Foth H, Aubrecht J, Höhne M, Walther U I, Kahl G F
Zentrum für Pharmakologie und Toxikologie, Universität Göttingen.
Clin Investig. 1992 Mar-Apr;70(3-4):175-81. doi: 10.1007/BF00184648.
The metabolic fate of cotinine, the major metabolite of nicotine, was studied in phenobarbital-induced and non-induced isolated perfused rat lung and liver and in isolated hepatocytes of rats and mice. The non-induced lung tissue showed low cotinine metabolizing capacity while the perfused liver was approximately four times more active. After phenobarbital pretreatment the metabolism of cotinine was increased eight-fold in the intact liver. A substantial increase in cotinine metabolism was also found in isolated hepatocytes from PB-induced rats and in cultured mouse hepatocytes grown in a medium supplemented with PB. This was paralleled by an increased formation of cotinine-N-oxide which could be inhibited by 100 microM metyrapone. In contrast, the pulmonary elimination of cotinine was not affected by PB. A dominant role of primary N-oxidation of nicotine compared to C-oxidation was apparent in non-induced rat liver. After PB treatment the rate of nicotine-N'-oxide formation dropped markedly while the cotinine related pathways were increased causing an inversion of the N- to C-oxidation ratio. In the lung, cotinine formation was the preferred metabolic pathway of nicotine already in non-induced organs. The pattern of nicotine metabolites was not altered by PB induction. In conscious PB-induced rats receiving nicotine orally or intravenously, 3'-hydroxycotinine was found as the main urinary metabolite of nicotine while only a small fraction was excreted as cotinine-N-oxide. This discrepancy between the profile of nicotine metabolites in perfused liver and lung and in the urine in vivo indicates that extrahepatic organs other than the lung may be important sites of cotinine metabolism.
可替宁是尼古丁的主要代谢产物，其代谢命运在苯巴比妥诱导和未诱导的离体灌注大鼠肺和肝脏以及大鼠和小鼠的离体肝细胞中进行了研究。未诱导的肺组织可替宁代谢能力较低，而灌注肝脏的活性约高四倍。苯巴比妥预处理后，完整肝脏中可替宁的代谢增加了八倍。在苯巴比妥诱导的大鼠分离的肝细胞以及在添加了苯巴比妥的培养基中培养的小鼠肝细胞中，也发现可替宁代谢大幅增加。这与可替宁 - N - 氧化物形成增加相平行，可被100微摩尔美替拉酮抑制。相比之下，苯巴比妥不影响可替宁的肺部消除。在未诱导的大鼠肝脏中，尼古丁的初级N - 氧化比C - 氧化起主导作用。苯巴比妥治疗后，尼古丁 - N'- 氧化物的形成速率明显下降，而与可替宁相关的途径增加，导致N - 氧化与C - 氧化比率倒置。在肺中，即使在未诱导的器官中，可替宁的形成也是尼古丁首选的代谢途径。苯巴比妥诱导并未改变尼古丁代谢产物的模式。在口服或静脉注射尼古丁的清醒苯巴比妥诱导大鼠中，发现3'- 羟基可替宁是尼古丁的主要尿代谢产物，而只有一小部分以可替宁 - N - 氧化物形式排出。灌注肝脏和肺以及体内尿液中尼古丁代谢产物谱之间的这种差异表明，除肺以外的肝外器官可能是可替宁代谢的重要部位。
