Scott W J, Collins M D, Nau H
Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
Environ Health Perspect. 1994 Dec;102 Suppl 11(Suppl 11):97-101. doi: 10.1289/ehp.94102s1197.
We have studied four organic acids of similar structure to further understand the basis of their developmental toxicity. Valproic acid (2-propyl pentanoic acid), ethylhexanoic acid, and octanoic acid are isomeric C8 organic acids but their teratologic potency varied widely. Valproic acid induced a moderate to severe teratologic outcome after a single oral administration of 6.25 mmoles/kg on day 12 of rat pregnancy. Twice as much ethylhexanoic acid (12.5 mmoles/kg) induced a less severe response. Octanoic acid was nonteratogenic even at the very high dose of 18.75 mmoles/kg. This latter result is undoubtedly due to poor intestinal absorption of octanoic acid, as the maternal plasma levels never reached half of those measured for valproic acid and ethylhexanoic acid. Moreover, only a tiny fraction of that in maternal plasma was actually transferred into the embryo. On the other hand, the peak concentration and duration of exposure to valproic acid and ethylhexanoic acid were very similar despite a more severe teratologic outcome following valproic acid, which indicated higher intrinsic activity of this latter agent. A fourth agent, methylhexanoic acid, was also studied and had no teratogenic effects when given at 14.1 mmoles/kg. Pharmacokinetic studies of this agent revealed higher peak concentrations in maternal plasma and embryo than valproic acid or ethylhexanoic acid, but the duration of exposure was shorter. We conclude that pharmacokinetic parameters can be important determinants of teratologic outcome and thereby help explain differing potencies of structurally similar chemicals.
我们研究了四种结构相似的有机酸，以进一步了解它们发育毒性的基础。丙戊酸（2-丙基戊酸）、乙基己酸和辛酸是同分异构的C8有机酸，但它们的致畸效力差异很大。在大鼠妊娠第12天单次口服6.25毫摩尔/千克丙戊酸后，会导致中度至重度的致畸结果。两倍剂量的乙基己酸（12.5毫摩尔/千克）引起的反应较轻。即使在高达18.75毫摩尔/千克的极高剂量下，辛酸也没有致畸性。后一结果无疑是由于辛酸的肠道吸收较差，因为母体血浆水平从未达到丙戊酸和乙基己酸测量值的一半。此外，母体血浆中的辛酸只有极小一部分实际转移到胚胎中。另一方面，尽管丙戊酸导致的致畸结果更严重，但其峰值浓度和暴露持续时间与乙基己酸非常相似，这表明丙戊酸具有更高的内在活性。还研究了第四种物质甲基己酸，当给予14.1毫摩尔/千克时没有致畸作用。对该物质的药代动力学研究表明，其在母体血浆和胚胎中的峰值浓度高于丙戊酸或乙基己酸，但暴露持续时间较短。我们得出结论，药代动力学参数可能是致畸结果的重要决定因素，从而有助于解释结构相似化学物质不同的效力。
