作者机构:
[Qiu, Li-Ling; Lin, Rui-Qing; Liu, Guo-Hua; Zhu, Xing-Quan] CASS, Dept Parasitol, State Key Lab Vet Etiol Biol, Lanzhou Vet Res Inst,Key Lab Vet Parasitol Gansu, Lanzhou 730046, Gansu, Peoples R China.;[Yuan, Zi-Guo; Qiu, Li-Ling; Lin, Rui-Qing; Pan, Hong; Weng, Ya-Biao; Hou, Jie] S China Agr Univ, Parasitol Lab, Coll Vet Med, Guangzhou 510642, Guangdong, Peoples R China.;[Liu, Guo-Hua] Hunan Agr Univ, Coll Vet Med, Changsha 410128, Hunan, Peoples R China.;[Wu, Xiang-Yun] Chinese Acad Sci, Key Lab Marine Bioresources Sustainable Utilizat, S China Sea Inst Oceanol, Guangzhou 510301, Guangdong, Peoples R China.;[Xie, Wen-Qin] Yongzhou Vocat Tech Coll, Dept Agr Sci & Technol, Yongzhou 425000, Hunan, Peoples R China.
通讯机构:
[Liu, Guo-Hua] C;CASS, Dept Parasitol, State Key Lab Vet Etiol Biol, Lanzhou Vet Res Inst,Key Lab Vet Parasitol Gansu, Lanzhou 730046, Gansu, Peoples R China.
作者:
Liu, Z. -Y.;Dai, M. -H.;Tao, Y. -F.;Chen, D. -M.;Yuan, Z. -H.*
期刊:
Journal of Veterinary Pharmacology and Therapeutics,2011年34(5):424-429 ISSN:0140-7783
通讯作者:
Yuan, Z. -H.
作者机构:
[Liu, Z. -Y.] Huazhong Agr Univ, Coll Vet Med, MAO Key Lab Food Safety Evaluat, Natl Reference Lab Vet Drug Residues HZAU, Wuhan 430070, Hubei, Peoples R China.;[Liu, Z. -Y.] Hunan Agr Univ, Fac Vet, Changsha, Hunan, Peoples R China.;[Yuan, Z. -H.] Huazhong Agr Univ, Coll Vet Med, MAO Key Lab Food Safety Evaluat, Natl Reference Lab Vet Drug Residues HZAU, Shizishan St, Wuhan 430070, Hubei, Peoples R China.
通讯机构:
[Yuan, Z. -H.] H;Huazhong Agr Univ, Coll Vet Med, MAO Key Lab Food Safety Evaluat, Natl Reference Lab Vet Drug Residues HZAU, Shizishan St, Wuhan 430070, Hubei, Peoples R China.
摘要:
Liu, Z.‐Y., Dai, M.‐H., Tao, Y.‐F., Chen, D.‐M., Yuan, Z.‐H. Inhibition of cytochrome P450 2A participating in coumarin 7‐hydroxylation in pig liver microsomes. J. vet. Pharmacol. Therap. 34, 424–429. Five commonly used human cytochrome P450 (CYP) inhibitors were examined for their effects on coumarin 7‐hydroxylase (CYP2A) activity in pig liver microsomes. The K m and V max values for coumarin 7‐hydroxylation in pig liver microsomes were estimated to be 1 μm and 0.26 nmol·mg/min, respectively. The following human CYP inhibitors caused little or no inhibition of CYP2A as defined by a K i > 200 μm: quinidine (CYP2D6), troleandomycin (CYP3A4), and sulfaphenazole (CYP2C9). The other two human CYP inhibitors were classified as strong inhibitors of CYP2A: 8‐methoxypsoralen (CYP2A6) and α‐naphthoflavone (CYP1A1/2). In the absence of a preincubation period, 8‐MOP inhibited the 7‐hydroxylation of coumarin with a K i value of 1.1 μm, which decreased to 0.1 μm when 8‐MOP was preincubated with pig liver microsomes for 3 min. α‐Naphthoflavone inhibited the 7‐hydroxylation of coumarin with a K i value of 32 μm, which did not increase ability to inhibitor CYP2A when α‐naphthoflavone was preincubated with pig liver microsomes for 3 min. These results of this study suggest that 8‐MOP is a potent, mechanism‐based inhibitor of pig CYP2A activity in pig liver microsomes.
