title: Plasma membrane as the target site of cholic acid analogs.
abstract: Although the mechanism is unknown, Calculus Bovis and its active components, cholic acid analogs (CAAs), have been used in China to treat a wide range of diseases. Based on the previous finding that the potency of CAA is strongly dependent on the intrinsic surface activity, this paper aimed to investigate the role of the plasma membrane in the pharmacological activity of CAAs. First, CAAs (0.1 mM) caused a surface activity-dependent depression on ATPase activity in the cell membrane extract, but it had no effects on other cellular extracts, suggesting an indispensable role of the membrane environment for pharmacological activity. Second, CAAs lowered the membrane fluidity of cultured Caco-2 cells with the same rank-order of potency sequence. Third, the hypothesis that any functional protein located on the membrane is influenced by changes in cellular membrane fluidity was supported by: ileal contraction that was induced by acetylcholine and mediated by the muscarinic receptor (M-receptor) or the relaxation induced by adrenaline and mediated by the β-adrenergic receptor (β-receptor) was inhibited by CAAs. They also had similar rank-order of potency and the effects on the plasma membrane. Collectively, the plasma membrane may be a target for the CAAs to exert the multiple pharmacological effects which are mediated by the alteration of the membrane mobility and the function of integral membrane proteins.
authors.affiliation: Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Tian Hong
authors.initials: TH
authors.lastname: Zhang
authors.forename: Chun Guang
authors.initials: CG
authors.lastname: Liu
authors.forename: Zhen Qing
authors.initials: ZQ
authors.lastname: Zhang
authors.forename: Jin Xiu
authors.initials: JX
authors.lastname: Ruan
mesh_terms: D000251:Adenosine Triphosphatases / Q000032:analysis / Q000502:physiology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism*; D002793:Cholic Acids / Q000737:chemistry / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D007082:Ileum / Q000187:drug effects; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D058990:Molecular Targeted Therapy; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D002352:Carrier Proteins; D002793:Cholic Acids; D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; C530451:niuhuang qingwei; D000251:Adenosine Triphosphatases; D004837:Epinephrine