Synthesis of deuterium- and tritium-labelled 4-hydroxyandrostene-3,17-dione, an aromatase inhibitor, and its metabolism in vitro and in vivo in the rat.
Synthesis of deuterium- and tritium-labelled 4-hydroxyandrostene-3,17-dione, an aromatase inhibitor, and its metabolism in vitro and in vivo in the rat.
复制标题
氘和氚标记的芳香酶抑制剂 4-羟基雄烯-3,17-二酮的合成及其在大鼠体外和体内的代谢。
DOI：
10.1016/0006-2952(82)90453-1
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发表时间：
1982
影响因子：
5.8
通讯作者：
Brodie,AM
中科院分区：
文献类型：
--
作者：
Marsh,DA;Romanoff,L;Williams,KI;Brodie,HJ;Brodie,AM
本文研究了芳香化酶抑制剂4-羟基雄烯二酮（4-OHA）在大鼠体内和体外的代谢。为了实现这一点，从4-羟基雄甾-4，6-二烯-3，17-二酮制备氘和氚标记的4-OHA。后者由4-雄甾烯-3，17-二酮合成。用氘代4-OHA体外孵育大鼠卵巢微粒体，经气相色谱/质谱鉴定其主要代谢产物为4-羟睾酮（4-OHT）。4-OHT约占卵巢微粒体孵育物中[6，7 - 3 H]-4-OHA总放射性的20%。[6，7 - 3 H]-4-OHA向4-羟基雌酮的转化率约为0.1%。在大鼠血液的游离中性部分中鉴定的[6，7 - 3 H]-4-OHA体内主要代谢产物为3β-羟基雄甾烷-4，17-二酮。该代谢物约占血液中总放射性的5%，而4-OHT仅占0.1%。4-OHT抑制卵巢芳构化作用达59%，而3β-羟基雄甾烷-4，17-二酮对卵巢芳构化作用不大。得出的结论是，虽然不能排除其代谢产物的其他影响，但以前报道的4-OHA的体内效应主要是由于其自身的活性。
The metabolism of the aromatase inhibitor 4-hydroxyandrostenedione (4-OHA) was studiedin vitroandin vivoin the rat. To accomplish this, deuterium- and tritium-labeled 4-OHA were prepared from 4-hydroxyandrosta-4,6-diene-3,17-dione. The latter was synthesized from 4-androstene-3,17-dione. Using deuterated 4-OHA inin vitroincubations of rat ovarian microsomes, 4-hydroxytesterone (4-OHT) was identified by gas chromatography/mass spectroscopy as the major metabolite. 4-OHT constituted approximately 20% of the total radioactivity from [6,7-3H]-4-OHA in the ovarian microsomal incubations. Conversion of [6,7-3H]-4-OHA to 4-hydroxyestrone was approximately 0.1%. The major metabolite of [6,7-3H]-4-OHAin vivoidentified in the free, neutral fraction of rat blood was 3β-hydroxyandrostane-4,17-dione. This metabolite accounted for approximately 5% of the total radioactivity in the blood, whereas 4-OHT accounted for only 0.1%. 4-OHT inhibitedin vitroovarian aromatization by 59%, but 3β-hydroxyandrostane-4,17-dione had little effect. It was concluded that thein vivoeffects of 4-OHA previously reported are largely due to its own activity although additional effects of its metabolic products cannot be excluded.