Activated sulfonamides are cleaved by glutathione-S-transferases
| Autor: | K A, Koeplinger, Z, Zhao, T, Peterson, J W, Leone, F S, Schwende, R L, Heinrikson, A G, Tomasselli |
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| Rok vydání: | 1999 |
| Předmět: |
Male
Sulfonamides Hydrolysis Molecular Sequence Data Chromatography Affinity Mass Spectrometry Cell Line Rats Isoenzymes Rats Sprague-Dawley Structure-Activity Relationship Dogs Animals Humans Electrophoresis Polyacrylamide Gel Amino Acid Sequence Diuretics Biotransformation Chromatography High Pressure Liquid Glutathione Transferase Subcellular Fractions |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 27(9) |
| ISSN: | 0090-9556 |
| Popis: | In preclinical pharmacokinetic studies and in in vitro rat, dog, and human primary hepatocyte incubations, the sulfonamide (-NH-SO(2)-) bond of a potent inhibitor of the HIV-1 protease containing the p-cyanopyridinyl moiety (PNU-109112), undergoes metabolic cleavage to form the corresponding amine metabolite (PNU-143070). Strikingly, a compound, PNU-140690, obtained by substituting the cyanopyridinyl group of PNU-109112 with a trifluoropyridinyl moiety, was stable under the same in vivo and in vitro conditions used for PNU-109112. The apparent "sulfonamidase activity" present in liver was localized to the cytosolic fraction and shown to be an enzyme-mediated reaction requiring reduced glutathione (GSH). The enzyme responsible was purified in a single step on a GSH immobilized gel and was identified as glutathione-S-transferase (GST) by sequence analysis of peptides obtained by tryptic digestion of the purified protein. Moreover, a mixture of GST isoenzymes purified from rat liver, and three recombinant human GST isoforms, A1-1, M1-1, and P1-1, were active toward PNU-109112 sulfonamide cleavage; the three isoforms exhibited differential rates of PNU-109112 cleavage, demonstrating isoenzyme selectivity. |
| Databáze: | OpenAIRE |
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