao AVB. Toxicity evaluation offluoride in silkworm Bombyx mori [J]. American-Eurasian Journal of ToxicologicalSciences,2010,2(2):96-99.
52. Vidyunmala S, Farhana AB, Nagalakshmamma K, Vijaya ABR. Toxicity Evaluationof Fluoride in Silkworm Bombyx mori L [J]. American-Eurasian Journal ofToxicological Sciences,2010,2(2):96-99.
53. Wang Q, Hasan G, Pikielny CW. Preferential expression of biotransformationenzymes in the olfactory organs of Drosophila melanogaster, the antennae [J].Journal of Biological Chemistry,1999,274(15):10309-10315.
54. Warren JT, Petryk A, Marqués G, Parvy JP, Shinoda T, Itoyama K, Kobayashi J,Jarcho M, Li Y, O’Connor MB, Dauphin-Villemant C, Gilbert L. Phantom encodesthe25-hydroxylase of Drosophila melanogaster and Bombyx mori: a P450enzymecritical in ecdysone biosynthesis [J]. Insect Biochemistry and Molecμlar Biology,2004,34(9):991-1010.
55. Wrighton S A, VandenBranden M, Ring B J. The human drug metabolizingcytochromes P450[J]. Journal of Pharmacokinetics and Biopharmaceutics,1996,24(5):461-473.
56. Matsumoto Y, Sumiya E, Sugita T, Sekimizu K. An invertebrate hyperglycemicmodel for the identification of anti-diabetic drugs. PLoS One.2011,6(3):e18292.
57. Yang H, Zhou Z, Zhang H, Chen M, Li J, Ma Y, Zhong B. Shotgun proteomicanalysis of the fat body during metamorphosis of domesticated silkworm (Bombyxmori)[J]. Amino Acids,2010,38(5):1333-1342.
58. Yu QY, Lu C, Li WL, Xiang ZH, Zhang Z. Annotation and expression ofcarboxylesterases in the silkworm, Bombyx mori [J]. Bmc Genomics,2009,10(1):553.
59. Yutaka Orihara, Hiroshi Hamamoto,Hiroshi Kasuga,Toru Shimada,YasushiKawaguchi5，Kazuhisa Sekimizu2,‘A silkworm–baculovirus model for assessing thetherapeutic effects of antiviral compounds:characterization and application to theisolation of antivirals from traditional medicines[J]，Journal of General Virology2008,89:188–194
60. Zhou SF. Polymorphism of human cytochrome P4502D6and its clinical significance[J]. Clinical Pharmacokinetics,2009,48(12):761-804.
61.艾均文,薛宏,何行健,孟繁利,朱勇,向仲怀.家蚕细胞色素P450基因的研究进展[J].昆虫学报,2011,54(8):918-926.
62.艾均文.家蚕全基因组细胞色素P450基因结构与进化分析及CYP18A1克隆与功能研究[D].重庆:西南大学,2008.
63.成碟，徐为人，刘昌孝．细胞色素P450(CYP450)遗传多态性研究进展[J]．中国药理学通报，2006,22(12):1409—1414．
64.丁媛媛,曾明,邱麟,许景峰.影响尿苷二磷酸葡醛酸转移酶活性的研究进展[J].解放军药学学报,2012,28(6):541-544.
65.董久鸣.家蚕(Bombyx mori)5龄幼虫脂肪体蛋白质组及其相关功能基因的研究[D]，杭州：浙江大学，2008
66.傅吉涛,刘朝良,凌尔军,查新民,李东升.家蚕血细胞分类和造血功能研究[J].安徽农业科学,2005,33(5):803-804.
67.高绘菊，苏振霞，窦学娥，王彦文，牟志美.盐酸诺氟沙星在健康及细菌感染家蚕中的药代动力学研究[J].蚕业科学,2008,34(2):280-283.
68.葛君,李兵,沈卫德.昆虫脂肪体与抗药性的关系研究现状与分析[J].江苏农业科学,2010,6:183-185.
