title: Bioelectric toxicity caused by chlorpromazine in human lung epithelial cells.
abstract: Endogeneous and exogeneous amine-containing substances possess pneumophilic properties. Among them, tricyclic amphiphilic amine drugs like neuroleptics intensively accumulate in the lung cell membrane and occasionally cause severe respiratory disorders. In the present study, we examined the bioelectric toxicity of chlorpromazine (CPZ), a commonly used neuroleptic, in human lung epithelial cells. CPZ concentration-dependently inhibited the isoproterenol (ISO)-generated short-circuit current (I(sc)) sensitive to a nonselective K(+) channel blocker, clotrimazole (30 microM), but insensitive to a selective Ca(2+)-activated K(+) (K(Ca)) channel blocker, charybdotoxin (ChTx, 100 nM). The effects of apical CPZ on the ISO-induced responses were greater than those of basolateral CPZ. Forskolin- and 8-bromo-cyclic AMP-induced I(sc) were partially prevented by CPZ. Nystatin permeabilization of the monolayers revealed that CPZ attenuated the basolateral K(+) current elicited by ISO more than that elicited by forskolin and that the apical Cl(-) current elicited by forskolin was instead potentiated by CPZ, although it inhibited the ISO-induced Cl(-) current. 1-Ethyl-2-benzimdazolinone (1-EBIO, a K(Ca) channel opener, 500 microM)- and ionomycin (Ca(2+) ionophore, 1 microM)-evoked Cl(-) secretions were also sensitive to CPZ. These results indicate that CPZ inhibits transepithelial Cl(-) transport, affecting at least two different targets: the beta-adrenergic receptor and the basolateral K(+) channels (especially the K(Ca) channel). Electrostatic interactions at the inner surface of the membrane between the protonated amines of CPZ and negatively charged portions of the plasma membrane may be involved in the mechanisms.
authors.affiliation: Respiratory Division, Internal Medicine II, School of Medicine, Nagoya University, Tsurumai, Showa, Japan. itoyasu@med.nagoya-u.ac.jp
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ito
authors.forename: Shinji
authors.initials: S
authors.lastname: Sato
authors.forename: Masami
authors.initials: M
authors.lastname: Son
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kume
authors.forename: Kenzo
authors.initials: K
authors.lastname: Takagi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yamaki
mesh_terms: D000433:1-Propanol / Q000737:chemistry; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism; D002746:Chlorpromazine / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D000242:Cyclic AMP / Q000494:pharmacology; D004553:Electric Conductivity; D004563:Electrochemistry; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007099:Imipramine / Q000737:chemistry; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000166:cytology*; D015394:Molecular Structure; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism
chemical_list: D002712:Chlorides; D015221:Potassium Channels; D015759:Ionomycin; D000433:1-Propanol; D000242:Cyclic AMP; D007099:Imipramine; D011188:Potassium; D002746:Chlorpromazine