DISCLOSURE OF THE METABOLIC RETROVERSION OF TRIMETHYLAMINE N-OXIDE IN HUMANS - A PHARMACOGENETIC APPROACH
DISCLOSURE OF THE METABOLIC RETROVERSION OF TRIMETHYLAMINE N-OXIDE IN HUMANS - A PHARMACOGENETIC APPROACH
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DOI：
10.1038/clpt.1987.207
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发表时间：
1987-12-01
影响因子：
6.7
通讯作者：
SMITH, RL
中科院分区：
文献类型：
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作者：
ALWAIZ, M;AYESH, R;SMITH, RL
根据最终产品分析判断，N-氧化三甲胺 (TMAO) 天然存在于食用海鱼中，吸收良好，且排泄明显未发生变化。这些观察结果可能掩盖了这样一个事实，即胺N-氧化物经历了一系列脱氧和氧化反应，只是为了恢复到母体形式并以这种形式排出体外。我们建议将这一过程称为代谢逆转。为了评估 TMAO 的这种现象，我们研究了健康志愿者和四名先前表型为三甲胺 (TMA) 代谢 N-氧化方面存在遗传缺陷的受试者中口服物质的命运。其中两名受试者被归类为纯合子受影响者，另外两名受试者被归类为“携带者”。如果口服TMAO在其假定的逆转代谢过程中发生显着减少，则假设这将通过四名受影响受试者大量尿液排泄未氧化的TMA来揭示。四名健康受试者口服 TMAO 后，> 94% 的尿液 TMA 为 TMAO 形式，只有 < 4% 为游离碱。然而，在两名纯合子受影响的受试者口服TMAO后，未氧化的TMA分别占尿TMA总量的35%和51%，其余部分是TMAO所致。对于携带者受试者，施用TMAO后，TMA分别占尿TMA总量的12%和16%。因此，很明显，在患有遗传性 N-氧化缺陷的受试者中，口服 TMAO 后，未氧化的 TMA 的尿排泄量大大增加。对于研究对象而言，作为逆转代谢过程的一部分，口服 TMAO 剂量的约 40% 至 60% 会减少。有人提出，使用人类代谢变异可以对 TMAO 发生的逆转代谢进行定性和定量评估，并且该原理可以有效地应用于其他情况。
Trimethylamine N-oxide (TMAO), which is naturally occurring in dietary marine fish, is well absorbed and excreted apparently unchanged as judged by end-product analysis. Such observations may conceal the fact that the amine N-oxide has undergone a sequence of deoxygenation and oxygenation reactions only to revert to the parental form and be excreted as such.sbd.a process that we propose to call metabolic retroversion. To evaluate this phenomenon for TMAO we have investigated the fate of the orally administered substance in healthy volunteers and in four subjects previously phenotyped as having an inherited deficiency with respect to the metabolic N-oxidation of trimethylamine (TMA). Two of these subjects were typed as homozygous affected and the other two as "carriers". If substantial reduction of orally administered TMAO occurs during the course of its postulated retroverted metabolism, it was hypothesized that this would be revealed by the extensive urinary excretion of unoxidized TMA by the four affected subjects. After oral TMAO administration in the four healthy subjects, > 94% of the urinary TMA was in the form of TMAO and only < 4% as the free base. However, after oral TMAO in the two homozygous-affected subjects, unoxidized TMA accounted for 35% and 51%, respectively, of the total urinary TMA, the balance being due to TMAO. For the carrier subjects, TMA accounted for 12% and 16% of the total urinary TMA after TMAO administration. It is thus clear that the urinary excretion of unoxidized TMA is increased greatly in affected subjects with an inherited deficiency of N-oxidation after the oral administration of TMAO. For the subjects investigated it appears that some 40% to 60% of an oral dose of TMAO undergoes reduction as part of the retroverted metabolic process. It is proposed that the use of human metabolic variants allows both a qualitative and quantitative assessment of retroverted metabolism as occurs with TMAO, and the principle may usefully be applied in other situations.