The effect of opiates on the activity of human placental aromatase/CYP19.
The effect of opiates on the activity of human placental aromatase/CYP19.
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阿片类药物对人胎盘芳香酶/CYP19活性的影响。
DOI：
10.1016/j.bcp.2006.08.019
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发表时间：
2007
影响因子：
5.8
通讯作者：
Ahmed,MahmoudS
中科院分区：
文献类型：
--
作者：
Zharikova,OlgaL;Deshmukh,SujalV;Kumar,Meena;Vargas,Ricardo;Nanovskaya,TatianaN;Hankins,GaryDV;Ahmed,MahmoudS
芳香化酶（细胞色素P450 19）是人胎盘合成雌激素的关键酶。它也是代谢阿片类药物l-乙酰美沙酮（LAAM）、美沙酮和丁丙诺啡（BUP）的主要胎盘酶。美沙酮和BUP用于治疗阿片类成瘾，是睾酮转化为雌二醇（E2）和16 α-羟基睾酮（16-OHT）转化为雌三醇（E3）的竞争性抑制剂。本研究的目的是确定20种阿片类药物对胎盘芳香化酶E2和E3形成的影响，这些药物可用于妊娠患者的治疗适应症或滥用。所获得的数据表明，阿片类药物增加，抑制，或对芳香酶活性没有影响。由于16-OHT对芳香化酶的亲和力低于睾酮，因此它们对E3形成的影响比对E2的影响更明显。抑制E3形成的阿片类药物的Ki值为舒芬太尼，7 ± 1 μ M; LAAM，13 ± 8 μ M;芬太尼，25 ± 5 μ M;羟考酮，92 ± 22 μ M;可待因，218 ± 69 μ M;（+）-喷他佐辛，225 ± 73 μ M。激动剂吗啡、海洛因、氢吗啡酮、羟吗啡酮、氢可酮、丙氧芬、哌替啶、左啡诺、右啡烷和（-）-喷他佐辛以及拮抗剂纳洛酮和纳洛酮导致E3形成增加对照的124 - 160%，但对E2形成没有影响。此外，羟考酮和可待因不抑制E2形成，芬太尼、舒芬太尼和（+）-喷他佐辛的IC 50值均> 1000 μ M。抑制雌激素形成的阿片类药物急性给药不太可能影响母体和/或新生儿结局。然而，在整个怀孕期间滥用其中任何一种药物的影响目前尚不清楚。
Aromatase, cytochrome P450 19, is a key enzyme in the biosynthesis of estrogens by the human placenta. It is also the major placental enzyme that metabolizes the opiates l-acetylmethadol (LAAM), methadone, and buprenorphine (BUP). Methadone and BUP are used in treatment of the opiate addict and are competitive inhibitors of testosterone conversion to estradiol (E2) and 16α-hydroxytestosterone (16-OHT) to estriol (E3) by aromatase. The aim of this investigation is to determine the effect of 20 opiates, which can be administered to pregnant patients for therapeutic indications or abused, on E2and E3formation by placental aromatase. Data obtained indicated that the opiates increased, inhibited, or had no effect on aromatase activity. Their effect on E3formation was more pronounced than that on E2due to the lower affinity of 16-OHT than testosterone to aromatase. The Kivalues for the opiates that inhibited E3formation were sufentanil, 7±1μM; LAAM, 13±8μM; fentanyl, 25±5μM; oxycodone, 92±22μM; codeine, 218±69μM; (+)-pentazocine, 225±73μM. The agonists morphine, heroin, hydromorphone, oxymorphone, hydrocodone, propoxyphene, meperidine, levorphanol, dextrorphan, and (−)-pentazocine and the antagonists naloxone and naltrexone caused an increase in E3formation by 124–160% of control but had no effect on E2formation. Moreover, oxycodone and codeine did not inhibit E2formation and the IC50values for fentanyl, sufentanil, and (+)-pentazocine were >1000μM. It is unlikely that the acute administration of the opiates that inhibit estrogen formation would affect maternal and/or neonatal outcome. However, the effects of abusing any of them during the entire pregnancy are unclear at this time.