TY - JOUR T1 - Activated Sulfonamides are Cleaved by Glutathione-<em>S</em>-Transferases JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 986 LP - 991 VL - 27 IS - 9 AU - Kenneth A. Koeplinger AU - Zhiyang Zhao AU - Tillie Peterson AU - Joseph W. Leone AU - Francis S. Schwende AU - Robert L. Heinrikson AU - Alfredo G. Tomasselli Y1 - 1999/09/01 UR - http://dmd.aspetjournals.org/content/27/9/986.abstract N2 - 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 ER -