Accumulation and metabolism of drugs and CYP probe substrates in zebrafish larvae
Accumulation and metabolism of drugs and CYP probe substrates in zebrafish larvae
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DOI：
10.3109/00498254.2010.493960
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发表时间：
2010-08-01
期刊：
影响因子：
1.8
通讯作者：
Gardner, I.
中科院分区：
文献类型：
--
作者：
Alderton, W.;Berghmans, S.;Gardner, I.
1.本研究在药理学和毒理学检测的相关条件下，研究了多种药物和常用的细胞色素P450(Cyps)探针在斑马鱼仔鱼体内的积累和代谢。对西沙必利、氯丙嗪、维拉帕米、睾酮和右美沙芬的研究表明，斑马鱼幼体催化一系列第一阶段(氧化、N-脱甲基、O-脱乙基和N-脱烷基)和第二阶段(硫化和葡萄糖醛酸化)反应。与哺乳动物相比，斑马鱼幼体的代谢途径既有相似之处，也有不同之处。在斑马鱼幼体中观察到非那西丁代谢为扑热息痛，右美沙芬代谢为右美沙芬(分别由CYP 1A2和2D6催化的代谢反应)。此外，斑马鱼幼体在受精后7天(7d.p.f.)羟基双氯芬酸、安非他酮、他克林和睾酮。虽然在斑马鱼幼体中检测到了几种化合物的代谢物，但在对代谢物数量进行量化的情况下，形成的任何特定代谢物的量都很低，仅占添加的母体化合物量的一小部分。此外，当斑马鱼幼体中的代谢物浓度与亲本化合物的测量水平进行比较时，代谢物浓度总是远远低于亲本化合物的浓度。总体而言，就目前研究中使用的化合物而言，量化的代谢物不太可能对在通常用于此类研究的范例下对斑马鱼幼体进行的安全药理学或毒理学研究的结果做出重大贡献。
1. This study examined the accumulation and metabolism of a number of drugs and commonly used probes for human cytochrome P450s (CYPs) in zebrafish larvae under conditions relevant to pharmacological and toxicological assays.2. Studies with cisapride, chlorpromazine, verapamil, testosterone, and dextromethorphan showed that the zebrafish larvae catalyze a range of phase 1 (oxidation, N-demethylation, O-de-ethylation, and N-dealkylation) and phase 2 (sulfation and glucuronidation) reactions. Both similarities and differences in the metabolic pathways were observed in zebrafish larvae when compared to mammals.3. Metabolism of phenacetin to paracetamol and dextromethorphan to dextrorphan (metabolic reactions catalyzed by CYP 1A2 and 2D6 in humans respectively) were observed in the zebrafish larvae. In addition the zebrafish larvae 7 days post fertilization (7 d.p.f.) hydroxylated diclofenac, bupropion, tacrine, and testosterone.4. Although metabolites of several compounds were detected in zebrafish larvae, in the instances where the metabolite amounts were quantified, the amount of any specific metabolite formed was low, accounting for only a small percentage of the amount of parent compound added. Furthermore, when the concentrations of metabolite present in the zebrafish larvae were compared with the measured level of parent compound, the metabolite concentrations were always much lower than that of parent compound. Overall, for the compounds used in the current study it is unlikely that the quantified metabolites would significantly contribute to the outcome of safety pharmacology or toxicology studies conducted in zebrafish larvae under the paradigms typically used for such investigations.