Aromatase is the major enzyme metabolizing buprenorphine in human placenta
Aromatase is the major enzyme metabolizing buprenorphine in human placenta
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DOI：
10.1124/jpet.103.053199
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发表时间：
2003-09-01
影响因子：
3.5
通讯作者：
Ahmed, MS
中科院分区：
文献类型：
--
作者：
Deshmukh, SV;Nanovskaya, TN;Ahmed, MS
丁丙诺啡(BUP)是一种部分阿片类激动剂，用于治疗成人和孕妇对这类毒品上瘾。经胎盘移植的动力学参数和BUP在胎盘小叶中的灌流过程中的代谢是我们实验室早期报告的主题。本研究的目的是鉴定和鉴定足月人胎盘中催化BUP代谢的酶。去丁丙诺啡(Norbuprenogine，NorBUP)是高效液相色谱和质谱法测定的唯一代谢物。负责BUP代谢的酶的活性在微粒体组分中最高，在胞质组分中最低，线粒体介于两者之间。对芳香酶(CYP 19)具有选择性亲和力的化合物，即4-羟基雄烯二酮和氨基戊二酰亚胺，对去甲基丁二醛的形成有70%的抑制作用。抗CyP19的单抗是最有效的BUP脱烷基化抑制剂。将胎盘微粒体的BUP脱烷基化饱和等温线与商品化的CYP 19系统进行比较，得到了相似的动力学参数，表观K-m值分别为12+/-4.0和14+/-8.0um。因此，芳香酶是催化正常妊娠胎盘中BUP生物转化为NorBUP的主要酶。不排除其他细胞色素P450亚型或酶(S)参与胎盘组织中BUP的代谢。
Buprenorphine (BUP) is a partial opiate agonist used for treatment of the adult and the pregnant addicted to this class of narcotics. The kinetic parameters for transplacental transfer and the metabolism of BUP during its perfusion in a placental lobule were the subject of an earlier report from our laboratory. The aim of this investigation is to identify and characterize the enzyme catalyzing the metabolism of BUP in term human placenta. Norbuprenorphine (norBUP) is the only metabolite formed as determined by high performance liquid chromatography and mass spectrometry. The activity of the enzyme responsible for BUP metabolism is highest in the microsomal fraction and lowest in the cytosolic, with the mitochondrial in between. Compounds with selective affinity to the enzyme aromatase (CYP 19), namely 4-hydroxyandrostenedione and aminoglutethimide, caused >70% inhibition of norBUP formation. Monoclonal antibodies raised against CYP 19 were the most potent inhibitors of BUP dealkylation. A comparison between the data obtained from the saturation isotherm for BUP dealkylation by placental microsomes and a commercially available system of cDNA-expressed CYP 19 indicated similar kinetic parameters, with apparent K-m values of 12+/-4.0 and 14+/-8.0 muM, respectively. Therefore, aromatase is the major enzyme catalyzing the biotransformation of BUP to norBUP in term human placentas obtained from healthy pregnancies. The minor involvement of other cytochrome P450 isoforms or enzyme(s) in the metabolism of BUP in placental tissue cannot be ruled out.