摘要:
Olaquindox is a growth-promoting feed additive for food-producing animals. Its toxicities were reported to be closely related to the metabolism. To provide the interpretation of toxicities in animals, this study explored the metabolism of olaquindox in rats, chickens and pigs of different genders by qualitative metabolite profiling. Animals were fed olaquindox in an oral dose, and then their urine, plasma, feces, liver, kidney and muscle were collected. Liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry was used for structural investigation and identification of metabolites. The structures of metabolites were elucidated based on the accurate MS2 spectra and comparison of their changes in accurate molecular masses and fragment ions with those of parent drug or metabolite. A total of 18, 18 and 16 metabolites of rats, chickens and pigs were identified, respectively. Among the identified metabolites, 8 known metabolites were confirmed as an early study had stated, and 15 metabolites were found for the first time in vivo. The major metabolic pathways of olaquindox were proposed to be N-O reduction and oxidation of hydroxyl to carboxylic acid followed by N-O reduction. The qualitative species difference on the metabolite profiles of olaquindox among the three species was observed. However, metabolite profiles of olaquindox appeared to be qualitatively similar between female and male for the same species. The proposed metabolic pathways of olaquindox in animals will provide comprehensive data to clarify the metabolism of olaquindox among different species, and will give scientific explanation for toxicities and residues of olaquindox. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
摘要:
Bisdesoxyolaquindox is a reduced metabolite of olaquindox which is used as a medicinal feed additive in veterinary medicine. The relevant metabolism studies of bisdesoxyolaquindox have been carried out for the first time in rat, chicken, and pig liver subcellular fractions in order to understand the metabolic enzymes that are possibly responsible for the metabolism of olaquindox. The metabolites were characterized by high-performance liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry. The major metabolic pathways of bisdesoxyolaquindox in the three species were the oxidation of hydroxyl to bisdesoxyolaquindox-2'-carboxyl acid (O10) and the N-dealkylation of the side chain to 3-methylquinoxaline 2-carboxamide (O12). Other metabolic pathways were also proposed which involved the direct methyl oxidation and N-oxide on the quinoxaline ring in the three species as well as N-hydroxylation only in rat. The intrinsic clearance values in the liver microsomes for O10 and O12 were ranked in the order of chicken > pig >> rat and rat > pig >> chicken, respectively. Inhibition studies indicated that 8-methoxypsoralen, 4-methylpyrazole and alpha-naphthoflavone could inhibit the formations of O10 and O12 in all species. Quinidine, troleandomycin, diethyldithiocarbamate, and disulfiram showed an interspecies difference in the inhibition of the formation of two metabolites. In rat and pig liver cytosol, 4-methylpyrazole, menadione and chlorpromazine strongly inhibited the formation of O10. Both diethyldithiocarbamate and disulfiram were found to inhibit O10 formation in rat cytosol but not in pig cytosol. These results indicated the following: In rat liver microsomes. CYP2A might be involved in the formation of O10, and CYP1A, CYP2A and CYP2E would be involved in the O12 formation. In pig liver microsomes, CYP1A and CYP2E might catalyze the formations of O10 and O12. In rat cytosol, alcohol dehydrogenase, aldehyde oxidase and aldehyde dehydrogenase should catalyze the O10 formation. In pig cytosol, alcohol dehydrogenase and aldehyde oxidase might be involved in the formation of O10. In chicken, it was found that various CYP isoenzymes were capable of catalyzing the two reactions: none of the inhibitors of cytosol enzymes inhibited O10 formation in chicken cytosol. (C) 2010 Elsevier Ireland Ltd. All rights reserved.