Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite.
Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite.
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DOI：
10.1371/journal.pone.0002337
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发表时间：
2008-06-11
期刊：
影响因子：
3.7
通讯作者：
Ravindranath V
中科院分区：
文献类型：
--
作者：
Agarwal V;Kommaddi RP;Valli K;Ryder D;Hyde TM;Kleinman JE;Strobel HW;Ravindranath V
细胞色素 P450 (P450) 是药物代谢酶的超家族。 P450酶具有双重功能；它们可以将药物代谢为药理学上无活性的代谢物，以促进其排泄，或者将药物生物转化为药理学上活性的代谢物，其半衰期可能比母体药物更长。通常在人群中出现的对精神活性药物的不同药理学反应通常不能通过考虑肝脏代谢的差异来解释。大脑特定细胞核的代谢可能在作用于中枢神经系统的药物的药理调节中发挥作用，并有助于解释患者群体对这些药物的一些不同反应。 P450 酶也存在于大脑中，药物代谢可以在大脑中进行，并在作用部位改变药物的治疗作用。我们之前已经证明阿普唑仑（ALP）在大脑和肝脏中的生物转化存在本质差异，与肝脏相比，大脑中形成的α-羟基阿普唑仑（α-OHALP）相对较多。在本研究中，我们表明重组 CYP3A43 将 ALP 代谢为 α-OHALP 和 4-羟基阿普唑仑 (4-OHALP)，而 CYP3A4 主要将 ALP 代谢为其无活性代谢物 4-OHALP。人脑样本中 CYP3A43 mRNA 的表达与相对较高水平的 α-OH ALP 的形成相关，表明大脑中表达较高水平 CYP3A43 的个体会产生较多量的 α-OHALP。此外，在不同种族人群中，与肝脏相比，CYP3A43在大脑中的表达相对较高。由于CYP3A酶在药物代谢中发挥着重要作用，CYP3A43的较高表达将在人脑中产生不同的药物代谢谱，从而影响精神活性药物在作用部位的药效学。
Cytochrome P450 (P450) is a super-family of drug metabolizing enzymes. P450 enzymes have dual function; they can metabolize drugs to pharmacologically inactive metabolites facilitating their excretion or biotransform them to pharmacologically active metabolites which may have longer half-life than the parent drug. The variable pharmacological response to psychoactive drugs typically seen in population groups is often not accountable by considering dissimilarities in hepatic metabolism. Metabolism in brain specific nuclei may play a role in pharmacological modulation of drugs acting on the CNS and help explain some of the diverse response to these drugs seen in patient population. P450 enzymes are also present in brain where drug metabolism can take place and modify therapeutic action of drugs at the site of action. We have earlier demonstrated an intrinsic difference in the biotransformation of alprazolam (ALP) in brain and liver, relatively more α-hydroxy alprazolam (α-OHALP) is formed in brain as compared to liver. In the present study we show that recombinant CYP3A43 metabolizes ALP to both α-OHALP and 4-hydroxy alprazolam (4-OHALP) while CYP3A4 metabolizes ALP predominantly to its inactive metabolite, 4-OHALP. The expression of CYP3A43 mRNA in human brain samples correlates with formation of relatively higher levels of α-OH ALP indicating that individuals who express higher levels of CYP3A43 in the brain would generate larger amounts of α-OHALP. Further, the expression of CYP3A43 was relatively higher in brain as compared to liver across different ethnic populations. Since CYP3A enzymes play a prominent role in the metabolism of drugs, the higher expression of CYP3A43 would generate metabolite profile of drugs differentially in human brain and thus impact the pharmacodynamics of psychoactive drugs at the site of action.
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影响因子：
30.8
作者：
Kuehl, P;Zhang, J;Schuetz, E
通讯作者：
Schuetz, E
DOI：
10.1124/jpet.104.068908
发表时间：
2004-11-01
影响因子：
3.5
作者：
Williams, ET;Leyk, M;Strobel, HW
通讯作者：
Strobel, HW
影响因子：
4.7
作者：
Kommaddi, Reddy P.;Turman, Cheri M.;Ravindranath, Vijayalakshmi
通讯作者：
Ravindranath, Vijayalakshmi
影响因子：
2.1
作者：
Hirota, N;Ito, K;Sugiyama, Y
通讯作者：
Sugiyama, Y
DOI：
10.1016/s0169-328x(02)00177-8
发表时间：
2002-06-30
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Chinta, SJ;Pai, HV;Ravindranath, V
通讯作者：
Ravindranath, V