Cationic drug analysis using matrix-assisted laser desorption/ionization mass spectrometry: application to influx kinetics, multidrug resistance, and intracellular chemical change.

Abstract

Highly sensitive and convenient analysis of intracellular cationic drugs has been achieved by applying matrix-assisted laser desorption/ionization mass spectrometry (MALD-MS). Tetraphenylphosphonium cation was readily identified and quantified (using methyltriphenylphosphonium cation as an internal standard) at subpicomole levels in crude lysate from < 4 x 10(3) FaDu human hypopharyngeal carcinoma cells. A quantitative MALD-MS time course for tetraphenylphosphonium cation accumulation into FaDu cells was comparable to a time course using scintillation counting with tritiated tetraphenylphosphonium. MALD-MS was also capable of demonstrating the reduced accumulation of the cationic drug rhodamine-123 by DoxR MCF7, a multiply drug-resistant human breast adenocarcinoma cell line, relative to the nonresistant parent line MCF7. In addition, MALD-MS was used to follow a chemical reaction inside intact FaDu cells: the formation of a hydrazone (II-51) from benzaldehyde and an acylhydrazide, 5-[tris(4-dimethylaminophenyl)phosphonio]pentanoyl hydrazide (II-25). These results suggest that MALD-MS may provide a rapid and practical alternative to existing methods for the analysis of cationic drugs, toxins, and their metabolites in cells and tissues.

• Authors: D Rideout, A Bustamante, G Siuzdak
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 90 Issue 21 Pg. 10226-9 (Nov 01 1993) ISSN: 0027-8424 [Print] United States
• PMID: 8234281 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzaldehydes
• Cations
• Onium Compounds
• Organophosphorus Compounds
• Trityl Compounds
• triphenylmethylphosphonium
• Doxorubicin
• benzaldehyde
• tetraphenylphosphonium

Topics

• Adenocarcinoma
• Benzaldehydes (chemistry, metabolism, toxicity)
• Biological Transport
• Breast Neoplasms
• Carcinoma, Squamous Cell
• Cations
• Cell Line
• Doxorubicin (toxicity)
• Drug Resistance (physiology)
• Female
• Humans
• Hypopharyngeal Neoplasms
• Kinetics
• Lasers
• Mass Spectrometry (methods)
• Molecular Structure
• Onium Compounds (chemistry, metabolism, toxicity)
• Organophosphorus Compounds (chemistry, metabolism, toxicity)
• Structure-Activity Relationship
• Trityl Compounds (chemistry, metabolism, toxicity)
• Tumor Cells, Cultured