尼古丁或可替宁对大鼠离体肺和肝中4-甲基亚硝胺基-1-(3-吡啶基)-1-丁酮（NNK）代谢的影响。

Effect of nicotine or cotinine on metabolism of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver.

作者信息

Schulze J, Schrader E, Foth H, Kahl G F, Richter E

机构信息

Walther-Straub-Institute of Pharmacology und Toxicology, Ludwig Maximilians University of München, Germany.

出版信息

Naunyn Schmiedebergs Arch Pharmacol. 1998 Mar;357(3):344-50. doi: 10.1007/pl00005177.

DOI:10.1007/pl00005177

PMID:9550308

Abstract

The scope of the present study was to investigate whether nicotine or cotinine will affect the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated perfused rat lungs and livers and to study the effect of starvation on pulmonary metabolism of NNK. NNK metabolism was investigated in isolated perfused liver and lung of male F344 rats perfused with 35 nM [5-3H]NNK in presence of a 1400-fold excess of the main tobacco alkaloid nicotine and its metabolite cotinine. In perfused rat livers, nicotine and cotinine inhibited NNK elimination and metabolism and led to a substantial increase of elimination half-life from 14.6 min in controls to 25.5 min after nicotine and 36.6 min after cotinine co-administration, respectively. In parallel, the pattern of NNK metabolites was changed by nicotine and cotinine. The pathway of alpha-hydroxylation representing the metabolic activation of NNK was decreased to 77% and 85% of control values, whereas N-oxidation of NNK and glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased 2.6- and 1.2-fold in presence of nicotine and cotinine, respectively. When isolated rat lungs were perfused with 35 nM NNK for 3 h neither the elimination nor the pattern of metabolites were substantially affected due to co-administration of 50 microM nicotine or cotinine. Cytochrome P450 2E1 is known to participate in the activation of NNK and can be induced by starvation. However, isolated rat lungs from male Sprague Dawley rats perfused with [1-14C]NNK at about 2 microM for 3 h, revealed only small differences in pulmonary elimination and pattern of NNK metabolites between fed and starved animals. These results suggest that nicotine and its main metabolite cotinine inhibit the metabolic activation of NNK predominantly in the liver whereas activation in lung, a main target organ of NNK induced carcinogenesis, remained almost unaffected.

摘要

本研究的目的是调查尼古丁或可替宁是否会影响4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）在离体灌注大鼠肺和肝脏中的代谢，并研究饥饿对NNK肺代谢的影响。在雄性F344大鼠的离体灌注肝脏和肺中，在存在1400倍过量的主要烟草生物碱尼古丁及其代谢产物可替宁的情况下，用35 nM [5-³H]NNK进行灌注，研究NNK的代谢。在灌注的大鼠肝脏中，尼古丁和可替宁抑制NNK的消除和代谢，导致消除半衰期从对照组的14.6分钟分别大幅增加到尼古丁给药后的25.5分钟和可替宁共同给药后的36.6分钟。同时，尼古丁和可替宁改变了NNK代谢产物的模式。代表NNK代谢活化的α-羟基化途径降至对照值的77%和85%，而在尼古丁和可替宁存在下，NNK的N-氧化和4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁醇（NNAL）的葡萄糖醛酸化分别增加了2.6倍和1.2倍。当用35 nM NNK灌注离体大鼠肺3小时时，由于共同给药50 μM尼古丁或可替宁，消除和代谢产物模式均未受到实质性影响。细胞色素P450 2E1已知参与NNK的活化，并且可被饥饿诱导。然而，用约2 μM的[1-¹⁴C]NNK灌注雄性Sprague Dawley大鼠的离体肺3小时，结果显示喂食和饥饿动物之间在肺消除和NNK代谢产物模式上只有微小差异。这些结果表明，尼古丁及其主要代谢产物可替宁主要在肝脏中抑制NNK的代谢活化，而在NNK诱导致癌作用的主要靶器官肺中，活化几乎未受影响。