Glutathione precursor and antioxidant activities of N-acetylcysteine and oxothiazolidine carboxylate compared in in vitro studies of HIV replication.
N-Acetyl-L-cysteine (NAC) and L-2-oxothiazolidine 4-carboxylate (OTC) are pro-GSH drugs that been proposed for AIDS therapy. In this article we compare the antiviral activities of these compounds in various in vitro HIV infection models. Although both compounds blocked cytokine induction of HIV in acute and chronic infection models, and in HIV-LTR reporter cell systems, NAC was far more effective than OTC, even at suboptimal doses. To test whether this difference is due to GSH conversion efficacies of these compounds, we measured GSH restoration by NAC or OTC in GSH-depleted peripheral blood mononuclear cells (PBMCs), using flow cytometry. In isolated PBMCs, NAC fully replenishes depleted intracellular GSH whereas OTC only minimally replenishes GSH. This ability to replenish GSH in vitro and its ability to scavenge free radicals directly explain why NAC has more potent antiviral activities in vitro.
Raju
P A
PA
Department of Genetics, Beckman Center B007, Stanford University Medical School, California 94305-5125.
Herzenberg
L A
LA
Herzenberg
L A
LA
Roederer
M
M
D000111:Acetylcysteine / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D002478:Cells, Cultured; D016166:Free Radical Scavengers / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D017930:Genes, Reporter; D005978:Glutathione / Q000096:biosynthesis*; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D009000:Monocytes / Q000821:virology; D011355:Prodrugs / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
D000963:Antimetabolites; D000975:Antioxidants; D000998:Antiviral Agents; D016166:Free Radical Scavengers; D011355:Prodrugs; D013844:Thiazoles; D053778:Thiazolidines; D014409:Tumor Necrosis Factor-alpha; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; D000111:Acetylcysteine; C029536:2-oxothiazolidine-4-carboxylic acid