Abe Jun, Tomigahara Yoshitaka, Tarui Hirokazu, Omori Rie, Kawamura Satoshi
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd , 1-98, Kasugade-Naka 3-Chome, Konohana-Ku, Osaka 554-8558, Japan.
J Agric Food Chem. 2018 Feb 28;66(8):1955-1963. doi: 10.1021/acs.jafc.7b05463. Epub 2018 Feb 15.
A metabolite of procymidone, hydroxylated-PCM, causes rat-specific developmental toxicity due to higher exposure to it in rats than in rabbits or monkeys. When procymidone was administered to chimeric mice with rat or human hepatocytes, the plasma level of hydroxylated-PCM was higher than that of procymidone in rat chimeric mice, and the metabolic profile of procymidone in intact rats was well reproduced in rat chimeric mice. In human chimeric mice, the plasma level of hydroxylated-PCM was less, resulting in a much lower exposure. The main excretion route of hydroxylated-PCM-glucuronide was bile (the point that hydroxylated-PCM enters the enterohepatic circulation) in rat chimeric mice, and urine in human chimeric mice. These data suggest that humans, in contrast to rats, extensively form the glucuronide and excrete it in urine, as do rabbits and monkeys. Overall, procymidone's potential for causing teratogenicity in humans must be low compared to that in rats.
腐霉利的一种代谢物——羟基化腐霉利，因大鼠对其暴露量高于兔子或猴子，从而导致大鼠特有的发育毒性。当给具有大鼠或人肝细胞的嵌合小鼠施用腐霉利时，大鼠嵌合小鼠中羟基化腐霉利的血浆水平高于腐霉利，并且完整大鼠中腐霉利的代谢谱在大鼠嵌合小鼠中得到了很好的重现。在人嵌合小鼠中，羟基化腐霉利的血浆水平较低，导致暴露量低得多。羟基化腐霉利 - 葡萄糖醛酸苷在大鼠嵌合小鼠中的主要排泄途径是胆汁（羟基化腐霉利进入肠肝循环这一点），而在人嵌合小鼠中是尿液。这些数据表明，与大鼠不同，人类会大量形成葡萄糖醛酸苷并通过尿液排泄，兔子和猴子也是如此。总体而言，与大鼠相比，腐霉利对人类造成致畸性的可能性一定较低。
