Alpha1-and beta2-adrenoceptors in the human liver with mass-forming intrahepatic cholangiocarcinoma: density and coupling to adenylate cyclase and phospholipase C

Besides the regulation of hepatic metabolic pathways in which adrenoceptors are mainly involved, their effect on the second messenger cAMP is thought to be related to the growth and differentiation of neoplastic cells. However, few studies have been done on the status of these structures in the human liver affected by cholangiocarcinoma (CC). Thus, in this study, changes in densities of α₁- and β₂-adrenoceptors (α₁-and β₂-ARs) were investigated in membranes of human liver with cholangiocarcinoma, and for comparison, in membranes of non-adjacent non-tumour liver using the potent antagonists ³H]-prazosin and ¹I]-iodocyanopindolol (ICYP) respectively. In addition, the activity of membrane-bound phospholipase C (PLC) and adenylate cyclase (AC) was also studied. In CC liver, the density of α₁-and β₂-ARs was significantly reduced, compared with non-tumour liver tissues (α₁-ARs: 23.38±4.69 vs 80.35±10.52, P=0.0002 β₂-ARs: 14.27±2.93 vs 33.22±4.32 fmol/mg protein, P=0.03), whereas the ligand affinities (K_D) remained unchanged. The β₂-selective antagonist ICI 118,551 was about 100 times more potent in inhibiting ICYP binding than the β₁-selective antagonist CGP 20712A; thus, more than 98% of the β-ARs were of the β₂-subtypes. The AC activity upon stimulants acting on β-AR (isoprenaline), G-protein (GTP, NaF) and AC (forskolin) was decreased in CC liver. Similarly, noradrenaline-stimulated PLC activity was significantly reduced in tumour tissues. In conclusion, in CC liver the α₁- and β₂-ARs density was down-regulated and the neoplastic invasion blunted AC and PLC activity. These quantitative changes may help to elucidate not fully understood pathogenetic mechanisms of disturbed hepatic metabolic processes, such as hypoglycemia during cancer in human liver.