DeHaven-Hudkins D L, Lanyon L F, Ford-Rice F Y, Ator M A
Department of Enzymology and Receptor Biochemistry, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, PA 19426-0900.
Biochem Pharmacol. 1994 Mar 29;47(7):1231-9. doi: 10.1016/0006-2952(94)90395-6.
Binding to sigma sites in subcellular fractions of brain and in crude homogenates from peripheral tissues of the guinea pig was characterized with the [3H]ligands (+)pentazocine and di(2-tolyl)guanidine (DTG). The inhibitory effects of representative sigma compounds and cytochrome P450 inhibitors were evaluated in guinea pig tissues, and the effects of cytochrome P450 induction on sigma binding in the rat were investigated. For both ligands, the majority of sites were localized to the microsomal fractions. The KD values for 3Hpentazocine- or [3H]DTG-labeled sigma sites in guinea pig liver and testes were 2-fold lower than those in brain and heart. The number of sites labeled by 3Hpentazocine varied, with an order of liver > testes > brain > heart. In contrast, the Bmax values for [3H]DTG-defined sigma sites were greatest in testes, followed by liver, brain and heart. The rank order of potency for representative sigma and P450 compounds was similar in brain, liver and testes for both [3H]ligands, and the potency of selective compounds to displace sigma binding in guinea pig liver failed to correlate with their abilities to inhibit cytochrome P450IID1 activity in human liver. Following induction of cytochrome P450IIB1 with phenobarbital or cytochrome P450IA1 with beta-naphthoflavone, neither the affinity nor the number of sigma sites was altered in rat brain or liver. These results suggest that sigma sites in the periphery are similar to those in the brain, and that the sigma binding site is not identical with cytochrome P450IIB1, P450IA1 or P450IID1.
用[3H]配体（+）喷他佐辛和二（2-甲苯基）胍（DTG）对豚鼠脑亚细胞组分和外周组织粗匀浆中与σ位点的结合进行了表征。评估了代表性σ化合物和细胞色素P450抑制剂在豚鼠组织中的抑制作用，并研究了细胞色素P450诱导对大鼠σ结合的影响。对于这两种配体，大多数位点定位于微粒体组分。豚鼠肝脏和睾丸中[3H]（+）喷他佐辛或[3H]DTG标记的σ位点的KD值比脑和心脏中的低2倍。[3H]（+）喷他佐辛标记的位点数量各不相同，顺序为肝脏>睾丸>脑>心脏。相比之下，[3H]DTG定义的σ位点的Bmax值在睾丸中最大，其次是肝脏、脑和心脏。对于两种[3H]配体，代表性σ化合物和P450化合物在脑、肝脏和睾丸中的效力排序相似，并且选择性化合物取代豚鼠肝脏中σ结合的效力与其抑制人肝脏中细胞色素P450IID1活性的能力无关。用苯巴比妥诱导细胞色素P450IIB1或用β-萘黄酮诱导细胞色素P450IA1后，大鼠脑或肝脏中σ位点的亲和力和数量均未改变。这些结果表明外周的σ位点与脑中的相似，并且σ结合位点与细胞色素P450IIB1、P450IA1或P450IID1不同。
