Abass Khaled, Reponen Petri, Mattila Sampo, Pelkonen Olavi
Institute of Biomedicine, University of Oulu, Finland.
Chem Biol Interact. 2009 Oct 7;181(2):210-9. doi: 10.1016/j.cbi.2009.06.001. Epub 2009 Jun 11.
The in vitro metabolism of carbosulfan, a widely used carbamate insecticide, by hepatic microsomes from human, rat, mouse, dog, rabbit, minipig, and monkey was studied. Altogether eight (8) phase I metabolites were detected by LC-MS; phase II metabolites were not found in human homogenates fortified with appropriate cofactors. The primary metabolic pathways were the initial oxidation of sulfur to carbosulfan sulfinamide ('sulfur oxidation pathway') and the cleavage of the nitrogen sulfur bond (N-S) to give carbofuran and dibutylamine ('carbofuran pathway'). Carbofuran was further hydroxylated to 3-hydroxycarbofuran and/or 7-phenolcarbofuran, which were further oxidized to 3-ketocarbofuran or 3-hydroxy-7-phenolcarbofuran, respectively, and finally to 3-keto-7-phenolcarbofuran. 3-Hydroxycarbofuran was the main metabolite in all species, but otherwise there were some qualitative interspecies differences in carbofuran pathway metabolites. Only rabbit liver microsomes were able to metabolize carbofuran via hydroxylation to 7-phenolcarbofuran. Carbofuran was not detected in dog liver microsomes due to rapid further metabolism. In general, liver microsomes from all seven species produced more toxic products (carbofuran, 3-hydroxy-carbofuran, 3-ketocarbofuran) more rapidly than a detoxification product (carbosulfan sulfinamide). Differences in intrinsic hepatic clearances (CL(int)) between the lowest and highest species were moderate; 2-fold for the carbofuran pathway, 2.7-fold for carbosulfan sulfinamide and 6.2-fold for dibutylamine. Our studies, although restricted to in vitro metabolic data from human and animal hepatic preparations, provide valuable quantitative carbosulfan-specific data for risk assessment, which suggest that interspecies differences, for carbosulfan active chemical moiety, in toxicokinetics are within the standard applied factor for species extrapolation in toxicokinetics. These results will be valuable in further defining the risks associated with exposure to carbosulfan.
研究了广泛使用的氨基甲酸酯类杀虫剂丁硫克百威在人、大鼠、小鼠、狗、兔子、小型猪和猴子的肝微粒体中的体外代谢情况。通过液相色谱 - 质谱联用共检测到8种I相代谢物；在用适当辅因子强化的人匀浆中未发现II相代谢物。主要代谢途径是硫最初氧化为丁硫克百威亚砜胺（“硫氧化途径”）以及氮硫键（N - S）断裂生成克百威和二丁胺（“克百威途径”）。克百威进一步羟基化生成3 - 羟基克百威和/或7 - 酚基克百威，它们分别进一步氧化为3 - 酮基克百威或3 - 羟基 - 7 - 酚基克百威，最终生成3 - 酮基 - 7 - 酚基克百威。3 - 羟基克百威是所有物种中的主要代谢物，但在克百威途径代谢物方面存在一些种间定性差异。只有兔肝微粒体能够通过羟基化将克百威代谢为7 - 酚基克百威。由于快速的进一步代谢，在狗肝微粒体中未检测到克百威。总体而言，所有七个物种的肝微粒体产生毒性产物（克百威、3 - 羟基克百威、3 - 酮基克百威）的速度比解毒产物（丁硫克百威亚砜胺）更快。最低和最高物种之间的内在肝清除率（CL(int)）差异适中；克百威途径为2倍，丁硫克百威亚砜胺为2.7倍，二丁胺为6.2倍。我们的研究虽然仅限于人和动物肝脏制剂的体外代谢数据，但为风险评估提供了有价值的丁硫克百威特异性定量数据，这表明丁硫克百威活性化学部分在毒代动力学方面的种间差异在毒代动力学物种外推的标准应用因子范围内。这些结果对于进一步确定与丁硫克百威接触相关的风险将是有价值的。
