Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication in vitro (ED50 approximately 10 microM), undergoes extensive metabolism in vivo. Most of the orally administered drug undergoes opening of the dithiolethione ring, reduction, recyclization, and methylation to form 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine ("metabolite III"). We report here that metabolite III inhibits viral replication in vitro (ED50 approximately 25 microM) in acutely infected H9 and CEM T cell lymphoma cell lines. Although both metabolite III and oltipraz were able to inhibit phorbol-12-myristate-13-acetate-stimulated viral replication in the chronically infected U1 promonocytic leukemia cell line, only metabolite III was able to inhibit phorbol-12-myristate-13-acetate-stimulated viral replication in chronically infected ACH-2 T cell lymphoma cells. The results with ACH-2 cells suggest that oltipraz inhibits an early stage of the viral life cycle, whereas metabolite III affects human immunodeficiency virus type 1 replication at a step distal to viral integration. This is consistent with the finding that oltipraz inhibits reverse transcriptase, whereas metabolite III does not. Although the mean ED50 for metabolite III in acutely infected peripheral blood mononuclear cells was 18 microM, the ED50 was below 5 microM in three of eight independent experiments. Studies of metabolite III in combination with oltipraz in acutely infected peripheral blood mononuclear cells demonstrated significant antiviral synergy. These results raise the possibility that the in vitro potency of oltipraz may underestimate its antiretroviral activity in vivo. Based on these results, the pharmacokinetics of oltipraz and metabolite III will be compared with the pharmacodynamic effects of orally administered oltipraz in a forthcoming phase I/II trial of oltipraz in patients with p24 antigenemia.
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PMID:Inhibition of human immunodeficiency virus type 1 replication by 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine, an in vivo metabolite of oltipraz. 754 38

Glutathione depletion may play a pivotal role in the pathogenesis of human immunodeficiency virus type-1 (HIV-1) infection. Since certain compounds prevent experimental carcinogenesis by elevating the levels of glutathione and phase II detoxication enzymes, we compared the potencies of several inducers with their ability to inhibit basal levels of HIV-1 replication in H9 cutaneous T-cell lymphoma cells. All monofunctional inducers tested elevated the levels of glutathione and quinone reductase, a marker for phase II enzyme induction. However, only oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione] was effective at inhibiting HIV-1 replication (IC50 = 14.8 +/- 3.1 microM). The antiviral effect of oltipraz was potentiated by 3'-azido-3'-deoxythymidine. Thus, 1,2-dithiole-3-thiones represent a hitherto unrecognized class of anti-HIV-1 agents. Oltipraz behaves kinetically as an irreversible inhibitor of HIV-1 reverse transcriptase in the template-primer binding domain. Oltipraz has been used to treat schistosomiasis in humans and is undergoing clinical evaluation as an anticarcinogen. Thus, oltipraz (and other 1,2-dithiole-3-thiones) may have therapeutic utility in HIV-1-infected individuals, not only because of their antiretroviral activity, but also by preventing the development of HIV-1-associated neoplasms.
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PMID:Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication. 768 14

Glutathione (GSH) levels are markedly depleted in patients infected with human immunodeficiency virus type 1 (HIV-1) and supplementation of media with high concentrations (5-20 mM) of low-molecular weight thiols prevents HIV-1 replication in cultured cells. We were intrigued whether chemopreventive enzyme inducers might represent a more pharmacologically feasible method to inhibit HIV-1 replication since these compounds elevate intracellular concentrations of GSH at nontoxic doses in vivo. After establishing that all inducers surveyed were able to elevate GSH levels in human T-cell and monocytoid cell lines, we were surprised to find that oltipraz (5-pyrazinyl-4-methyl-1,2-dithiole-3-thione) was uniquely able to inhibit HIV-1 replication (IC50 = 5-15 microM). Oltipraz and other antiviral 1,2-dithiole-3-thiones (DTTs) appear to inhibit acute HIV-1 replication by inactivating reverse transcriptase (RT). However, among DTTs that inhibit HIV-1 replication in acutely infected cells, only oltipraz was able to inhibit HIV-1 replication in a chronic infection model. Thus, in addition to inactivating RT, oltipraz appears to have an additional antiviral mechanism distal to viral integration. Our laboratories are attempting to determine the mechanism by which oltipraz inhibits HIV-1 replication in chronically infected cells; we are also attempting to determine the bioorganic mechanism for the inactivation of RT. Since the covalent modification of schistosomal proteins and transcription factor(s) are thought to be responsible for the antiparasitic and chemopreventive activities of DTTs, respectively, our studies should be relevant to understanding the diverse medicinal properties of DTTs. Oltipraz, an antischistosomal drug undergoing clinical evaluation as an anticarcinogen, inhibits HIV-1 replication at concentrations achievable in human serum. It is intriguing to consider oltipraz as a therapeutic agent not only for its antiretroviral activity, but also for the prevention of HIV-1 associated neoplasms.
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PMID:Oltipraz, a novel inhibitor of human immunodeficiency virus type 1 (HIV-1) replication. 853 88

Molecular epidemiological studies of populations at high risk for liver cancer have shown that hepatitis B virus (HBV) and aflatoxin B1 exposures are two major risk factors for this disease. Oltipraz is currently being considered for clinical trial to protect against aflatoxin B1-induced hepatocarcinogenesis based on its proven protective effect in many different animal models. In addition, oltipraz inhibits human immunodeficiency virus (HIV) replication. The inactivation of reverse transcriptase of HIV appears to be the antiviral mechanism. It has been demonstrated that a number of compounds that inhibit HIV replication also inhibit HBV replication in vitro. Therefore, we tested the possibility of oltipraz blocking HBV replication in 2.2.15 cells (clonal cells derived from HepG2 cells that were transfected with a plasmid containing HBV DNA) in vitro. Results of the experiments indicate that oltipraz has a dose-dependent inhibitory effect on HBV replication and specifically blocks HBV transcription in 2.2.15 cells. In addition, oltipraz induces endogenous wild-type p53 protein in a dose- and time-course-dependent manner. Taken together, we speculate that the effects of oltipraz against replication of HBV and specific blocking of HBV transcription may be through the induction of p53-mediated pathway in 2.2.15 cells. In addition to its known chemopreventive action on aflatoxin B1 hepatocarcinogenesis, oltipraz was shown here to inhibit HBV replication. These dual effects put oltipraz as the excellent candidate for the chemopreventive agent of human hepatocellular carcinoma.
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PMID:Oltipraz, a novel inhibitor of hepatitis B virus transcription through elevation of p53 protein. 988 68