Binding of aminoalkylphosphorothioate radioprotective drugs to rodent tissue proteins

ORCiD

0000-0001-9010-5970

Document Type

Article

Publication Title

Biochemical Pharmacology

Volume

39

Issue

11

DOI

10.1016/0006-2952(90)90129-9

First Page

1807

Last Page

1812

Publication Date

6-1-1990

Abstract

The formation of protein mixed disulfides which influences the pharmacodynamics of the phosphorothioate radioprotective drugs WR2721 [S-2-(3-aminopropyl)aminoethylphosphorothioic acid, Ethiofos] and WR3689 [S-2-(3-methylaminopropylamino)ethylphosphorothioic acid] and their metabolites was investigated. WR3689-derived thiols and disulfides bound to rat serum protein to about 45 and 40% of the total drug in the incubation when present at a 400 μM concentration. Metabolites of WR2721 were nearly indistinguishable from the corresponding metabolites of WR3689 in their mixed disulfide binding propensity. Mixed disulfide formation was saturable; binding sites on bovine albumin or rat serum protein amounted to 0.15 and 2.4 μmol/mg protein respectively. The sum of all WR3689 metabolites (when measured by NMR spectroscopy) was reduced to the same degree as drug binding, suggesting that a portion of the bound drug was not NMR observable. Approximately 2–4 nmol WR3689-thiol/mg protein was bound to homogenates of mouse tissues (liver, kidney, lung, brain, and serum) when incubated in vitro, whereas after in vivo injection drug binding appeared to be limited more by drug distribution than by the capacity for mixed disulfide formation.

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