title: Influence of cell membrane potential, and selectivity of the Na+/H+ exchanger and Cl-/HCO3- exchanger on the intracellular accumulation of adriamycin.
abstract: Intracellular accumulation of adriamycin (ADR) has been reported to be influenced by cell membrane potential. We first evaluated intracellular accumulation of ADR and 3,3'-(di-n-hexyl)-2,2'-oxacarbocyanine iodide (NK-2280), an indicator of cell membrane potential, and found a good correlation between ADR and NK-2280 intracellular accumulation in several cell lines. This suggests that ADR accumulation may be influenced by cell membrane potential or the mechanisms of NK-2280 accumulation may be similar to those of ADR accumulation. Next, we observed the influence of the NA+/H+ exchanger and Cl-/HCO3- exchanger on the intracellular accumulation of ADR and NK-2280, and found that ADR accumulation decreased with increasing concentrations of 3,5-diamino-6-chloro-N-(diaminomethylene)pyrazinecarboxamide (amiloride), an inhibitor of the Na+/H+ exchanger, and 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS), an inhibitor of the Cl-/HCO3- exchanger, however, NK-2280 accumulation was increased by amiloride, and decreased by DIDS. The increased accumulation of NK-2280 induced by amiloride may be due to the increased cell membrane potential caused by the inhibition of H+ ion efflux and NA+ ion influx due to the inhibition of the Na+/H+ exchanger. The decreased accumulation of NK-2280 may be also due to the decreased cell membrane potential caused by the inhibition of Cl- ion efflux due to the inhibition of the Cl-/HCO3- exchanger by DIDS. However, the decreased rate caused by DIDS was greater than the increased rate caused by amiloride. Therefore, it is suggested that the decreased accumulation of NK-2280 by DIDS may be influenced by other factors apart from cell membrane potential. These results suggest that the Cl-/HCO3- exchanger may be related to both ADR accumulation, and NK-2280 accumulation, and that the Na+/H+ exchanger may be related to ADR accumulation, but not NK-2280. This suggests that the Cl-/HCO3- exchanger is of low selectivity.
authors.affiliation: Department of Radiology, Okayama University Medical School, Japan.
authors.forename: J I
authors.initials: JI
authors.lastname: Asaumi
authors.forename: S
authors.initials: S
authors.lastname: Kawasaki
authors.forename: X S
authors.initials: XS
authors.lastname: Gao
authors.forename: M
authors.initials: M
authors.lastname: Kuroda
authors.forename: Y
authors.initials: Y
authors.lastname: Hiraki
mesh_terms: D016475:3T3 Cells / Q000378:metabolism; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D017920:Antiporters / Q000502:physiology*; D027963:Chloride-Bicarbonate Antiporters; D004317:Doxorubicin / Q000378:metabolism*; D007202:Indicators and Reagents / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology*
chemical_list: D000903:Antibiotics, Antineoplastic; D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D007202:Indicators and Reagents; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; D004317:Doxorubicin; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid