AZT oxidation 31 August 2004
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Nicholas Bennett,
Infectious Disease Postdoc/Clinician
Department of Pediatrics, University Hospital, Syracuse NY

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Re: AZT oxidation

I thank Jean Umber for bringing up a few interesting clarifications on the metabolism of AZT in cells.

I would stress though that having a chemical reduced by another agent doesn't make it itself an "oxidising agent" beyond the fact it is in that particular reaction. Although clearly chemicals like dithiothrietol (DTT) will "be oxidized" by AZT, in fact it is the powerful reducing power of the DTT that drives the reaction: oxidized DTT is a byproduct of the reaction, due to the balance inherent in a redox state. Fluorine oxidises water, but this doesn't make water a reducing agent...not at least in common understanding.

In fact, the reduction of AZT to another nucleotide analogue neatly refutes the Perth Group's attempts to argue that AZT is ineffective because AZT-triphosphate may not be found in sufficient quantities. In this situation it is clearly acting as a prodrug, similarly to the ACE inhibitor Enalapril. AZT incorporation however can be detected using specific radio-immunoassays, although without knowing a comparision of whether cross-reactivity exists between AZT and D4T in this situation one cannot put hand-on-heart and say that AZT as opposed to d4T is definitively proven to incorporate.

It doesn't really detract from the argument of "AZT resistance mutations", especially since these mutations seem to give cross-resistance to d4T - they are probably working AT the level of the d4T (reduced) form of AZT. A quick review of the literature does indeed suggest that current understanding of the mechanism of AZT's action may well be through its conversion to d4T, so the "AZT-resistance" is perhaps better thought of as "AZT/d4T-resistance". If only a third of the AZT is reduced to d4T that is 1/3 fully active antiretroviral! Since dosing regimens are around 300mg twice daily for AZT and 40mg twice daily for d4T there is clearly enough antiviral to be effective, all else being equal.

Competing interests: None declared