Isoniazid hydrolase

Isoniazid hydrolase is a metabolic enzyme, primarily localized in the liver, that facilitates the direct hydrolysis of the first-line antitubercular drug isoniazid into isonicotinic acid and hydrazine. While the majority of isoniazid is typically inactivated by N-acetylation via the NAT2 enzyme, the hydrolytic pathway mediated by isoniazid hydrolase is of critical clinical importance due to the generation of hydrazine, a potent hepatotoxin. The activity of this enzyme is significantly induced by rifampin, which explains the synergistic hepatotoxicity often observed when isoniazid and rifampin are co-administered during tuberculosis treatment. In certain mycobacterial species, a similar enzyme known as hydrazidase or PzaA can degrade isoniazid, thereby contributing to innate or acquired drug resistance by reducing the concentration of the active drug. Consequently, isoniazid hydrolase represents a significant pharmacological target for the development of inhibitors aimed at mitigating drug-induced liver injury and potentially overcoming bacterial resistance mechanisms. Understanding the regulation and genetic variability of this enzyme is essential for optimizing tuberculosis therapy and improving patient safety profiles.

Other names

HydrazidaseIsoniazid-hydrolyzing enzymeIsonicotinic acid hydrazide hydrolasePzaA

Hydrolytic deactivation of isoniazid; Induction of enzyme expression by rifampin; Inhibition of hydrazine production by experimental inhibitors.