ATP7B detoxifies silver in ciliated airway epithelial cells

Journal Article · Mon Mar 15 04:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.11.023· OSTI ID:21344889

Ibricevic, Aida ^[1]

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1. Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 (United States)

Silver is a centuries-old antibiotic agent currently used to treat infected burns. The sensitivity of a wide range of drug-resistant microorganisms to silver killing suggests that it may be useful for treating refractory lung infections. Toward this goal, we previously developed a methylated caffeine silver acetate compound, SCC1, that exhibits broad-spectrum antimicrobial activity against clinical strains of bacteria in vitro and when nebulized to lungs in mouse infection models. Preclinical testing of high concentrations of SCC1 in primary culture mouse tracheal epithelial cells (mTEC) showed selective ciliated cell death. Ciliated cell death was induced by both silver- and copper-containing compounds but not by the methylated caffeine portion of SCC1. We hypothesized that copper transporting P-type ATPases, ATP7A and ATP7B, play a role in silver detoxification in the airway. In mTEC, ATP7A was expressed in non-ciliated cells, whereas ATP7B was expressed only in ciliated cells. The exposure of mTEC to SCC1 induced the trafficking of ATP7B, but not ATP7A, suggesting the presence of a cell-specific silver uptake and detoxification mechanisms. Indeed, the expression of the copper uptake protein CTR1 was also restricted to ciliated cells. A role of ATP7B in silver detoxification was further substantiated when treatment of SCC1 significantly increased cell death in ATP7B shRNA-treated HepG2 cells. In addition, mTEC from ATP7B{sup -/-} mice showed enhanced loss of ciliated cells compared to wild type. These studies are the first to demonstrate a cell type-specific expression of the Ag{sup +}/Cu{sup +} transporters ATP7A, ATP7B, and CTR1 in airway epithelial cells and a role for ATP7B in detoxification of these metals in the lung.

• OSTI ID: 21344889
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 243; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACETATES
ANALEPTICS
ANIMALS
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
APOPTOSIS
AROMATICS
AZAARENES
BODY
CAFFEINE
CARBOXYLIC ACID SALTS
CENTRAL NERVOUS SYSTEM AGENTS
CHARGED PARTICLES
COPPER
COPPER IONS
DETOXIFICATION
DRUGS
ELEMENTS
HETEROCYCLIC COMPOUNDS
IN VITRO
IONS
LUNGS
MAMMALS
METALS
MICE
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PURINES
RESPIRATORY SYSTEM
RODENTS
SENSITIVITY
SILVER
SILVER IONS
TRANSITION ELEMENTS
VERTEBRATES
XANTHINES