Abood L G, Grassi S, Junig J, Crane A, Costanzo M
Arch Int Pharmacodyn Ther. 1985 Jan;273(1):62-73.
The specific binding of (-)- and (+)-[3H]-nicotine, as well as their relative rates of metabolism, were investigated in isolated rat hepatocytes and hepatocyte membranes. A Scatchard plot of both [3H]-enantiomers revealed two components, with the higher affinity site having Kd values of 2 X 10(-10) and 3 X 10(-9) M and Bmax values of 5 X 10(-15) and 4 X 10(-15) moles/mg protein for the (-)- and (+)-enantiomers, respectively. The lower affinity site for both enantiomers had a Kd of 4 X 10(-9) M and Bmax of 5 X 10(-14) moles/mg protein. The pH optimum of binding was in the higher pH range, in contrast to brain membranes where the optimum was 6.5 involving the protonated form of nicotine. A good correlation was observed between the pharmacologic potency of a group of nicotine analogues and their ability to bind to intact and hepatocyte membranes. The rate of conversion of nicotine to cotinine in hepatocytes membranes. The rate of conversion of nicotine to cotinine in hepatocytes is related to the degree of binding and accumulation. The results are discussed in terms of the possible relationship of the nicotine binding and translocation to its metabolism.
在分离的大鼠肝细胞和肝细胞膜中研究了（-）-和（+）-[³H]-尼古丁的特异性结合及其相对代谢速率。两种[³H]-对映体的Scatchard图显示有两个成分，对于（-）-和（+）-对映体，高亲和力位点的Kd值分别为2×10⁻¹⁰和3×10⁻⁹ M，Bmax值分别为5×10⁻¹⁵和4×10⁻¹⁵摩尔/毫克蛋白质。两种对映体的低亲和力位点的Kd为4×10⁻⁹ M，Bmax为5×10⁻¹⁴摩尔/毫克蛋白质。结合的最适pH在较高pH范围内，这与脑膜不同，脑膜的最适pH为6.5，涉及尼古丁的质子化形式。观察到一组尼古丁类似物的药理效力与其与完整细胞膜和肝细胞膜结合的能力之间有良好的相关性。尼古丁在肝细胞膜中转化为可替宁的速率。尼古丁在肝细胞中转化为可替宁的速率与结合和积累程度有关。根据尼古丁结合和转运与其代谢的可能关系对结果进行了讨论。