69.郭栋,庞良芳,周宏灏.尿苷二磷酸葡萄糖醛酸基转移酶基因多态性的研究进展[J]，生理科学进展,2010,42(2):107-111.
70.郭晶,高菊芳,唐振华.羧酸酯酶及其在含酯类化合物代谢中的作用[J].农药,2007,46(6):365-368.
71.胡蒙蒙,王青,杨益众.重金属在昆虫体内的累积、分布与排泄[J].中国农学通报,2012,28(18):213-217.
72.李芬,刘小宁.棉铃虫细胞色素P450CYP6B6基因启动子活性检测条件的优化[J].生物技术通报,2012,5:031.
73.李秋菊,蕾义雄,何建平,王映芬. Ebselen对扑热息痛的毒性代谢产物NAPQI的体外清除作用[J].中国药学(英文版).1996,5(1):13-19.
74.李晓宇,刘皋林. CYP450酶特性及其应用研究进展[J].中国临床药理学与治疗学,2008,13(8):942-946.
75.李新,余应年.药物的II相代谢与酶系及其进展[J].中国临床药理学杂志,2000,16(6):458-465.
76.林国杂,陈芳艳,黄志君,李文楚.败血病菌感染家蚕马氏管组织碱性磷酸酶的病理学研究[J].广东蚕业,39(4):28-31.
77.林金明,屈峰.活性氧测定的基本原理与方法[J].分析化学评述与进展,2002，30(12):1507-1514.
78.彭然.家蚕常用内参基因的稳定性分析及两种实时荧光定量PCR方法比较[D].苏州大学,2012.
79.齐艳萍,许宇霞,王端.药物性肝损伤小鼠血清指标及肝脏组织学变化[J].黑龙江兽医科技,2010,(13):128-129.
80.钱惠田,周仙美.中国三蚕解剖图谱[M].广西科学技术出版社,南宁（第一版）,1989
81.王静. Columbin对实验性2型糖尿病大鼠肝脏药物代谢酶CYP450的影响[D].华中科技大学,2011.
82.王猛.家蚕几种尿苷二磷酸-葡萄糖基转移酶的基因表达与功能研究[D]，苏州：苏州大学,2011.
83.王猛,牛艳山,司马杨虎,徐世清.家蚕不同茧色品种中尿苷二磷酸-葡萄糖基转移酶(UGT)基因的表达差异[J].蚕业科学,2010,36(1):0033-0039.
84.滕霞,孙曼霁.羧酸酯酶研究进展[J].生命科学,2003,(1):31-35.
85.夏木斯亚.对乙酰氨基酚的药代动力学及其肝毒性的生理节律调控[D].南京：南京理工大学，2010.
86.向仲怀主编.蚕丝生物学[M].中国林业出版社,北京(第一版):2005.
87.肖龙云,程嘉翎,王俊,王春华.家蚕氟化物中毒后血淋巴中脂质过氧化物和抗氧化物含量及抗氧化酶活性的变化[J].蚕业科学,2010,36(006):1047-1051.
88.杨帅,王玲,赵奎军,韩岚岚.大豆蚜羧酸酯酶基因AgCarE的克隆、表达及活性分析[J],中国农业科学2012,45(18):3755-3763
89.杨亦桦.棉铃虫对拟除虫菊酯氧化代谢抗性的生化与分子机理[D]，南京：南京农业大学,2005.
90.姚慧鹏,郭爱芹,何芳青,鲁兴萌;吴小锋.家蚕幼虫5龄期消化管蛋白质组学[J].生物工程学报,2008,24(1):89-94.
91.袁红霞,裔洪根,徐世清.壬基酚对家蚕生长发育的影响[J].农业环境科学学报,2009,28(4):777-782.
92.张瑶华、李端.中国常用药品集[M].上海交通大学出版社，上海(第一版)：2006.
93.周庆祥,张志芳.家蚕血球的生成机理[J].中国蚕业,2004,25(2):82-84.
94.朱晓苏,宋艳,徐世清.家蚕作为模式生物在现代生物学中的应用[J].实验动物与比较医学,2009,29(1):61-65.