Radical Metabolic Pathway of Isoniazid Oxidation and Reduction 2017

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Non-Enzymatic Radical Activation of the Potent Anti-
Tubercular Isoniazid by Cu(II)

Isoniazid (INH) is one of the most potent drugs available for modern tuberculosis treatment.

As a pro-drug it requires activation by catalase/ peroxidase to produce the reactive isonicotinic acyl radical intermediate responsible for its anti-tuberculosis activity,

However, it is not clear whether INH can be activated nonenzymatically by Cu(II).

 

Here we found that INH and Cu(II) together could induce synergistic DNA damage (strand breakage and 8-oxo dG  formation),

while neither of them alone has any effects.

 

DNA damage by INH/Cu(II) could be inhibited by Cu(I)-specific chelator  and catalase, but not by SOD and the typical ●OH radical scavengers.

Interestingly, ESR spin-trapping method showed that
●OH,  ●H  and a  C-centered radical  were produced during Cu(II )catalyzed oxidation of INH.

 

We proposed that the synergistic DNA damage induced by INH/Cu(II) might be due to the synergistic and site-specific production of  ●OH near the binding site of copper and DNA.

 

The C-centered radical was further unequivocally identified
by ESR and HPLC-MS as isonicotinic acyl radical,

which can react with nicotinamide coenzyme NADH to form the critical isonicotinic acyl-NAD adduct.

 

The adduct can effectively inhibit in vitro activity of the enoyl-acyl carrier protein reductase InhA, an INH target in the biosynthetic pathway of mycolic acids.

 

This study provided a new insight on non-enzymatic activation of INH by Cu(II) to produce the reactive isonicotinic acyl radical, ●OH and ●H, which may have important biological implications for future research on INH.

 

doi: 10.1016/j.freeradbiomed.2016.10.089