General Pharmacology: The Vascular System
REVIEWMitochondria as Cell Targets of AZT (Zidovudine)
Introduction
3′-Azido-3′-deoxythymidine (AZT, zidovudine) is the first drug, in use since 1986, in the therapy of acquired immunodeficiency syndrome (AIDS), because it is the most effective compound of a class of nucleoside analogues that can inhibit the replication of the human immunodeficiency virus 1 (HIV-1) Fischl et al. 1987, Mitsuya and Broder 1987, Yarchoan et al. 1986. The antiretroviral activity of AZT proved to derive from its conversion into AZT triphosphate (AZTTP) catalyzed by the enzymes of the thymidine-phosphorylation pathway—that is, thymidine kinase (EC 2.7.1.21), thymidylate kinase (EC 2.7.4.9) and the nucleoside diphosphate kinase (EC 2.7.4.6) Balzarini et al. 1989, Furman et al. 1986. AZTTP was found both to inhibit HIV-1 reverse transcriptase and to terminate the newly synthesized viral DNA chain (Hao et al., 1988).
Unfortunately, in AIDS therapy, the clinical efficacy of AZT is limited by its toxic side effects, which are principally directed to the bone marrow and skeletal cardiac muscle. As a result of long-term treatment of patients with AZT, anemia, leukopenia (Richman et al., 1987), myalgia, muscle weakness and elevated serum creatine kinase levels (Dalakas et al., 1990) were observed, which required the discontinuation of the therapy.
To prevent AZT side effects, the elucidation of the processes leading to AZT cytoxicity is needed. Different hypotheses have been suggested to account for the biochemical mechanism(s) responsible for the cytotoxic effects induced by AZT in human host cells: namely, the decrease in physiological levels of thymidine triphosphate (TTP) and other deoxyribonucleotides needed for host-cell DNA synthesis Frick et al. 1988, Mitsuya and Broder 1987; AZT incorporation into newly synthesized host-cell DNA (Sommadossi et al., 1989), with inhibition of the elongation by chain termination (Copeland et al., 1992); the formation of 3′-amino-3′-deoxythymidine, a highly toxic catabolite (Cretton et al., 1991); and the inhibition of protein glycosylation and nucleotide–sugar import into the Golgi complex (Hall et al., 1994).
However, both because energy-related pathologies (Dalakas et al., 1989) were observed in the AZT-treated patients and in the light of the pioneering in vitro studies by Simpson et al. (1989), the possibility that mitochondria were the cell targets of the toxic effects of AZT was considered. Nevertheless, the mechanisms by which AZT–mitochondrion interaction takes place remain as yet far from being exhaustively elucidated.
In this review, we report studies that describe the effect of AZT on mitochondrial structure and function with special attention paid to molecular studies dealing with the interaction between AZT and mitochondrial components taking part in oxidative phosphorylation.
Section snippets
Mitochondria as the cell energy source
For a better understanding of the AZT–mitochondrion interaction, a survey of mitochondrial features is presented here. Mitochondria are the cellular sites of the majority of energy-supplying biochemical reactions. A mitochondrion consists of four compartments that differ from one another both in chemical composition and in enzyme profile: the smooth outer membrane, the folded inner membrane, the intermembrane space and the inner membrane delimited matrix. Each compartment plays a specific role
Mitochondria as cell azt targets
The history of the identification of the mitochondrion as a cellular target of AZT began in 1989 on the basis of both clinical observations made on HIV-infected patients Dalakas et al. 1989, Dalakas et al. 1990 and measurements carried out on isolated mitochondria in vitro (Simpson et al., 1989). Dalakas proposed that long-term treatment with AZT induces a toxic mitochondrial myopathy characterized by various changes in the mitochondrial structure, which are independent of HIV infection. On the
The mechanism(s) of azt-induced mitochondrial alterations
In spite of the demonstration of a number of structural and functional mitochondrial modifications, owing to long-term AZT administration to AIDS patients, rats and isolated cells, the answer to the question of what the molecular mechanism(s) responsible for these effects is remained unsolved and was considered in a further series of investigations carried out at the molecular level.
Perspectives in azt therapy
In the light of the reported findings, we conclude that the early primary targets of AZT are the mitochondrial adenylate kinase and ADP/ATP translocator. Because AZT accumulation in the intermembrane space is possible (Barile et al., 1997), we think that inhibition both of adenylate kinase and of the ADP/ATP translocase could take place in vivo, with a consequent decrease in the cell ATP availability. To prevent this damage, the development of AZT derivatives that can exert no effect on the
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