Neurotoxicity 751 Isoniazid

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As well as being implicated as a hepatotoxin, the antitubercular drug isoniazid may also cause peripheral neuropathy with chronic use. In practice this can be avoided by the concomitant administration of vitamin B6 (pyridoxine).

In experimental animals, however, chronic dosing with isoniazid causes degeneration of the peripheral nerves. The biochemical basis for this involves interference with vitamin B6 metabolism. Isoniazid reacts with pyridoxal phosphate to form a hydrazone (figure 7.28) which is a very potent inhibitor of pyridoxal phosphate kinase. The hydrazone has a much greater affinity for the enzyme (100-1000*) than the normal substrate, pyridoxal. The result of this is a depletion of tissue pyridoxal phosphate. This cofactor is of importance particularly in nervous tissue for reactions involving decarboxylation and transamination. The decarboxylation reactions are principally affected however, with the result that

CHAT

IswiazM

Pyrldosal phosptaiLt hi yd razone

FIGURE 7.28 Reaction of isoniazid with pyridoxal phosphate to form a hydrazone.

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transamination reactions assume a greater importance.

In man peripheral neuropathy due to isoniazid is influenced by the acetylator phenotype (see page 135), being predominantly found in slow acetylators. This is probably due to the higher plasma level of isoniazid in this phenotype. In this case, therefore, acetylation is a detoxication reaction, removing the isoniazid and rendering it unreactive towards pyridoxal phosphate.

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