Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.
Anti-HIV nucleoside analogs and mitochondria.
Diss Abstr Int [B]; 52(7):3543 1992. Unique Identifier : AIDSLINE ICDB/93682498 Chen C; Univ. of North Carolina at Chapel Hill
Abstract:
Human immunodeficiency virus (HIV) is believed to be the causative agent of acquired immunodeficiency syndrome (AIDS). The incidence of this fatal disease has increased in recent years. Efforts have been taken to develop effective AIDS therapies. One strategy is to inhibit the viral reverse transcriptase which is essential for HIV replication plays a pivotal role in AIDS therapy. Dideoxynucleoside analogs are a group of compounds whose target is the HIV reverse transcriptase. Azidothymidine is one of the dideoxynucleosides that has a potent effect on HIV replication, and it is currently used in the clinic for AIDS therapy. Compounds such as dideoxycytidine (ddC), dideoxyinosine (ddI), and dideoxydidehydrocytidine (D4T) were reported to inhibit viral replication and have a beneficial effect in clinic, however, the side effects caused by these drugs often limit their clinical usefulness. The limiting toxicity of ddC, ddI, and D4T is peripheral neuropathy. This side effect develops after long-term treatment with ddC, ddI or D4T. The mechanisms by which the dideoxynucleosides induce this side effect are not clear. Some of the nucleoside analogs, especially ddC and ddI, selectively and severely deplete mitochondrial DNA in either proliferating cells such as T-lymphoblastoid cells (CEM cells) or nonproliferating cells such as neuronal-like cells (differentiated PC12 cells). One consequence of the loss of the mitochondrial DNA is delayed cytotoxicity in vitro. Mechanisms such as increased glycolysis were found to compensate for the mitochondrial deficiency caused by the drug treatment. The mitochondrial effect of ddC was reversible upon its removal from the cell culture medium, which is consistent with the clinical observation peripheral neuropathy is reversible once ddC treatment is discontinued. The mitochondrial toxicity of ddC is highly dependent on the cell type, which suggests that cellular metabolism may play an important role in the mitochondrial effects of ddC. Despite the fact that mitochondrial enzymes are capable of phosphorylating ddC to its active metabolite ddCTP, we proposed that cytoplasmic metabolism rather than mitochondrial metabolism provides the ddCTP pool in mitochondria. The cytoplasmic deoxycytidine kinase was found to play an important role in the mitochondrial effect of ddC in CEM cells. It appears that ddC is phosphorylated to ddCTP in the cytoplasm and the ddCTP is then transported into the mitochondria to exert its inhibitory effect on the synthesis of mitochondrial DNA. In summary, the data of this study suggest that the mitochondrial effect of the nucleoside analogs on susceptible organs may be related to their side effects observed in clinic. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD91-35237).
Keywords: Antiviral Agents/ADVERSE EFFECTS/*PHARMACOLOGY Cytotoxicity, Immunologic DNA, Mitochondrial/*DRUG EFFECTS/METABOLISM Glycolysis Human HIV/*DRUG EFFECTS/PHYSIOLOGY Mitochondria/DRUG EFFECTS T-Lymphocytes/IMMUNOLOGY/METABOLISM Virus Replication/*DRUG EFFECTS THESIS 930228
M9320869
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.
