RT Journal Article SR Electronic T1 Activated Sulfonamides are Cleaved by Glutathione-S-Transferases JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 986 OP 991 VO 27 IS 9 A1 Kenneth A. Koeplinger A1 Zhiyang Zhao A1 Tillie Peterson A1 Joseph W. Leone A1 Francis S. Schwende A1 Robert L. Heinrikson A1 Alfredo G. Tomasselli YR 1999 UL http://dmd.aspetjournals.org/content/27/9/986.abstract AB In preclinical pharmacokinetic studies and in in vitro rat, dog, and human primary hepatocyte incubations, the sulfonamide (-NH-SO2-) 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. The American Society for Pharmacology and Experimental Therapeutics