Teratogenicity in vitro of 2-acetylaminofluorene: role of biotransformation in the rat.
Teratogenicity in vitro of 2-acetylaminofluorene: role of biotransformation in the rat.
复制标题
2-乙酰氨基芴的体外致畸性：生物转化在大鼠中的作用。
DOI：
10.1002/tera.1420270105
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发表时间：
1983
期刊：
影响因子：
--
通讯作者：
Juchau,MR
中科院分区：
文献类型：
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作者：
Faustman-Watts,E;Greenaway,JC;Namkung,MJ;Fantel,AG;Juchau,MR
在胚胎培养系统中，对高效致突变剂和致癌物2-乙酰氨基荧烯(AAF)进行了直接致畸试验。浓度高达75μg/ml(336μM)的AAF不会产生可检测到的畸形，在第10天(怀孕第11天；受精后一天被指定为第0天)移植的大鼠胚胎的存活率和生长只有轻微的下降。然而，在培养液中加入微粒体单加氧酶系统(从大鼠肝脏中制备)，导致了活力和生长的显著变化。所有移植胚胎暴露于浓度高于60μg/ml(269μM)的AAF和微粒体单加氧酶系统后，均表现出明显的畸形，大小和大分子含量均显著降低。两种代谢物N-羟基-2-乙酰氨基荧烯(N-OH-AAF)和N-乙酰氧基-2-乙酰氨基荧烯(AAAF)在没有单加氧酶系统的情况下都会产生畸形。当浓度为25μg/ml(10~5和88μM)时，暴露于这些代谢物的胚胎约有50%畸形。与代谢物相关的主要畸形是前脑区腹外突出和发育不良，而AAF加上单氧合酶系统会导致神经管闭合中断。这提示其他代谢产物可能参与了AAF诱导的畸形综合征。在含有N-OH-AAF或AAAF的培养物中加入单加氧酶系统可增加畸形率，但不会增加致死率或降低生长速度。
2‐Acetylaminofluorene (AAF), a highly effective mutagen and carcinogen, was tested as a direct‐acting teratogen in an embryo culture system. Concentrations of up to 75 μg/ml (336 μM) of AAF produced no detectable malformations and only minimal decreases in viability and growth of rat embryos explanted on day 10 (11th day of gestation; the day after fertilization was designated as day 0). Inclusion of a microsomal monooxygenase system (prepared from rat liver) in the culture medium, however, resulted in marked changes in viability and growth. All explanted embryos exposed to concentrations of AAF above 60 μg/ml (269 μM) plus the microsomal monooxygenase system exhibited readily observable malformations as well as significant decreases in size and macromolecular content. Two metabolites, N‐hydroxy‐2‐acetylaminofluorene (N‐OH‐AAF) and N‐acetoxy‐2‐acetylaminofluorene (AAAF), each produced malformations in the absence of a monooxygenase system. At concentrations of 25 μg/ml (105 and 88 μM) approximately 50% of the embryos exposed to these metabolites were malformed. The predominant malformations associated with the metabolites were ventrolateral protrusions and hypoplasia of the prosencephalic region, whereas AAF plus the monooxygenase system produced an interruption of neural tube closure. This suggested the possibility that other metabolites may participate in the AAF‐induced malformation syndrome. The addition of the monooxygenase system to cultures containing N‐OH‐AAF or AAAF increased the frequency of malformations without increasing lethality or decreasing growth.