Elevation of glutathione levels by phase II enzyme inducers: lack of inhibition of human immunodeficiency virus type 1 replication in chronically infected monocytoid cells.
Supplementation of media with high concentrations of thiols (5-20 mM) inhibits human immunodeficiency virus type 1 (HIV-1) replication in vitro. Compounds that prevent carcinogenesis via induction of phase II enzymes also elevate intracellular GSH levels, thus raising the possibility that chemopreventive enzyme inducers may represent a more pharmacologically feasible method to inhibit viral replication. Previous studies revealed that oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] was the only GSH inducer tested that could inhibit HIV-1 replication in acutely infected H9 cells. Because thiols are proposed to suppress transcription of the integrated HIV-1 genome by preventing the activation of nuclear factor-kappa B, experiments evaluating inducers of GSH levels in acutely infected H9 cells do not rule out the ability of these compounds to inhibit viral replication in chronically infected cells exposed to cytokines or mitogens. Therefore, we determined the antiviral effects of several inducers in phorbol-12-myristate-13- acetate-stimulated U1 cells, a monocytoid cell line that contains two integrated copies of the HIV-1 genome. Although 1,2-dithiole-3-thione, dimethyl fumarate, and oltipraz can elevate cytosolic thiol levels, only oltipraz inhibited HIV-1 replication. Moreover, decreased nuclear factor-kappa B binding activity could be correlated with increases in cytosolic thiols produced by various treatments (r2 = 0.8) but not with suppression of viral replication (r2 = 0.01). These data suggest that oltipraz-induced increases in GSH are not responsible for the antiviral action of oltipraz and that elevation of intracellular GSH levels by chemopreventive enzyme inducers does not inhibit viral replication.
Prochaska
H J
HJ
Molecular Pharmacology and Therapeutics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Rubinson
L
L
Yeh
Y
Y
Baron
P
P
Polsky
B
B
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D000069462:Dimethyl Fumarate; D004229:Dithiothreitol / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects*; D005650:Fumarates / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D009000:Monocytes / Q000382:microbiology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013871:Thiones; D013876:Thiophenes; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D005650:Fumarates; D016328:NF-kappa B; D011719:Pyrazines; D013438:Sulfhydryl Compounds; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D016660:NAD(P)H Dehydrogenase (Quinone); D000069462:Dimethyl Fumarate; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate; D004229:Dithiothreitol